|
1
|
Simões‐Pires EN, Torrente D, Singh P, Strickland S, Norris EH. Synergistic effects of the Aβ/fibrinogen complex on synaptotoxicity, neuroinflammation, and blood-brain barrier damage in Alzheimer's disease models. Alzheimers Dement 2025; 21:e70119. [PMID: 40344319 PMCID: PMC12061846 DOI: 10.1002/alz.70119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/16/2024] [Accepted: 01/12/2025] [Indexed: 05/11/2025]
Abstract
INTRODUCTION Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ), hyperphosphorylated tau, chronic neuroinflammation, blood-brain barrier (BBB) damage, and synaptic dysfunction, leading to neuronal loss and cognitive deficits. Vascular proteins, including fibrinogen, extravasate into the brain, further contributing to damage and inflammation. Fibrinogen's interaction with Aβ is well-established, but how this interaction contributes to synaptic dysfunction in AD is unknown. METHODS Organotypic hippocampal cultures (OHC) were exposed to Aβ42 oligomers, fibrinogen, or Aβ42/fibrinogen complexes. Synaptotoxicity was analyzed by Western blot. Aβ42 oligomers, fibrinogen, or their complexes were intracerebroventricularly injected into mice. Histopathological AD markers, synaptotoxicity, neuroinflammation, and vascular markers were observed by Western blot and immunofluorescence. RESULTS Aβ42/fibrinogen complexes led to synaptic loss, tau181 phosphorylation, neuroinflammation, and BBB disruption, independent of Mac1/CD11b receptor signaling. Blocking Aβ42/fibrinogen complex formation prevented synaptotoxicity. DISCUSSION These findings indicate that the Aβ42/fibrinogen complex has a synergistic impact on hippocampal synaptotoxicity and neuroinflammation. HIGHLIGHTS Fibrinogen binds to the central region of Aβ, forming a plasmin-resistant complex. The Aβ/fibrinogen complex induces synaptotoxicity, inflammation, and BBB disruption. Synaptotoxicity induced by the complex is independent of Mac1 receptor signaling.
Collapse
Affiliation(s)
- Elisa Nicoloso Simões‐Pires
- Patricia and John Rosenwald Laboratory of Neurobiology and GeneticsThe Rockefeller UniversityNew YorkNew YorkUSA
| | - Daniel Torrente
- Patricia and John Rosenwald Laboratory of Neurobiology and GeneticsThe Rockefeller UniversityNew YorkNew YorkUSA
| | - Pradeep Singh
- Patricia and John Rosenwald Laboratory of Neurobiology and GeneticsThe Rockefeller UniversityNew YorkNew YorkUSA
| | - Sidney Strickland
- Patricia and John Rosenwald Laboratory of Neurobiology and GeneticsThe Rockefeller UniversityNew YorkNew YorkUSA
| | - Erin H. Norris
- Patricia and John Rosenwald Laboratory of Neurobiology and GeneticsThe Rockefeller UniversityNew YorkNew YorkUSA
| |
Collapse
|
|
2
|
Ortiz-Islas E, Montes P, Rodríguez-Pérez CE, Ruiz-Sánchez E, Sánchez-Barbosa T, Pichardo-Rojas D, Zavala-Tecuapetla C, Carvajal-Aguilera K, Campos-Peña V. Evolution of Alzheimer's Disease Therapeutics: From Conventional Drugs to Medicinal Plants, Immunotherapy, Microbiotherapy and Nanotherapy. Pharmaceutics 2025; 17:128. [PMID: 39861773 PMCID: PMC11768419 DOI: 10.3390/pharmaceutics17010128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 01/27/2025] Open
Abstract
Alzheimer's disease (AD) represents an escalating global health crisis, constituting the leading cause of dementia among the elderly and profoundly impairing their quality of life. Current FDA-approved drugs, such as rivastigmine, donepezil, galantamine, and memantine, offer only modest symptomatic relief and are frequently associated with significant adverse effects. Faced with this challenge and in line with advances in the understanding of the pathophysiology of this neurodegenerative condition, various innovative therapeutic strategies have been explored. Here, we review novel approaches inspired by advanced knowledge of the underlying pathophysiological mechanisms of the disease. Among the therapeutic alternatives, immunotherapy stands out, employing monoclonal antibodies to specifically target and eliminate toxic proteins implicated in AD. Additionally, the use of medicinal plants is examined, as their synergistic effects among components may confer neuroprotective properties. The modulation of the gut microbiota is also addressed as a peripheral strategy that could influence neuroinflammatory and degenerative processes in the brain. Furthermore, the therapeutic potential of emerging approaches, such as the use of microRNAs to regulate key cellular processes and nanotherapy, which enables precise drug delivery to the central nervous system, is analyzed. Despite promising advances in these strategies, the incidence of Alzheimer's disease continues to rise. Therefore, it is proposed that achieving effective treatment in the future may require the integration of combined approaches, maximizing the synergistic effects of different therapeutic interventions.
Collapse
Affiliation(s)
- Emma Ortiz-Islas
- Laboratorio de Neurofarmacologia Molecular y Nanotecnologia, Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco Suárez, Mexico City 14269, Mexico; (E.O.-I.); (C.E.R.-P.)
| | - Pedro Montes
- Laboratorio de Neuroinmunoendocrinología, Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco Suárez, Mexico City 14269, Mexico;
| | - Citlali Ekaterina Rodríguez-Pérez
- Laboratorio de Neurofarmacologia Molecular y Nanotecnologia, Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco Suárez, Mexico City 14269, Mexico; (E.O.-I.); (C.E.R.-P.)
| | - Elizabeth Ruiz-Sánchez
- Laboratorio de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco Suárez, Mexico City 14269, Mexico;
| | - Talía Sánchez-Barbosa
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco Suárez, Mexico City 14269, Mexico; (T.S.-B.); (C.Z.-T.)
- Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City 07360, Mexico
| | - Diego Pichardo-Rojas
- Programa Prioritario de Epilepsia, Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco Suárez, Mexico City 14269, Mexico;
| | - Cecilia Zavala-Tecuapetla
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco Suárez, Mexico City 14269, Mexico; (T.S.-B.); (C.Z.-T.)
| | - Karla Carvajal-Aguilera
- Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, Mexico City 04530, Mexico;
| | - Victoria Campos-Peña
- Laboratorio Experimental de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco Suárez, Mexico City 14269, Mexico; (T.S.-B.); (C.Z.-T.)
| |
Collapse
|
|
3
|
Hu NW, Ondrejcak T, Klyubin I, Yang Y, Walsh DM, Livesey FJ, Rowan MJ. Patient-derived tau and amyloid-β facilitate long-term depression in vivo: role of tumour necrosis factor-α and the integrated stress response. Brain Commun 2024; 6:fcae333. [PMID: 39391333 PMCID: PMC11465085 DOI: 10.1093/braincomms/fcae333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 08/22/2024] [Accepted: 09/25/2024] [Indexed: 10/12/2024] Open
Abstract
Alzheimer's disease is characterized by a progressive cognitive decline in older individuals accompanied by the deposition of two pathognomonic proteins amyloid-β and tau. It is well documented that synaptotoxic soluble amyloid-β aggregates facilitate synaptic long-term depression, a major form of synaptic weakening that correlates with cognitive status in Alzheimer's disease. Whether synaptotoxic tau, which is also associated strongly with progressive cognitive decline in patients with Alzheimer's disease and other tauopathies, also causes facilitation remains to be clarified. Young male adult and middle-aged rats were employed. Synaptotoxic tau and amyloid-β were obtained from different sources including (i) aqueous brain extracts from patients with Alzheimer's disease and Pick's disease tauopathy; (ii) the secretomes of induced pluripotent stem cell-derived neurons from individuals with trisomy of chromosome 21; and (iii) synthetic amyloid-β. In vivo electrophysiology was performed in urethane anaesthetized animals. Evoked field excitatory postsynaptic potentials were recorded from the stratum radiatum in the CA1 area of the hippocampus with electrical stimulation to the Schaffer collateral-commissural pathway. To study the enhancement of long-term depression, relatively weak low-frequency electrical stimulation was used to trigger peri-threshold long-term depression. Synaptotoxic forms of tau or amyloid-β were administered intracerebroventricularly. The ability of agents that inhibit the cytokine tumour necrosis factor-α or the integrated stress response to prevent the effects of amyloid-β or tau on long-term depression was assessed after local or systemic injection, respectively. We found that diffusible tau from Alzheimer's disease or Pick's disease patients' brain aqueous extracts or the secretomes of trisomy of chromosome 21 induced pluripotent stem cell-derived neurons, like Alzheimer's disease brain-derived amyloid-β and synthetic oligomeric amyloid-β, potently enhanced synaptic long-term depression in live rats. We further demonstrated that long-term depression facilitation by both tau and amyloid-β was age-dependent, being more potent in middle-aged compared with young animals. Finally, at the cellular level, we provide pharmacological evidence that tumour necrosis factor-α and the integrated stress response are downstream mediators of long-term depression facilitation by both synaptotoxic tau and amyloid-β. Overall, these findings reveal the promotion of an age-dependent synaptic weakening by both synaptotoxic tau and amyloid-β. Pharmacologically targeting shared mechanisms of tau and amyloid-β synaptotoxicity, such as tumour necrosis factor-α or the integrated stress response, provides an attractive strategy to treat early Alzheimer's disease.
Collapse
Affiliation(s)
- Neng-Wei Hu
- Department of Pharmacology & Therapeutics, School of Medicine, and Institute of Neuroscience, Trinity College, Dublin 2, Dublin, Ireland
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Tomas Ondrejcak
- Department of Pharmacology & Therapeutics, School of Medicine, and Institute of Neuroscience, Trinity College, Dublin 2, Dublin, Ireland
| | - Igor Klyubin
- Department of Pharmacology & Therapeutics, School of Medicine, and Institute of Neuroscience, Trinity College, Dublin 2, Dublin, Ireland
| | - Yin Yang
- Department of Pharmacology & Therapeutics, School of Medicine, and Institute of Neuroscience, Trinity College, Dublin 2, Dublin, Ireland
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Dominic M Walsh
- Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Frederick J Livesey
- UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research into Rare Disease in Children, University College London, London WC1N 1DZ, UK
| | - Michael J Rowan
- Department of Pharmacology & Therapeutics, School of Medicine, and Institute of Neuroscience, Trinity College, Dublin 2, Dublin, Ireland
| |
Collapse
|
|
4
|
Yassaghi Y, Nazerian Y, Ghasemi M, Nazerian A, Sayehmiri F, Perry G, Gholami Pourbadie H. Microglial modulation as a therapeutic strategy in Alzheimer's disease: Focus on microglial preconditioning approaches. J Cell Mol Med 2024; 28:e18554. [PMID: 39103747 DOI: 10.1111/jcmm.18554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 06/15/2024] [Accepted: 07/05/2024] [Indexed: 08/07/2024] Open
Abstract
Alzheimer's disease (AD) is a progressive disease that causes an impairment of learning and memory. Despite the highly complex pathogenesis of AD, amyloid beta (Aβ) deposition and neurofibrillary tangles (NFTs) formation are the main hallmarks of AD. Neuroinflammation also has a crucial role in the development of AD. As the central nervous system's innate immune cells, microglial cells are activated in AD and induce inflammation by producing pro-inflammatory mediators. However, microglial activation is not always deleterious. M2-activated microglial cells are considered anti-inflammatory cells, which develop neuroprotection. Various approaches are proposed for managing AD, yet no effective therapy is available for this disorder. Considering the potential protective role of M2 microglia in neurodegenerative disorders and the improvement of these disorders by preconditioning approaches, it can be suggested that preconditioning of microglial cells may be beneficial for managing AD progression. Therefore, this study review microglial preconditioning approaches for preventing and improving AD.
Collapse
Affiliation(s)
- Younes Yassaghi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yasaman Nazerian
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobina Ghasemi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Fatemeh Sayehmiri
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - George Perry
- Department of Neuroscience, Development, and Regenerative Biology, University of Texas at San Antonio, San Antonio, Texas, USA
| | | |
Collapse
|
|
5
|
Gaire BP, Koronyo Y, Fuchs DT, Shi H, Rentsendorj A, Danziger R, Vit JP, Mirzaei N, Doustar J, Sheyn J, Hampel H, Vergallo A, Davis MR, Jallow O, Baldacci F, Verdooner SR, Barron E, Mirzaei M, Gupta VK, Graham SL, Tayebi M, Carare RO, Sadun AA, Miller CA, Dumitrascu OM, Lahiri S, Gao L, Black KL, Koronyo-Hamaoui M. Alzheimer's disease pathophysiology in the Retina. Prog Retin Eye Res 2024; 101:101273. [PMID: 38759947 PMCID: PMC11285518 DOI: 10.1016/j.preteyeres.2024.101273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 04/23/2024] [Accepted: 05/10/2024] [Indexed: 05/19/2024]
Abstract
The retina is an emerging CNS target for potential noninvasive diagnosis and tracking of Alzheimer's disease (AD). Studies have identified the pathological hallmarks of AD, including amyloid β-protein (Aβ) deposits and abnormal tau protein isoforms, in the retinas of AD patients and animal models. Moreover, structural and functional vascular abnormalities such as reduced blood flow, vascular Aβ deposition, and blood-retinal barrier damage, along with inflammation and neurodegeneration, have been described in retinas of patients with mild cognitive impairment and AD dementia. Histological, biochemical, and clinical studies have demonstrated that the nature and severity of AD pathologies in the retina and brain correspond. Proteomics analysis revealed a similar pattern of dysregulated proteins and biological pathways in the retina and brain of AD patients, with enhanced inflammatory and neurodegenerative processes, impaired oxidative-phosphorylation, and mitochondrial dysfunction. Notably, investigational imaging technologies can now detect AD-specific amyloid deposits, as well as vasculopathy and neurodegeneration in the retina of living AD patients, suggesting alterations at different disease stages and links to brain pathology. Current and exploratory ophthalmic imaging modalities, such as optical coherence tomography (OCT), OCT-angiography, confocal scanning laser ophthalmoscopy, and hyperspectral imaging, may offer promise in the clinical assessment of AD. However, further research is needed to deepen our understanding of AD's impact on the retina and its progression. To advance this field, future studies require replication in larger and diverse cohorts with confirmed AD biomarkers and standardized retinal imaging techniques. This will validate potential retinal biomarkers for AD, aiding in early screening and monitoring.
Collapse
Affiliation(s)
- Bhakta Prasad Gaire
- Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yosef Koronyo
- Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Dieu-Trang Fuchs
- Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Haoshen Shi
- Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Altan Rentsendorj
- Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ron Danziger
- Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jean-Philippe Vit
- Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Nazanin Mirzaei
- Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jonah Doustar
- Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Julia Sheyn
- Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Harald Hampel
- Sorbonne University, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France
| | - Andrea Vergallo
- Sorbonne University, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France
| | - Miyah R Davis
- Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ousman Jallow
- Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Filippo Baldacci
- Sorbonne University, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France; Department of Clinical and Experimental Medicine, Neurology Unit, University of Pisa, Pisa, Italy
| | | | - Ernesto Barron
- Department of Ophthalmology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA; Doheny Eye Institute, Los Angeles, CA, USA
| | - Mehdi Mirzaei
- Department of Clinical Medicine, Health and Human Sciences, Macquarie Medical School, Macquarie University, Sydney, NSW, Australia
| | - Vivek K Gupta
- Department of Clinical Medicine, Health and Human Sciences, Macquarie Medical School, Macquarie University, Sydney, NSW, Australia
| | - Stuart L Graham
- Department of Clinical Medicine, Health and Human Sciences, Macquarie Medical School, Macquarie University, Sydney, NSW, Australia; Department of Clinical Medicine, Macquarie University, Sydney, NSW, Australia
| | - Mourad Tayebi
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
| | - Roxana O Carare
- Department of Clinical Neuroanatomy, University of Southampton, Southampton, UK
| | - Alfredo A Sadun
- Department of Ophthalmology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA; Doheny Eye Institute, Los Angeles, CA, USA
| | - Carol A Miller
- Department of Pathology Program in Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | | | - Shouri Lahiri
- Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Liang Gao
- Department of Bioengineering, University of California Los Angeles, Los Angeles, CA, USA
| | - Keith L Black
- Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Maya Koronyo-Hamaoui
- Department of Neurosurgery, Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Division of Applied Cell Biology and Physiology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| |
Collapse
|
|
6
|
Meftah S, Cavallini A, Murray TK, Jankowski L, Bose S, Ashby MC, Brown JT, Witton J. Synaptic alterations associated with disrupted sensory encoding in a mouse model of tauopathy. Brain Commun 2024; 6:fcae134. [PMID: 38712321 PMCID: PMC11073755 DOI: 10.1093/braincomms/fcae134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 02/09/2024] [Accepted: 04/11/2024] [Indexed: 05/08/2024] Open
Abstract
Synapse loss is currently the best biological correlate of cognitive decline in Alzheimer's disease and other tauopathies. Synapses seem to be highly vulnerable to tau-mediated disruption in neurodegenerative tauopathies. However, it is unclear how and when this leads to alterations in function related to the progression of tauopathy and neurodegeneration. We used the well-characterized rTg4510 mouse model of tauopathy at 5-6 months and 7-8 months of age, respectively, to study the functional impact of cortical synapse loss. The earlier age was used as a model of prodromal tauopathy, with the later age corresponding to more advanced tau pathology and presumed progression of neurodegeneration. Analysis of synaptic protein expression in the somatosensory cortex showed significant reductions in synaptic proteins and NMDA and AMPA receptor subunit expression in rTg4510 mice. Surprisingly, in vitro whole-cell patch clamp electrophysiology from putative pyramidal neurons in layer 2/3 of the somatosensory cortex suggested no functional alterations in layer 4 to layer 2/3 synaptic transmission at 5-6 months. From these same neurons, however, there were alterations in dendritic structure, with increased branching proximal to the soma in rTg4510 neurons. Therefore, in vivo whole-cell patch clamp recordings were utilized to investigate synaptic function and integration in putative pyramidal neurons in layer 2/3 of the somatosensory cortex. These recordings revealed a significant increase in the peak response to synaptically driven sensory stimulation-evoked activity and a loss of temporal fidelity of the evoked signal to the input stimulus in rTg4510 neurons. Together, these data suggest that loss of synapses, changes in receptor expression and dendritic restructuring may lead to alterations in synaptic integration at a network level. Understanding these compensatory processes could identify targets to help delay symptomatic onset of dementia.
Collapse
Affiliation(s)
- Soraya Meftah
- Faculty of Health and Life Sciences, Department of Clinical and Biomedical Science, University of Exeter, Exeter, EX1 2LU, UK
- School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, BS8 1TD, UK
| | - Annalisa Cavallini
- Erl Wood Manor, Eli Lilly Pharmaceuticals, Windlesham, Surrey, GU20 6PH, UK
| | - Tracey K Murray
- Erl Wood Manor, Eli Lilly Pharmaceuticals, Windlesham, Surrey, GU20 6PH, UK
| | - Lukasz Jankowski
- Erl Wood Manor, Eli Lilly Pharmaceuticals, Windlesham, Surrey, GU20 6PH, UK
| | - Suchira Bose
- Erl Wood Manor, Eli Lilly Pharmaceuticals, Windlesham, Surrey, GU20 6PH, UK
| | - Michael C Ashby
- School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, BS8 1TD, UK
| | - Jonathan T Brown
- Faculty of Health and Life Sciences, Department of Clinical and Biomedical Science, University of Exeter, Exeter, EX1 2LU, UK
| | - Jonathan Witton
- Faculty of Health and Life Sciences, Department of Clinical and Biomedical Science, University of Exeter, Exeter, EX1 2LU, UK
- School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, BS8 1TD, UK
| |
Collapse
|
|
7
|
Lista S, Santos-Lozano A, Emanuele E, Mercuri NB, Gabelle A, López-Ortiz S, Martín-Hernández J, Maisto N, Imbimbo C, Caraci F, Imbimbo BP, Zetterberg H, Nisticò R. Monitoring synaptic pathology in Alzheimer's disease through fluid and PET imaging biomarkers: a comprehensive review and future perspectives. Mol Psychiatry 2024; 29:847-857. [PMID: 38228892 DOI: 10.1038/s41380-023-02376-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 12/04/2023] [Accepted: 12/12/2023] [Indexed: 01/18/2024]
Abstract
Alzheimer's disease (AD) is currently constrained by limited clinical treatment options. The initial pathophysiological event, which can be traced back to decades before the clinical symptoms become apparent, involves the excessive accumulation of amyloid-beta (Aβ), a peptide comprised of 40-42 amino acids, in extraneuronal plaques within the brain. Biochemical and histological studies have shown that overaccumulation of Aβ instigates an aberrant escalation in the phosphorylation and secretion of tau, a microtubule-binding axonal protein. The accumulation of hyperphosphorylated tau into intraneuronal neurofibrillary tangles is in turn correlated with microglial dysfunction and reactive astrocytosis, culminating in synaptic dysfunction and neurodegeneration. As neurodegeneration progresses, it gives rise to mild clinical symptoms of AD, which may eventually evolve into overt dementia. Synaptic loss in AD may develop even before tau alteration and in response to possible elevations in soluble oligomeric forms of Aβ associated with early AD. These findings largely rely on post-mortem autopsy examinations, which typically involve a limited number of patients. Over the past decade, a range of fluid biomarkers such as neurogranin, α-synuclein, visinin-like protein 1 (VILIP-1), neuronal pentraxin 2, and β-synuclein, along with positron emission tomography (PET) markers like synaptic vesicle glycoprotein 2A, have been developed. These advancements have facilitated the exploration of how synaptic markers in AD patients correlate with cognitive impairment. However, fluid biomarkers indicating synaptic loss have only been validated in cerebrospinal fluid (CSF), not in plasma, with the exception of VILIP-1. The most promising PET radiotracer, [11C]UCB-J, currently faces significant challenges hindering its widespread clinical use, primarily due to the necessity of a cyclotron. As such, additional research geared toward the exploration of synaptic pathology biomarkers is crucial. This will not only enable their extensive clinical application, but also refine the optimization process of AD pharmacological trials.
Collapse
Affiliation(s)
- Simone Lista
- i+HeALTH Strategic Research Group, Department of Health Sciences, Miguel de Cervantes European University (UEMC), 47012, Valladolid, Spain.
| | - Alejandro Santos-Lozano
- i+HeALTH Strategic Research Group, Department of Health Sciences, Miguel de Cervantes European University (UEMC), 47012, Valladolid, Spain
- Physical Activity and Health Research Group (PaHerg), Research Institute of the Hospital 12 de Octubre ('imas12'), 28041, Madrid, Spain
| | | | - Nicola B Mercuri
- Experimental Neurology Laboratory, IRCCS Santa Lucia Foundation, 00143, Rome, Italy
- Department of Systems Medicine, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Audrey Gabelle
- CMRR, Memory Resources and Research Center, Montpellier University of Excellence i-site, 34295, Montpellier, France
| | - Susana López-Ortiz
- i+HeALTH Strategic Research Group, Department of Health Sciences, Miguel de Cervantes European University (UEMC), 47012, Valladolid, Spain
| | - Juan Martín-Hernández
- i+HeALTH Strategic Research Group, Department of Health Sciences, Miguel de Cervantes European University (UEMC), 47012, Valladolid, Spain
| | - Nunzia Maisto
- Laboratory of Pharmacology of Synaptic Plasticity, EBRI Rita Levi-Montalcini Foundation, 00143, Rome, Italy
- Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, 00185, Rome, Italy
| | - Camillo Imbimbo
- Department of Brain and Behavioral Sciences, University of Pavia, 27100, Pavia, Italy
| | - Filippo Caraci
- Department of Drug and Health Sciences, University of Catania, 95125, Catania, Italy
- Neuropharmacology and Translational Neurosciences Research Unit, Oasi Research Institute-IRCCS, 94018, Troina, Italy
| | - Bruno P Imbimbo
- Department of Research and Development, Chiesi Farmaceutici, 43122, Parma, Italy
| | - Henrik Zetterberg
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, 431 80, Mölndal, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 431 80, Mölndal, Sweden
- Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, WC1N, London, UK
- UK Dementia Research Institute at UCL, WC1E 6BT, London, UK
- Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China
- Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, 53726, WI, USA
| | - Robert Nisticò
- Laboratory of Pharmacology of Synaptic Plasticity, EBRI Rita Levi-Montalcini Foundation, 00143, Rome, Italy.
- School of Pharmacy, University of Rome "Tor Vergata", 00133, Rome, Italy.
| |
Collapse
|
|
8
|
Kanaan NM. Tau here, tau there, tau almost everywhere: Clarifying the distribution of tau in the adult CNS. Cytoskeleton (Hoboken) 2024; 81:107-115. [PMID: 38102924 PMCID: PMC10851165 DOI: 10.1002/cm.21820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 12/01/2023] [Accepted: 12/04/2023] [Indexed: 12/17/2023]
Abstract
The microtubule-associated protein tau has gained significant attention over the last several decades primarily due to its apparent role in the pathogenesis of several diseases, most notably Alzheimer's disease. While the field has focused largely on tau's potential contributions to disease mechanisms, comparably less work has focused on normal tau physiology. Moreover, as the field has grown, some misconceptions and dogmas regarding normal tau physiology have become engrained in the traditional narrative. Here, one of the most common misconceptions regarding tau, namely its normal cellular/subcellular distribution in the CNS, is discussed. The literature describing the presence of tau in neuronal somata, dendrites, axons and synapses, as well as in glial cells is described. The origins for the erroneous description of tau as an "axon-specific," "axon-enriched" and/or "neuron-specific" protein are discussed as well. The goal of this work is to help address these specific dogmatic misconceptions and provide a concise description of tau's normal cellular/subcellular localization in the adult CNS. This information can help refine our collective understanding of- and hypotheses about tau biology and pathobiology.
Collapse
Affiliation(s)
- Nicholas M. Kanaan
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA
- Neuroscience Program, Michigan State University, East Lansing, Michigan, USA
| |
Collapse
|
|
9
|
Uzunhisarcıklı E, Çelik İ, Yerer MB. Detection of natural compounds by virtual screening, molecular docking and dynamics studies and evaluation of their effects on tau level in vitro Alzheimer's model. J Biomol Struct Dyn 2024; 42:384-392. [PMID: 36946204 DOI: 10.1080/07391102.2023.2192806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 03/13/2023] [Indexed: 03/23/2023]
Abstract
In Alzheimer's disease (AD), neurofibrillary tangles are composed of hyperphosphorylated tau protein, and tau hyperphosphorylation reduces microtubule binding. Many protein kinases are thought to be involved in tau hyperphosphorylation. Based on the fact that tau hyperphosphorylation can be prevented by inhibition of glycogen synthase kinase-3β (GSK-3β), which is one of the tau kinases, the effectiveness of potential GSK-3β inhibitors determined by virtual screening, molecular docking, and dynamics simulations studies on Alzheimer's pathology has been examined and its role in neurodegeneration has been investigated by studies. Neomangiferin was determined as the most effective molecule according to the results of studies with potential compounds determined by virtual screening and molecular docking to be GSK-3β inhibitors in the in vitro Alzheimer's model created by neuronal differentiation studies. Neomangiferin has been shown to have a protective role in induced neurodegeneration by the MTT method and Real Time Cell Analysis. It has been determined that Neomangiferin inhibits GSK-3β and reduces the level of phosphorylated tau. In summary, our findings suggested Neomangiferin can be a therapeutic candidate for AD treatment.Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Ebru Uzunhisarcıklı
- Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey
| | - İsmail Çelik
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey
| | - Mükerrem Betül Yerer
- Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey
| |
Collapse
|
|
10
|
Drieu A, Du S, Kipnis M, Bosch ME, Herz J, Lee C, Jiang H, Manis M, Ulrich JD, Kipnis J, Holtzman DM, Gratuze M. Parenchymal border macrophages regulate tau pathology and tau-mediated neurodegeneration. Life Sci Alliance 2023; 6:e202302087. [PMID: 37562846 PMCID: PMC10415611 DOI: 10.26508/lsa.202302087] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 07/31/2023] [Accepted: 07/31/2023] [Indexed: 08/12/2023] Open
Abstract
Parenchymal border macrophages (PBMs) reside close to the central nervous system parenchyma and regulate CSF flow dynamics. We recently demonstrated that PBMs provide a clearance pathway for amyloid-β peptide, which accumulates in the brain in Alzheimer's disease (AD). Given the emerging role for PBMs in AD, we explored how tau pathology affects the CSF flow and the PBM populations in the PS19 mouse model of tau pathology. We demonstrated a reduction of CSF flow, and an increase in an MHCII+PBM subpopulation in PS19 mice compared with WT littermates. Consequently, we asked whether PBM dysfunction could exacerbate tau pathology and tau-mediated neurodegeneration. Pharmacological depletion of PBMs in PS19 mice led to an increase in tau pathology and tau-dependent neurodegeneration, which was independent of gliosis or aquaporin-4 depolarization, essential for the CSF-ISF exchange. Together, our results identify PBMs as novel cellular regulators of tau pathology and tau-mediated neurodegeneration.
Collapse
Affiliation(s)
- Antoine Drieu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
- Center for Brain Immunology and Glia, Washington University School of Medicine, St. Louis, MO, USA
| | - Siling Du
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
- Center for Brain Immunology and Glia, Washington University School of Medicine, St. Louis, MO, USA
| | - Michal Kipnis
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
- Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
- Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Megan E Bosch
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
- Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
- Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Jasmin Herz
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
- Center for Brain Immunology and Glia, Washington University School of Medicine, St. Louis, MO, USA
| | - Choonghee Lee
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
- Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
- Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Hong Jiang
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
- Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
- Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Melissa Manis
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
- Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
- Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Jason D Ulrich
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
- Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
- Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Jonathan Kipnis
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
- Center for Brain Immunology and Glia, Washington University School of Medicine, St. Louis, MO, USA
| | - David M Holtzman
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
- Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
- Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Maud Gratuze
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
- Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
- Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
- Institute of Neurophysiopathology (INP UMR7051), Aix-Marseille University, Marseille, France
| |
Collapse
|
|
11
|
Morris M, Coste GI, Redding-Ochoa J, Guo H, Graves AR, Troncoso JC, Huganir RL. Hippocampal synaptic alterations associated with tau pathology in primary age-related tauopathy. J Neuropathol Exp Neurol 2023; 82:836-844. [PMID: 37595576 PMCID: PMC10516464 DOI: 10.1093/jnen/nlad064] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/20/2023] Open
Abstract
Primary age-related tauopathy (PART) is characterized by aggregation of tau in the mesial temporal lobe in older individuals. High pathologic tau stage (Braak stage) or a high burden of hippocampal tau pathology has been associated with cognitive impairment in PART. However, the potential underlying mechanisms are not well understood. Cognitive impairment in many neurodegenerative diseases correlates with synaptic loss, raising the question of whether synaptic loss also occurs in PART. To address this, we investigated synaptic changes associated with tau Braak stage and high tau pathology burden in PART using synaptophysin and phospho-tau immunofluorescence. We compared 12 cases of definite PART with 6 controls and 6 Alzheimer disease cases. In this study, the hippocampal CA2 region showed loss of synaptophysin puncta and intensity in cases of PART with either a high stage (Braak IV) or a high burden of neuritic tau pathology. There was also loss of synaptophysin intensity in CA3 associated with a high stage or high burden of tau pathology. Loss of synaptophysin was present in Alzheimer disease, but the pattern appeared distinct. These novel findings suggest the presence of synaptic loss associated with either a high hippocampal tau burden or a Braak stage IV in PART.
Collapse
Affiliation(s)
- Meaghan Morris
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Gabrielle I Coste
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Javier Redding-Ochoa
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Haidan Guo
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Austin R Graves
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, Maryland, USA
- Department of Biomedical Engineering, Johns Hopkins University School of Engineering, Baltimore, Maryland, USA
| | - Juan C Troncoso
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Richard L Huganir
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, Maryland, USA
| |
Collapse
|
|
12
|
Hromadkova L, Kim C, Haldiman T, Peng L, Zhu X, Cohen M, de Silva R, Safar JG. Evolving prion-like tau conformers differentially alter postsynaptic proteins in neurons inoculated with distinct isolates of Alzheimer's disease tau. Cell Biosci 2023; 13:174. [PMID: 37723591 PMCID: PMC10507869 DOI: 10.1186/s13578-023-01133-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 09/12/2023] [Indexed: 09/20/2023] Open
Abstract
OBJECTIVES Although accumulation of misfolded tau species has been shown to predict cognitive decline in patients with Alzheimer's disease (AD) and other tauopathies but with the remarkable diversity of clinical manifestations, neuropathology profiles, and time courses of disease progression remaining unexplained by current genetic data. We considered the diversity of misfolded tau conformers present in individual AD cases as an underlying driver of the phenotypic variations of AD and progressive loss of synapses. METHODS To model the mechanism of tau propagation and synaptic toxicity of distinct tau conformers, we inoculated wild-type primary mouse neurons with structurally characterized Sarkosyl-insoluble tau isolates from the frontal cortex of six AD cases and monitored the impact for fourteen days. We analyzed the accumulation rate, tau isoform ratio, and conformational characteristics of de novo-induced tau aggregates with conformationally sensitive immunoassays, and the dynamics of synapse formation, maintenance, and their loss using a panel of pre-and post-synaptic markers. RESULTS At the same concentrations of tau, the different AD tau isolates induced accumulation of misfolded predominantly 4-repeat tau aggregates at different rates in mature neurons, and demonstrated distinct conformational characteristics corresponding to the original AD brain tau. The time-course of the formation of misfolded tau aggregates and colocalization correlated with significant loss of synapses in tau-inoculated cell cultures and the reduction of synaptic connections implicated the disruption of postsynaptic compartment as an early event. CONCLUSIONS The data obtained with mature neurons expressing physiological levels and adult isoforms of tau protein demonstrate markedly different time courses of endogenous tau misfolding and differential patterns of post-synaptic alterations. These and previous biophysical data argue for an ensemble of various misfolded tau aggregates in individual AD brains and template propagation of their homologous conformations in neurons with different rates and primarily postsynaptic interactors. Modeling tau aggregation in mature differentiated neurons provides a platform for investigating divergent molecular mechanisms of tau strain propagation and for identifying common structural features of misfolded tau and critical interactors for new therapeutic targets and approaches in AD.
Collapse
Affiliation(s)
- Lenka Hromadkova
- Departments of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH, 44106, USA
| | - Chae Kim
- Departments of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH, 44106, USA
| | - Tracy Haldiman
- Departments of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH, 44106, USA
| | - Lihua Peng
- Departments of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH, 44106, USA
| | - Xiongwei Zhu
- Departments of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH, 44106, USA
- Departments of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Mark Cohen
- Departments of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH, 44106, USA
- National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Rohan de Silva
- Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, WC1N 1PJ, UK
| | - Jiri G Safar
- Departments of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH, 44106, USA.
- Departments of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
- Departments of Neuroscience, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
| |
Collapse
|
|
13
|
Opland CK, Bryan MR, Harris B, McGillion-Moore J, Tian X, Chen Y, Itano MS, Diering GH, Meeker RB, Cohen TJ. Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity. iScience 2023; 26:106905. [PMID: 37305696 PMCID: PMC10251131 DOI: 10.1016/j.isci.2023.106905] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 03/08/2023] [Accepted: 05/12/2023] [Indexed: 06/13/2023] Open
Abstract
Tau-mediated toxicity is associated with cognitive decline and Alzheimer's disease (AD) progression. In particular, tau post-translational modifications (PTMs) are thought to generate aberrant tau species resulting in neuronal dysfunction. Despite being well characterized in postmortem AD brain, it is unclear how caspase-mediated C-terminal tau cleavage promotes neurodegeneration, as few studies have developed the models to dissect this pathogenic mechanism. Here, we show that proteasome impairment results in cleaved tau accumulation at the post-synaptic density (PSD), a process that is modulated by neuronal activity. Cleaved tau (at residue D421) impairs neuronal firing and causes inefficient initiation of network bursts, consistent with reduced excitatory drive. We propose that reduced neuronal activity, or silencing, is coupled to proteasome dysfunction, which drives cleaved tau accumulation at the PSD and subsequent synaptotoxicity. Our study connects three common themes in the progression of AD: impaired proteostasis, caspase-mediated tau cleavage, and synapse degeneration.
Collapse
Affiliation(s)
- Carli K. Opland
- UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Miles R. Bryan
- UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Braxton Harris
- Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Jake McGillion-Moore
- UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Xu Tian
- UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Youjun Chen
- UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Michelle S. Itano
- UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Cell Biology and Physiology, Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Graham H. Diering
- UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Cell Biology and Physiology, Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Rick B. Meeker
- Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Todd J. Cohen
- UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Cell Biology and Physiology, Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC 27599, USA
- Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599-7260, USA
| |
Collapse
|
|
14
|
Morris M, Coste GI, Redding-Ochoa J, Guo H, Graves AR, Troncoso JC, Huganir RL. Hippocampal Synaptic Alterations Associated with Tau Pathology in Primary Age-Related Tauopathy. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.02.22.23286323. [PMID: 36865237 PMCID: PMC9980270 DOI: 10.1101/2023.02.22.23286323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
Primary Age-Related Tauopathy (PART) is characterized by the aggregation of tau in the mesial temporal lobe in older individuals. High pathologic tau stage (Braak stage) or a high burden of hippocampal tau pathology have been associated with cognitive impairment in PART. However, the underlying mechanisms of cognitive impairment in PART are not well understood. Cognitive impairment in many neurodegenerative diseases correlates with synaptic loss, raising the question of whether synaptic loss occurs in PART. To address this, we investigated synaptic changes associated with tau Braak stage and a high tau pathology burden in PART using synaptophysin and phospho-tau immunofluorescence. We compared twelve cases of definite PART with six young controls and six Alzheimer's disease cases. In this study, we identified loss of synaptophysin puncta and intensity in the CA2 region of the hippocampus in cases of PART with either a high stage (Braak IV) or a high burden of neuritic tau pathology. There was also loss of synaptophysin intensity in CA3 associated with a high stage or high burden of tau pathology. Loss of synaptophysin signal was present in AD, but the pattern was distinct from that seen in PART. These novel findings suggest the presence of synaptic loss in PART associated with either a high hippocampal tau burden or a Braak stage IV. These synaptic changes raise the possibility that synaptic loss in PART could contribute to cognitive impairment, though future studies including cognitive assessments are needed to address this question.
Collapse
Affiliation(s)
- Meaghan Morris
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Gabrielle I Coste
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Javier Redding-Ochoa
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Haidan Guo
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Austin R Graves
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD
- Kavli Neuroscience Discovery Institute, Baltimore, MD
- Department of Biomedical Engineering, Johns Hopkins University School of Engineering, Baltimore, MD
| | - Juan C Troncoso
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Richard L Huganir
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD
- Kavli Neuroscience Discovery Institute, Baltimore, MD
| |
Collapse
|
|
15
|
Meftah S, Gan J. Alzheimer's disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression. Front Synaptic Neurosci 2023; 15:1129036. [PMID: 36970154 PMCID: PMC10033629 DOI: 10.3389/fnsyn.2023.1129036] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 02/23/2023] [Indexed: 03/11/2023] Open
Abstract
The synapse has consistently been considered a vulnerable and critical target within Alzheimer's disease, and synapse loss is, to date, one of the main biological correlates of cognitive decline within Alzheimer's disease. This occurs prior to neuronal loss with ample evidence that synaptic dysfunction precedes this, in support of the idea that synaptic failure is a crucial stage within disease pathogenesis. The two main pathological hallmarks of Alzheimer's disease, abnormal aggregates of amyloid or tau proteins, have had demonstrable effects on synaptic physiology in animal and cellular models of Alzheimer's disease. There is also growing evidence that these two proteins may have a synergistic effect on neurophysiological dysfunction. Here, we review some of the main findings of synaptic alterations in Alzheimer's disease, and what we know from Alzheimer's disease animal and cellular models. First, we briefly summarize some of the human evidence to suggest that synapses are altered, including how this relates to network activity. Subsequently, animal and cellular models of Alzheimer's disease are considered, highlighting mouse models of amyloid and tau pathology and the role these proteins may play in synaptic dysfunction, either in isolation or examining how the two pathologies may interact in dysfunction. This specifically focuses on neurophysiological function and dysfunction observed within these animal models, typically measured using electrophysiology or calcium imaging. Following synaptic dysfunction and loss, it would be impossible to imagine that this would not alter oscillatory activity within the brain. Therefore, this review also discusses how this may underpin some of the aberrant oscillatory patterns seen in animal models of Alzheimer's disease and human patients. Finally, an overview of some key directions and considerations in the field of synaptic dysfunction in Alzheimer's disease is covered. This includes current therapeutics that are targeted specifically at synaptic dysfunction, but also methods that modulate activity to rescue aberrant oscillatory patterns. Other important future avenues of note in this field include the role of non-neuronal cell types such as astrocytes and microglia, and mechanisms of dysfunction independent of amyloid and tau in Alzheimer's disease. The synapse will certainly continue to be an important target within Alzheimer's disease for the foreseeable future.
Collapse
Affiliation(s)
- Soraya Meftah
- UK Dementia Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
- Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, United Kingdom
| | - Jian Gan
- UK Dementia Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
- Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, United Kingdom
| |
Collapse
|
|
16
|
Arvidsson Rådestig M, Skoog I, Skillbäck T, Zetterberg H, Kern J, Zettergren A, Andreasson U, Wetterberg H, Kern S, Blennow K. Cerebrospinal fluid biomarkers of axonal and synaptic degeneration in a population-based sample. Alzheimers Res Ther 2023; 15:44. [PMID: 36869347 PMCID: PMC9983206 DOI: 10.1186/s13195-023-01193-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 02/14/2023] [Indexed: 03/05/2023]
Abstract
BACKGROUND Neurofilament light (NfL) and neurogranin (Ng) are promising candidate AD biomarkers, reflecting axonal and synaptic damage, respectively. Since there is a need to understand the synaptic and axonal damage in preclinical Alzheimer's disease (AD), we aimed to determine the cerebrospinal fluid (CSF) levels of NfL and Ng in cognitively unimpaired elderly from the Gothenburg H70 Birth Cohort Studies classified according to the amyloid/tau/neurodegeneration (A/T/N) system. METHODS The sample consisted of 258 cognitively unimpaired older adults (age 70, 129 women and 129 men) from the Gothenburg Birth Cohort Studies. We compared CSF NfL and Ng concentrations in A/T/N groups using Student's T-test and ANCOVA. RESULTS CSF NfL concentration was higher in the A-T-N+ group (p=0.001) and the A-T+N+ group (p=0.006) compared with A-T-N-. CSF Ng concentration was higher in the A-T-N+, A-T+N+, A+T-N+, and A+T+N+ groups (p<0.0001) compared with A-T-N-. We found no difference in NfL or Ng concentration in A+ compared with A- (disregarding T- and N- status), whereas those with N+ had higher concentrations of NfL and Ng compared with N- (p<0.0001) (disregarding A- and T- status). CONCLUSIONS CSF NfL and Ng concentrations are increased in cognitively normal older adults with biomarker evidence of tau pathology and neurodegeneration.
Collapse
Affiliation(s)
- Maya Arvidsson Rådestig
- Department of Neuropsychiatric Epidemiology Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.,Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Ingmar Skoog
- Department of Neuropsychiatric Epidemiology Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.,Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.,Department of Psychiatry, Cognition and Old Age Psychiatry, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Tobias Skillbäck
- Department of Neuropsychiatric Epidemiology Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. .,Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
| | - Henrik Zetterberg
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.,Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.,Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.,UK Dementia Research Institute at UCL, London, WC1N 3BG, UK.,Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
| | - Jürgen Kern
- Department of Neuropsychiatric Epidemiology Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Anna Zettergren
- Department of Neuropsychiatric Epidemiology Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.,Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Ulf Andreasson
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.,Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
| | - Hanna Wetterberg
- Department of Neuropsychiatric Epidemiology Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.,Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Silke Kern
- Department of Neuropsychiatric Epidemiology Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.,Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.,Department of Psychiatry, Cognition and Old Age Psychiatry, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Kaj Blennow
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.,Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
| |
Collapse
|
|
17
|
Rawat P, Sehar U, Bisht J, Selman A, Culberson J, Reddy PH. Phosphorylated Tau in Alzheimer's Disease and Other Tauopathies. Int J Mol Sci 2022; 23:12841. [PMID: 36361631 PMCID: PMC9654278 DOI: 10.3390/ijms232112841] [Citation(s) in RCA: 165] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/21/2022] [Accepted: 10/22/2022] [Indexed: 07/29/2023] Open
Abstract
Alzheimer's disease (AD) is the leading cause of dementia in elderly people. Amyloid beta (Aβ) deposits and neurofibrillary tangles are the major pathological features in an Alzheimer's brain. These proteins are highly expressed in nerve cells and found in most tissues. Tau primarily provides stabilization to microtubules in the part of axons and dendrites. However, tau in a pathological state becomes hyperphosphorylated, causing tau dysfunction and leading to synaptic impairment and degeneration of neurons. This article presents a summary of the role of tau, phosphorylated tau (p-tau) in AD, and other tauopathies. Tauopathies, including Pick's disease, frontotemporal dementia, corticobasal degeneration, Alzheimer's disease, argyrophilic grain disease, progressive supranuclear palsy, and Huntington's disease, are the result of misprocessing and accumulation of tau within the neuronal and glial cells. This article also focuses on current research on the post-translational modifications and genetics of tau, tau pathology, the role of tau in tauopathies and the development of new drugs targeting p-tau, and the therapeutics for treating and possibly preventing tauopathies.
Collapse
Affiliation(s)
- Priyanka Rawat
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Ujala Sehar
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Jasbir Bisht
- Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Ashley Selman
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - John Culberson
- Department of Family Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - P. Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
- Nutritional Sciences Department, College Human Sciences, Texas Tech University, Lubbock, TX 79409, USA
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
- Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
- Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
- Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| |
Collapse
|
|
18
|
Aβ and Tau Interact with Metal Ions, Lipid Membranes and Peptide-Based Amyloid Inhibitors: Are These Common Features Relevant in Alzheimer’s Disease? Molecules 2022; 27:molecules27165066. [PMID: 36014310 PMCID: PMC9414153 DOI: 10.3390/molecules27165066] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/04/2022] [Accepted: 08/05/2022] [Indexed: 12/13/2022] Open
Abstract
In the last two decades, the amyloid hypothesis, i.e., the abnormal accumulation of toxic Aβ assemblies in the brain, has been considered the mainstream concept sustaining research in Alzheimer’s Disease (AD). However, the course of cognitive decline and AD development better correlates with tau accumulation rather than amyloid peptide deposition. Moreover, all clinical trials of amyloid-targeting drug candidates have been unsuccessful, implicitly suggesting that the amyloid hypothesis needs significant amendments. Accumulating evidence supports the existence of a series of potentially dangerous relationships between Aβ oligomeric species and tau protein in AD. However, the molecular determinants underlying pathogenic Aβ/tau cross interactions are not fully understood. Here, we discuss the common features of Aβ and tau molecules, with special emphasis on: (i) the critical role played by metal dyshomeostasis in promoting both Aβ and tau aggregation and oxidative stress, in AD; (ii) the effects of lipid membranes on Aβ and tau (co)-aggregation at the membrane interface; (iii) the potential of small peptide-based inhibitors of Aβ and tau misfolding as therapeutic tools in AD. Although the molecular mechanism underlying the direct Aβ/tau interaction remains largely unknown, the arguments discussed in this review may help reinforcing the current view of a synergistic Aβ/tau molecular crosstalk in AD and stimulate further research to mechanism elucidation and next-generation AD therapeutics.
Collapse
|
|
19
|
Engelender S, Stefanis L, Oddo S, Bellucci A. Can We Treat Neurodegenerative Proteinopathies by Enhancing Protein Degradation? Mov Disord 2022; 37:1346-1359. [PMID: 35579450 DOI: 10.1002/mds.29058] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 04/20/2022] [Accepted: 04/22/2022] [Indexed: 12/16/2022] Open
Abstract
Neurodegenerative proteinopathies are defined as a class of neurodegenerative disorders, with either genetic or sporadic age-related onset, characterized by the pathological accumulation of aggregated protein deposits. These mainly include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) as well as frontotemporal lobar degeneration (FTLD). The deposition of abnormal protein aggregates in the brain of patients affected by these disorders is thought to play a causative role in neuronal loss and disease progression. On that account, the idea of improving the clearance of pathological protein aggregates has taken hold as a potential therapeutic strategy. Among the possible approaches to pursue for reducing disease protein accumulation, there is the stimulation of the main protein degradation machineries of eukaryotic cells: the ubiquitin proteasomal system (UPS) and autophagy lysosomal pathway (ALP). Of note, several clinical trials testing the efficacy of either UPS- or ALP-active compounds are currently ongoing. Here, we discuss the main gaps and controversies emerging from experimental studies and clinical trials assessing the therapeutic efficacy of modulators of either the UPS or ALP in neurodegenerative proteinopathies, to gather whether they may constitute a real gateway from these disorders. © 2022 International Parkinson and Movement Disorder Society.
Collapse
Affiliation(s)
- Simone Engelender
- Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research, Technion-Israel Institute of Technology, Haifa, Israel
| | - Leonidas Stefanis
- Biomedical Research Foundation of the Academy of Athens, Athens, Greece.,First Department of Neurology, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Salvatore Oddo
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Messina, Italy
| | - Arianna Bellucci
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| |
Collapse
|
|
20
|
Kivisäkk P, Carlyle BC, Sweeney T, Quinn JP, Ramirez CE, Trombetta BA, Mendes M, Brock M, Rubel C, Czerkowicz J, Graham D, Arnold SE. Increased levels of the synaptic proteins PSD-95, SNAP-25, and neurogranin in the cerebrospinal fluid of patients with Alzheimer's disease. Alzheimers Res Ther 2022; 14:58. [PMID: 35461266 PMCID: PMC9034610 DOI: 10.1186/s13195-022-01002-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 04/08/2022] [Indexed: 01/08/2023]
Abstract
Background There is currently a lack of reliable and easily accessible biomarkers predicting cognitive decline in Alzheimer’s disease (AD). Synaptic dysfunction and loss occur early in AD and synaptic loss measured in the brain tissue and by PET are closely linked to cognitive decline, rendering synaptic proteins a promising target for biomarker development. Methods We used novel Simoa assays to measure cerebrospinal fluid (CSF) levels of two synaptic biomarker candidates, postsynaptic density protein 95 (PSD-95/DLG4), and the presynaptically localized synaptosomal-associated protein 25 (SNAP-25), as well as neurogranin (Ng), an established postsynaptic biomarker. CSF samples from two well-characterized cohorts (n=178 and n=156) were selected from banked samples obtained from diagnostic lumbar punctures containing subjects with amyloid-ß (Aß) positive AD, subjects with non-AD neurodegenerative diseases, subjects with other neurological conditions, and healthy controls (HC). Results All subjects had detectable CSF levels of PSD-95, SNAP-25, and Ng. CSF levels of PSD-95, SNAP-25, and Ng were all correlated, with the strongest correlation between the presynaptic SNAP-25 and the postsynaptic neurogranin. AD subjects had on average higher concentrations of all three synaptic markers compared to those with non-AD neurodegenerative diseases, other neurological disorders, and HCs. Increased CSF levels of PSD-95, SNAP-25, and Ng were, however, not specific for AD and were present in sporadic cases with inflammatory or vascular disorders as well. High CSF levels of PSD-95 were also observed in a few subjects with other neurodegenerative disorders. Conclusion The data establishes PSD-95 as a promising CSF marker for neurodegenerative disease synaptic pathology, while SNAP-25 and Ng appear to be somewhat more specific for AD. Together, these synaptic markers hold promise to identify early AD pathology, to correlate with cognitive decline, and to monitor responses to disease-modifying drugs reducing synaptic degeneration. Supplementary Information The online version contains supplementary material available at 10.1186/s13195-022-01002-x.
Collapse
Affiliation(s)
- Pia Kivisäkk
- Department of Neurology, Alzheimer's Clinical and Translational Research Unit, Massachusetts General Hospital, 114 16th Street, Room 2300, Charlestown, MA, 02129, USA.
| | - Becky C Carlyle
- Department of Neurology, Alzheimer's Clinical and Translational Research Unit, Massachusetts General Hospital, 114 16th Street, Room 2300, Charlestown, MA, 02129, USA
| | - Thadryan Sweeney
- Department of Neurology, Alzheimer's Clinical and Translational Research Unit, Massachusetts General Hospital, 114 16th Street, Room 2300, Charlestown, MA, 02129, USA
| | - James P Quinn
- Department of Neurology, Alzheimer's Clinical and Translational Research Unit, Massachusetts General Hospital, 114 16th Street, Room 2300, Charlestown, MA, 02129, USA
| | - Christopher E Ramirez
- Department of Neurology, Alzheimer's Clinical and Translational Research Unit, Massachusetts General Hospital, 114 16th Street, Room 2300, Charlestown, MA, 02129, USA
| | - Bianca A Trombetta
- Department of Neurology, Alzheimer's Clinical and Translational Research Unit, Massachusetts General Hospital, 114 16th Street, Room 2300, Charlestown, MA, 02129, USA
| | | | - Mary Brock
- Quanterix Corporation, Billerica, MA, USA
| | | | | | | | - Steven E Arnold
- Department of Neurology, Alzheimer's Clinical and Translational Research Unit, Massachusetts General Hospital, 114 16th Street, Room 2300, Charlestown, MA, 02129, USA
| |
Collapse
|
|
21
|
Association of entorhinal cortical tau deposition and hippocampal synaptic density in older individuals with normal cognition and early Alzheimer's disease. Neurobiol Aging 2022; 111:44-53. [PMID: 34963063 PMCID: PMC8761170 DOI: 10.1016/j.neurobiolaging.2021.11.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 11/09/2021] [Accepted: 11/16/2021] [Indexed: 01/26/2023]
Abstract
Sites of early neuropathologic change provide important clues regarding the initial clinical features of Alzheimer's disease (AD). We have shown significant reductions in hippocampal synaptic density in participants with AD, consistent with the early degeneration of entorhinal cortical (ERC) cells that project to hippocampus via the perforant path. In this study, [11C]UCB-J binding to synaptic vesicle glycoprotein 2A (SV2A) and [18F]flortaucipir binding to tau were measured via PET in 10 participants with AD (5 mild cognitive impairment, 5 mild dementia) and 10 cognitively normal participants. In the overall sample, ERC tau was inversely associated with hippocampal synaptic density (r = -0.59, p = 0.009). After correction for partial volume effects, the association of ERC tau with hippocampal synaptic density was stronger in the overall sample (r = -0.61, p = 0.007) and in the AD group where the effect size was large, but not statistically significant (r = -0.58, p = 0.06). This inverse association of ERC tau and hippocampal synaptic density may reflect synaptic failure due to tau pathology in ERC neurons projecting to the hippocampus.
Collapse
|
|
22
|
Tsamou M, Pistollato F, Roggen EL. A Tau-Driven Adverse Outcome Pathway Blueprint Toward Memory Loss in Sporadic (Late-Onset) Alzheimer's Disease with Plausible Molecular Initiating Event Plug-Ins for Environmental Neurotoxicants. J Alzheimers Dis 2021; 81:459-485. [PMID: 33843671 DOI: 10.3233/jad-201418] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The worldwide prevalence of sporadic (late-onset) Alzheimer's disease (sAD) is dramatically increasing. Aging and genetics are important risk factors, but systemic and environmental factors contribute to this risk in a still poorly understood way. Within the frame of BioMed21, the Adverse Outcome Pathway (AOP) concept for toxicology was recommended as a tool for enhancing human disease research and accelerating translation of data into human applications. Its potential to capture biological knowledge and to increase mechanistic understanding about human diseases has been substantiated since. In pursuit of the tau-cascade hypothesis, a tau-driven AOP blueprint toward the adverse outcome of memory loss is proposed. Sequences of key events and plausible key event relationships, triggered by the bidirectional relationship between brain cholesterol and glucose dysmetabolism, and contributing to memory loss are captured. To portray how environmental factors may contribute to sAD progression, information on chemicals and drugs, that experimentally or epidemiologically associate with the risk of AD and mechanistically link to sAD progression, are mapped on this AOP. The evidence suggests that chemicals may accelerate disease progression by plugging into sAD relevant processes. The proposed AOP is a simplified framework of key events and plausible key event relationships representing one specific aspect of sAD pathology, and an attempt to portray chemical interference. Other sAD-related AOPs (e.g., Aβ-driven AOP) and a better understanding of the impact of aging and genetic polymorphism are needed to further expand our mechanistic understanding of early AD pathology and the potential impact of environmental and systemic risk factors.
Collapse
|
|
23
|
Sex-Related Motor Deficits in the Tau-P301L Mouse Model. Biomedicines 2021; 9:biomedicines9091160. [PMID: 34572348 PMCID: PMC8471835 DOI: 10.3390/biomedicines9091160] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/31/2021] [Accepted: 09/01/2021] [Indexed: 01/22/2023] Open
Abstract
The contribution of mouse models for basic and translational research at different levels is important to understand neurodegenerative diseases, including tauopathies, by studying the alterations in the corresponding mouse models in detail. Moreover, several studies demonstrated that pathological as well as behavioral changes are influenced by the sex. For this purpose, we performed an in-depth characterization of the behavioral alterations in the transgenic Tau-P301L mouse model. Sex-matched wild type and homozygous Tau-P301L mice were tested in a battery of behavioral tests at different ages. Tau-P301L male mice showed olfactory and motor deficits as well as increased Tau pathology, which was not observed in Tau-P301L female mice. Both Tau-P301L male and female mice had phenotypic alterations in the SHIRPA test battery and cognitive deficits in the novel object recognition test. This study demonstrated that Tau-P301L mice have phenotypic alterations, which are in line with the histological changes and with a sex-dependent performance in those tests. Summarized, the Tau-P301L mouse model shows phenotypic alterations due to the presence of neurofibrillary tangles in the brain.
Collapse
|
|
24
|
Holland N, Malpetti M, Rittman T, Mak EE, Passamonti L, Kaalund SS, Hezemans FH, Jones PS, Savulich G, Hong YT, Fryer TD, Aigbirhio FI, O'Brien JT, Rowe JB. Molecular pathology and synaptic loss in primary tauopathies: an 18F-AV-1451 and 11C-UCB-J PET study. Brain 2021; 145:340-348. [PMID: 34398211 PMCID: PMC8967099 DOI: 10.1093/brain/awab282] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 07/02/2021] [Accepted: 07/10/2021] [Indexed: 12/02/2022] Open
Abstract
The relationship between in vivo synaptic density and molecular pathology in primary tauopathies is key to understanding the impact of tauopathy on functional decline and in informing new early therapeutic strategies. In this cross-sectional observational study, we determine the in vivo relationship between synaptic density and molecular pathology in the primary tauopathies of progressive supranuclear palsy and corticobasal degeneration as a function of disease severity. Twenty-three patients with progressive supranuclear palsy and 12 patients with corticobasal syndrome were recruited from a tertiary referral centre. Nineteen education-, sex- and gender-matched control participants were recruited from the National Institute for Health Research ‘Join Dementia Research’ platform. Cerebral synaptic density and molecular pathology, in all participants, were estimated using PET imaging with the radioligands 11C-UCB-J and 18F-AV-1451, respectively. Patients with corticobasal syndrome also underwent amyloid PET imaging with 11C-PiB to exclude those with likely Alzheimer’s pathology—we refer to the amyloid-negative cohort as having corticobasal degeneration, although we acknowledge other underlying pathologies exist. Disease severity was assessed with the progressive supranuclear palsy rating scale; regional non-displaceable binding potentials of 11C-UCB-J and 18F-AV-1451 were estimated in regions of interest from the Hammersmith Atlas, excluding those with known off-target binding for 18F-AV-1451. As an exploratory analysis, we also investigated the relationship between molecular pathology in cortical brain regions and synaptic density in subcortical areas. Across brain regions, there was a positive correlation between 11C-UCB-J and 18F-AV-1451 non-displaceable binding potentials (β = 0.4, t = 3.6, P = 0.001), independent of age or time between PET scans. However, this correlation became less positive as a function of disease severity in patients (β = −0.02, t = −2.9, P = 0.007, R = −0.41). Between regions, cortical 18F-AV-1451 binding was negatively correlated with synaptic density in subcortical areas (caudate nucleus, putamen). Brain regions with higher synaptic density are associated with a higher 18F-AV-1451 binding in progressive supranuclear palsy/corticobasal degeneration, but this association diminishes with disease severity. Moreover, higher cortical 18F-AV-1451 binding correlates with lower subcortical synaptic density. Longitudinal imaging is required to confirm the mediation of synaptic loss by molecular pathology. However, the effect of disease severity suggests a biphasic relationship between synaptic density and molecular pathology with synapse-rich regions vulnerable to accrual of pathological aggregates, followed by a loss of synapses in response to the molecular pathology. Given the importance of synaptic function for cognition and action, our study elucidates the pathophysiology of primary tauopathies and may inform the design of future clinical trials.
Collapse
Affiliation(s)
- Negin Holland
- Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0SZ, UK.,Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
| | - Maura Malpetti
- Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0SZ, UK
| | - Timothy Rittman
- Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0SZ, UK.,Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
| | - Elijah E Mak
- Department of Psychiatry, University of Cambridge, School of Clinical Medicine, Cambridge Biomedical Campus, CB2 0QQ, UK
| | - Luca Passamonti
- Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0SZ, UK.,Istituto di Bioimmagini e Fisiologia Molecolare (IBFM), Consiglio Nazionale delle Ricerche (CNR), 20090, Milano, Italy
| | - Sanne S Kaalund
- Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0SZ, UK
| | - Frank H Hezemans
- Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0SZ, UK.,Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, CB2 7EF, UK
| | - P Simon Jones
- Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0SZ, UK
| | - George Savulich
- Department of Psychiatry, University of Cambridge, School of Clinical Medicine, Cambridge Biomedical Campus, CB2 0QQ, UK
| | - Young T Hong
- Wolfson Brain Imaging Centre, University of Cambridge, CB2 0QQ, UK
| | - Tim D Fryer
- Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0SZ, UK.,Wolfson Brain Imaging Centre, University of Cambridge, CB2 0QQ, UK
| | - Franklin I Aigbirhio
- Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0SZ, UK
| | - John T O'Brien
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.,Department of Psychiatry, University of Cambridge, School of Clinical Medicine, Cambridge Biomedical Campus, CB2 0QQ, UK
| | - James B Rowe
- Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0SZ, UK.,Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.,Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, CB2 7EF, UK
| |
Collapse
|
|
25
|
Ma D, Huang R, Guo K, Zhao Z, Wei W, Gu L, Li L, Zhang L. Cornel Iridoid Glycoside Protects Against STAT1-Dependent Synapse and Memory Deficits by Increasing N-Methyl-D-aspartate Receptor Expression in a Tau Transgenic Mice. Front Aging Neurosci 2021; 13:671206. [PMID: 34113246 PMCID: PMC8185567 DOI: 10.3389/fnagi.2021.671206] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/13/2021] [Indexed: 12/14/2022] Open
Abstract
P301S transgenic mice are an animal model of tauopathy and Alzheimer’s disease (AD), exhibiting tau pathology and synaptic dysfunction. Cornel iridoid glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. In the present study, the purpose was to investigate the effects and mechanisms of CIG on tau pathology and synaptic dysfunction using P301S transgenic mice. The results showed that intragastric administration of CIG for 3.5 months improved cognitive impairments and the survival rate of P301S mice. Electrophysiological recordings and transmission electron microscopy study showed that CIG improved synaptic plasticity and increased the ultrastructure and number of synapse. Moreover, CIG increased the expression levels of N-methyl-D-aspartate receptors (NMDAR) subunits GluN1, GluN2A, and GluN2B, and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit GluA1. We inferred that the major mechanism of CIG involving in the regulation of synaptic dysfunctions was inhibiting the activation of Janus kinase-2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) signaling pathway and alleviating STAT1-induced suppression of NMDAR expressions. Based on our findings, we thought CIG might be a promising candidate for the therapy of tauopathy such as AD.
Collapse
Affiliation(s)
- Denglei Ma
- Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacy, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Rui Huang
- Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacy, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Kaiwen Guo
- Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacy, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Zirun Zhao
- Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, United States
| | - Weipeng Wei
- Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacy, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Lihong Gu
- Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacy, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Lin Li
- Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacy, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Lan Zhang
- Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacy, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
| |
Collapse
|
|
26
|
Remnestål J, Bergström S, Olofsson J, Sjöstedt E, Uhlén M, Blennow K, Zetterberg H, Zettergren A, Kern S, Skoog I, Nilsson P, Månberg A. Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds. ALZHEIMERS RESEARCH & THERAPY 2021; 13:54. [PMID: 33653397 PMCID: PMC7923505 DOI: 10.1186/s13195-021-00789-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 02/11/2021] [Indexed: 12/22/2022]
Abstract
Background Increased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer’s disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognized, the need for further characterization of the pathophysiological mechanisms behind AD still remains. Methods In this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody- and bead-based technology. Results The protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and amyloid beta (Aβ42) in all individuals. Sixty-three proteins showed significant correlations to either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins with CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid-negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score. Conclusions We identified a series of transmembrane proteins, proteins associated with or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport to be associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore these proteins’ role in AD pathophysiology. Supplementary Information The online version contains supplementary material available at 10.1186/s13195-021-00789-5.
Collapse
Affiliation(s)
- Julia Remnestål
- Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Tomtebodvägen 23A, Solna, Stockholm, Sweden
| | - Sofia Bergström
- Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Tomtebodvägen 23A, Solna, Stockholm, Sweden
| | - Jennie Olofsson
- Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Tomtebodvägen 23A, Solna, Stockholm, Sweden
| | - Evelina Sjöstedt
- Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Tomtebodvägen 23A, Solna, Stockholm, Sweden.,Department of Neuroscience, Karolinska Institutet, Solna, Sweden
| | - Mathias Uhlén
- Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Tomtebodvägen 23A, Solna, Stockholm, Sweden.,Department of Neuroscience, Karolinska Institutet, Solna, Sweden
| | - Kaj Blennow
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
| | - Henrik Zetterberg
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.,Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.,UK Dementia Research Institute at UCL, London, UK
| | - Anna Zettergren
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg, Sweden
| | - Silke Kern
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry, Cognition and Old Age Psychiatry Clinic, Gothenburg, Sweden
| | - Ingmar Skoog
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry, Cognition and Old Age Psychiatry Clinic, Gothenburg, Sweden
| | - Peter Nilsson
- Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Tomtebodvägen 23A, Solna, Stockholm, Sweden
| | - Anna Månberg
- Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Tomtebodvägen 23A, Solna, Stockholm, Sweden.
| |
Collapse
|
|
27
|
Camporesi E, Lashley T, Gobom J, Lantero-Rodriguez J, Hansson O, Zetterberg H, Blennow K, Becker B. Neuroligin-1 in brain and CSF of neurodegenerative disorders: investigation for synaptic biomarkers. Acta Neuropathol Commun 2021; 9:19. [PMID: 33522967 PMCID: PMC7852195 DOI: 10.1186/s40478-021-01119-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 01/09/2021] [Indexed: 02/02/2023] Open
Abstract
Synaptic pathology is a central event in Alzheimer’s disease (AD) and other neurodegenerative conditions, and investigation of synaptic proteins can provide valuable tools to follow synaptic dysfunction and loss in these diseases. Neuroligin-1 (Nlgn1) is a postsynaptic cell adhesion protein, important for synapse stabilization and formation. Nlgn1 has been connected to cognitive disorders, and specifically to AD, as target of the synaptotoxic effect of amyloid-β (Aβ) oligomers and Aβ fibrils. To address changes in Nlgn1 expression in human brain, brain regions in different neurological disorders were examined by Western blot and mass spectrometry. Brain specimens from AD (n = 23), progressive supranuclear palsy (PSP, n = 11), corticobasal degeneration (CBD, n = 10), and Pick’s disease (PiD, n = 9) were included. Additionally, cerebrospinal fluid (CSF) samples of AD patients (n = 43) and non-demented controls (n = 42) were analysed. We found decreased levels of Nlgn1 in temporal and parietal cortex (~ 50–60% reductions) in AD brains compared with controls. In frontal grey matter the reduction was not seen for AD patients; however, in the same region, marked reduction was found for PiD (~ 77%), CBD (~ 66%) and to a lesser extent for PSP (~ 43%), which could clearly separate these tauopathies from controls. The Nlgn1 level was reduced in CSF from AD patients compared to controls, but with considerable overlap. The dramatic reduction of Nlgn1 seen in the brain extracts of tauopathies warrants further investigation regarding the potential use of Nlgn1 as a biomarker for these neurodegenerative diseases.
Collapse
|
|
28
|
Gazarian K, Ramirez-Garcia L, Tapía Orozco L, Luna-Muñoz J, Pacheco-Herrero M. Human Dental Pulp Stem Cells Display a Potential for Modeling Alzheimer Disease-Related Tau Modifications. Front Neurol 2021; 11:612657. [PMID: 33569035 PMCID: PMC7868559 DOI: 10.3389/fneur.2020.612657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 11/27/2020] [Indexed: 11/25/2022] Open
Abstract
We present here the first description of tau in human dental pulp stem cells (DPSCs) evidenced by RT-PCR data on expression of the gene MAPT and by immunocytochemical detection of epitopes by 12 anti-tau antibodies. The tau specificity of eight of these antibodies was confirmed by their affinity to neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) postmortem brain samples. We therefore used DPSCs and AD brain samples as a test system for determining the probability of the involvement of tau epitopes in the mechanisms converting tau into NFT in AD. Three antibodies to non-phosphorylated and seven antibodies to phosphorylated epitopes bound tau in both DPSCs and AD NFTs, thus suggesting that their function was not influenced by inducers of formation of NFTs in the AD brain. In contrast, AT100, which recognizes a hyperphosphorylated epitope, did not detect it in the cytoplasm of DPSCs but detected it in AD brain NFTs, demonstrating its AD diagnostic potential. This indicated that the phosphorylation/conformational events required for the creation of this epitope do not occur in normal cytoplasm and are a part of the mechanism (s) leading to NFT in AD brain. TG3 bound tau in the cytoplasm and in mitotic chromosomes but did not find it in nuclei. Collectively, these observations characterize DPSCs as a novel tau-harboring neuronal lineage long-term propagable in vitro cellular system for the normal conformational state of tau sites, detectable by antibodies, with their state in AD NFTs revealing those involved in the pathological processes converting tau into NFTs in the course of AD. With this information, one can model the interaction of tau with inducers and inhibitors of hyperphosphorylation toward NFT-like aggregates to search for drug candidates. Additionally, the clonogenicity of DPSCs provides the option for generation of cell lineages with CRISPR-mutagenized genes of familial AD modeling.
Collapse
Affiliation(s)
- Karlen Gazarian
- Laboratorio de Reprogramación Celular, Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
| | - Luis Ramirez-Garcia
- Laboratorio de Reprogramación Celular, Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
| | - Luis Tapía Orozco
- Laboratorio de Reprogramación Celular, Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
| | - José Luna-Muñoz
- National Dementia BioBank, Ciencias Biológicas, Facultad de Estudios Superiores, Cuautitlán, Universidad Nacional Autónoma de México (UNAM), Cuautitlán Izcalli, Mexico.,Banco Nacional de Cerebros-UNPHU, Universidad Nacional Pedro Henríquez Ureña, Santo Domingo, Dominican Republic
| | - Mar Pacheco-Herrero
- Neuroscience Research Laboratory, Faculty of Health Sciences, Pontificia Universidad Católica Madre y Maestra, Santiago De Los Caballeros, Dominican Republic
| |
Collapse
|
|
29
|
Analyzing the effect of APOE on Alzheimer's disease progression using an event-based model for stratified populations. Neuroimage 2020; 227:117646. [PMID: 33338617 DOI: 10.1016/j.neuroimage.2020.117646] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/12/2020] [Accepted: 12/10/2020] [Indexed: 02/08/2023] Open
Abstract
Alzheimer's disease (AD) is the most common form of dementia and is phenotypically heterogeneous. APOE is a triallelic gene which correlates with phenotypic heterogeneity in AD. In this work, we determined the effect of APOE alleles on the disease progression timeline of AD using a discriminative event-based model (DEBM). Since DEBM is a data-driven model, stratification into smaller disease subgroups would lead to more inaccurate models as compared to fitting the model on the entire dataset. Hence our secondary aim is to propose and evaluate novel approaches in which we split the different steps of DEBM into group-aspecific and group-specific parts, where the entire dataset is used to train the group-aspecific parts and only the data from a specific group is used to train the group-specific parts of the DEBM. We performed simulation experiments to benchmark the accuracy of the proposed approaches and to select the optimal approach. Subsequently, the chosen approach was applied to the baseline data of 417 cognitively normal, 235 mild cognitively impaired who convert to AD within 3 years, and 342 AD patients from the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset to gain new insights into the effect of APOE carriership on the disease progression timeline of AD. In the ε4 carrier group, the model predicted with high confidence that CSF Amyloidβ42 and the cognitive score of Alzheimer's Disease Assessment Scale (ADAS) are early biomarkers. Hippocampus was the earliest volumetric biomarker to become abnormal, closely followed by the CSF Phosphorylated Tau181 (PTAU) biomarker. In the homozygous ε3 carrier group, the model predicted a similar ordering among CSF biomarkers. However, the volume of the fusiform gyrus was identified as one of the earliest volumetric biomarker. While the findings in the ε4 carrier and the homozygous ε3 carrier groups fit the current understanding of progression of AD, the finding in the ε2 carrier group did not. The model predicted, with relatively low confidence, CSF Neurogranin as one of the earliest biomarkers along with cognitive score of Mini-Mental State Examination (MMSE). Amyloid β42 was found to become abnormal after PTAU. The presented models could aid understanding of the disease, and in selecting homogeneous group of presymptomatic subjects at-risk of developing symptoms for clinical trials.
Collapse
|
|
30
|
Guo X, Liu Y, Morgan D, Zhao LR. Reparative Effects of Stem Cell Factor and Granulocyte Colony-Stimulating Factor in Aged APP/PS1 Mice. Aging Dis 2020; 11:1423-1443. [PMID: 33269098 PMCID: PMC7673847 DOI: 10.14336/ad.2020.0201] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 02/01/2020] [Indexed: 01/06/2023] Open
Abstract
Alzheimer's disease (AD), characterized by the accumulation of β-amyloid (Aβ) plaques and tau neurofibrillary tangles in the brain, neuroinflammation and neurodegeneration, is the most common form of neurodegenerative disease among the elderly. No effective treatment is available now in restricting the pathological progression of AD. The aim of this study is to determine the therapeutic efficacy of stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) in aged APPswe/PS1dE9 (APP/PS1) mice. SCF+G-CSF was subcutaneously injected for 12 days to 25-month-old male APP/PS1 mice. We observed that SCF+G-CSF treatment reduced the Aβ plaques in both the cortex and hippocampus. SCF+G-CSF treatment increased the association of TREM2+/Iba1+ cells with Aβ plaques and enhanced Aβ uptake by Iba1+ and CD68+cells in the brains of aged APP/PS1 mice. Importantly, cerebral expression area of P2RY12+and TMEM119+ homeostatic microglia and the branches of P2RY12+ homeostatic microglia were increased in the SCF+G-CSF-treated aged APP/PS1 mice. SCF+G-CSF treatment also decreased NOS-2 and increased IL-4 in the brains of aged APP/PS1 mice. Moreover, the loss of MAP2+dendrites and PSD-95+post-synapses and the accumulation of aggregated tau in the brains of aged APP/PS1 mice were ameliorated by SCF+G-CSF treatment. Furthermore, the density of P2RY12+ microglia was negatively correlated with Aβ deposits, but positively correlated with the densities of MAP2+ dendrites and PSD-95+ puncta in the brains of aged APP/PS1 mice. These findings reveal the therapeutic potential of SCF+G-CSF treatment in ameliorating AD pathology at the late stage.
Collapse
Affiliation(s)
- Xingzhi Guo
- Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York, 13210, USA
| | - Yanying Liu
- Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York, 13210, USA
| | - David Morgan
- Translational Neuroscience, Michigan State University, College of Human Medicine, Grand Rapids, Michigan, 49503, USA
| | - Li-Ru Zhao
- Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, New York, 13210, USA
| |
Collapse
|
|
31
|
Siano G, Varisco M, Scarlatti A, Caiazza MC, Dunville K, Cremisi F, Costa M, Pancrazi L, Di Primio C, Cattaneo A. Gene Expression of Disease-related Genes in Alzheimer's Disease is Impaired by Tau Aggregation. J Mol Biol 2020; 432:166675. [PMID: 33058882 DOI: 10.1016/j.jmb.2020.10.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 09/24/2020] [Accepted: 10/07/2020] [Indexed: 12/19/2022]
Abstract
Neuronal hyperexcitability linked to an increase in glutamate signalling is a peculiar trait of the early stages of Alzheimer's disease (AD) and tauopathies, however, a progressive reduction in glutamate release follows in advanced stages. We recently reported that in the early phases of the neurodegenerative process, soluble, non-aggregated Tau accumulates in the nucleus and modulates the expression of disease-relevant genes directly involved in glutamatergic transmission, thus establishing a link between Tau instability and altered neurotransmission. Here we report that while the nuclear translocation of Tau in cultured cells is not impaired by its own aggregation, the nuclear amyloid inclusions of aggregated Tau abolish Tau-dependent increased expression of the glutamate transporter. Remarkably, we observed that in the prefrontal cortex (PFC) of AD patient brain, the glutamate transporter is upregulated at early stages and is downregulated at late stages. The Gene Set Enrichment Analysis indicates that the modulation of Tau-dependent gene expression along the disease progression can be extended to all protein pathways of the glutamatergic synapse. Together, this evidence links the altered glutamatergic function in the PFC during AD progression to the newly discovered function of nuclear Tau.
Collapse
Affiliation(s)
- G Siano
- Laboratorio di Biologia BIO@SNS, Scuola Normale Superiore, Pisa, Italy
| | - M Varisco
- Laboratorio di Biologia BIO@SNS, Scuola Normale Superiore, Pisa, Italy
| | - A Scarlatti
- Laboratorio di Biologia BIO@SNS, Scuola Normale Superiore, Pisa, Italy
| | - M C Caiazza
- Laboratorio di Biologia BIO@SNS, Scuola Normale Superiore, Pisa, Italy
| | - K Dunville
- Laboratorio di Biologia BIO@SNS, Scuola Normale Superiore, Pisa, Italy
| | - F Cremisi
- Laboratorio di Biologia BIO@SNS, Scuola Normale Superiore, Pisa, Italy
| | - M Costa
- Istituto di Neuroscienze, CNR, Pisa, Italy
| | - L Pancrazi
- Istituto di Neuroscienze, CNR, Pisa, Italy
| | - C Di Primio
- Laboratorio di Biologia BIO@SNS, Scuola Normale Superiore, Pisa, Italy; Istituto di Neuroscienze, CNR, Pisa, Italy.
| | - A Cattaneo
- Laboratorio di Biologia BIO@SNS, Scuola Normale Superiore, Pisa, Italy.
| |
Collapse
|
|
32
|
Ng PY, Chang IS, Koh RY, Chye SM. Recent advances in tau-directed immunotherapy against Alzheimer's disease: an overview of pre-clinical and clinical development. Metab Brain Dis 2020; 35:1049-1066. [PMID: 32632666 DOI: 10.1007/s11011-020-00591-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 06/23/2020] [Indexed: 02/01/2023]
Abstract
Alzheimer's disease (AD) has been a worldwide concern for many years now. This is due to the fact that AD is an irreversible and progressive neurodegenerative disease that affects quality of life. Failure of some Phase II/III clinical trials in AD targeting accumulation of β-amyloid in the brain has led to an increase in interest in studying alternative treatments against tubulin-associated unit (Tau) pathology. These alternative treatments include active and passive immunisation. Based on numerous studies, Tau is reported as a potential immunotherapeutic target for tauopathy-related diseases including AD. Accumulation and aggregation of hyperphosphorylated Tau as neuropil threads and neurofibrillary tangles (NFT) are pathological hallmarks of AD. Both active and passive immunisation targeting Tau protein have shown the capabilities to decrease or prevent Tau pathology and improve either motor or cognitive impairment in various animal models. In this review, we summarise recent advances in active and passive immunisation targeting pathological Tau protein, and will discuss with data obtained from both animal and human trials. Together, we give a brief overview about problems being encountered in these immunotherapies.
Collapse
Affiliation(s)
- Pei Ying Ng
- School of Postgraduate, International Medical University, 57000, Kuala Lumpur, Malaysia
| | - I Shuen Chang
- School of Health Science, Division of Biomedical Science and Biotechnology, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Rhun Yian Koh
- School of Health Science, Division of Biomedical Science and Biotechnology, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Soi Moi Chye
- School of Health Science, Division of Biomedical Science and Biotechnology, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.
| |
Collapse
|
|
33
|
Liu XY, Yang LP, Zhao L. Stem cell therapy for Alzheimer's disease. World J Stem Cells 2020; 12:787-802. [PMID: 32952859 PMCID: PMC7477654 DOI: 10.4252/wjsc.v12.i8.787] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/10/2020] [Accepted: 07/26/2020] [Indexed: 02/07/2023] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and cognitive impairment. It is caused by synaptic failure and excessive accumulation of misfolded proteins. To date, almost all advanced clinical trials on specific AD-related pathways have failed mostly due to a large number of neurons lost in the brain of patients with AD. Also, currently available drug candidates intervene too late. Stem cells have improved characteristics of self-renewal, proliferation, differentiation, and recombination with the advent of stem cell technology and the transformation of these cells into different types of central nervous system neurons and glial cells. Stem cell treatment has been successful in AD animal models. Recent preclinical studies on stem cell therapy for AD have proved to be promising. Cell replacement therapies, such as human embryonic stem cells or induced pluripotent stem cell-derived neural cells, have the potential to treat patients with AD, and human clinical trials are ongoing in this regard. However, many steps still need to be taken before stem cell therapy becomes a clinically feasible treatment for human AD and related diseases. This paper reviews the pathophysiology of AD and the application prospects of related stem cells based on cell type.
Collapse
Affiliation(s)
- Xin-Yu Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
| | - Lin-Po Yang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
| | - Lan Zhao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- Tianjin Key Laboratory of Acupuncture and Moxibustion, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China.
| |
Collapse
|
|
34
|
Green TRF, Ortiz JB, Wonnacott S, Williams RJ, Rowe RK. The Bidirectional Relationship Between Sleep and Inflammation Links Traumatic Brain Injury and Alzheimer's Disease. Front Neurosci 2020; 14:894. [PMID: 32982677 PMCID: PMC7479838 DOI: 10.3389/fnins.2020.00894] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 07/31/2020] [Indexed: 12/18/2022] Open
Abstract
Traumatic brain injury (TBI) and Alzheimer's disease (AD) are diseases during which the fine-tuned autoregulation of the brain is lost. Despite the stark contrast in their causal mechanisms, both TBI and AD are conditions which elicit a neuroinflammatory response that is coupled with physical, cognitive, and affective symptoms. One commonly reported symptom in both TBI and AD patients is disturbed sleep. Sleep is regulated by circadian and homeostatic processes such that pathological inflammation may disrupt the chemical signaling required to maintain a healthy sleep profile. In this way, immune system activation can influence sleep physiology. Conversely, sleep disturbances can exacerbate symptoms or increase the risk of inflammatory/neurodegenerative diseases. Both TBI and AD are worsened by a chronic pro-inflammatory microenvironment which exacerbates symptoms and worsens clinical outcome. Herein, a positive feedback loop of chronic inflammation and sleep disturbances is initiated. In this review, the bidirectional relationship between sleep disturbances and inflammation is discussed, where chronic inflammation associated with TBI and AD can lead to sleep disturbances and exacerbated neuropathology. The role of microglia and cytokines in sleep disturbances associated with these diseases is highlighted. The proposed sleep and inflammation-mediated link between TBI and AD presents an opportunity for a multifaceted approach to clinical intervention.
Collapse
Affiliation(s)
- Tabitha R. F. Green
- BARROW Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ, United States
- Department of Child Health, University of Arizona College of Medicine – Phoenix, Phoenix, AZ, United States
| | - J. Bryce Ortiz
- BARROW Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ, United States
- Department of Child Health, University of Arizona College of Medicine – Phoenix, Phoenix, AZ, United States
| | - Sue Wonnacott
- Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
| | - Robert J. Williams
- Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
| | - Rachel K. Rowe
- BARROW Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ, United States
- Department of Child Health, University of Arizona College of Medicine – Phoenix, Phoenix, AZ, United States
- Phoenix Veteran Affairs Health Care System, Phoenix, AZ, United States
| |
Collapse
|
|
35
|
Camporesi E, Nilsson J, Brinkmalm A, Becker B, Ashton NJ, Blennow K, Zetterberg H. Fluid Biomarkers for Synaptic Dysfunction and Loss. Biomark Insights 2020; 15:1177271920950319. [PMID: 32913390 PMCID: PMC7444114 DOI: 10.1177/1177271920950319] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 07/13/2020] [Indexed: 12/11/2022] Open
Abstract
Synapses are the site for brain communication where information is transmitted between neurons and stored for memory formation. Synaptic degeneration is a global and early pathogenic event in neurodegenerative disorders with reduced levels of pre- and postsynaptic proteins being recognized as a core feature of Alzheimer's disease (AD) pathophysiology. Together with AD, other neurodegenerative and neurodevelopmental disorders show altered synaptic homeostasis as an important pathogenic event, and due to that, they are commonly referred to as synaptopathies. The exact mechanisms of synapse dysfunction in the different diseases are not well understood and their study would help understanding the pathogenic role of synaptic degeneration, as well as differences and commonalities among them and highlight candidate synaptic biomarkers for specific disorders. The assessment of synaptic proteins in cerebrospinal fluid (CSF), which can reflect synaptic dysfunction in patients with cognitive disorders, is a keen area of interest. Substantial research efforts are now directed toward the investigation of CSF synaptic pathology to improve the diagnosis of neurodegenerative disorders at an early stage as well as to monitor clinical progression. In this review, we will first summarize the pathological events that lead to synapse loss and then discuss the available data on established (eg, neurogranin, SNAP-25, synaptotagmin-1, GAP-43, and α-syn) and emerging (eg, synaptic vesicle glycoprotein 2A and neuronal pentraxins) CSF biomarkers for synapse dysfunction, while highlighting possible utilities, disease specificity, and technical challenges for their detection.
Collapse
Affiliation(s)
- Elena Camporesi
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Johanna Nilsson
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ann Brinkmalm
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Bruno Becker
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
| | - Nicholas J Ashton
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- King’s College London, Institute of Psychiatry, Psychology & Neuroscience, The Maurice Wohl Clinical Neuroscience Institute, London, UK
- NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK
- Wallenberg Centre for Molecular and Translational Medicine, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Kaj Blennow
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
| | - Henrik Zetterberg
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
- UK Dementia Research Institute at UCL, London, UK
| |
Collapse
|
|
36
|
Lo Cascio F, Garcia S, Montalbano M, Puangmalai N, McAllen S, Pace A, Palumbo Piccionello A, Kayed R. Modulating disease-relevant tau oligomeric strains by small molecules. J Biol Chem 2020; 295:14807-14825. [PMID: 32737202 PMCID: PMC7606668 DOI: 10.1074/jbc.ra120.014630] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/23/2020] [Indexed: 12/12/2022] Open
Abstract
The pathological aggregation of tau plays an important role in Alzheimer's disease and many other related neurodegenerative diseases, collectively referred to as tauopathies. Recent evidence has demonstrated that tau oligomers, small and soluble prefibrillar aggregates, are highly toxic due to their strong ability to seed tau misfolding and propagate the pathology seen across different neurodegenerative diseases. We previously showed that novel curcumin derivatives affect preformed tau oligomer aggregation pathways by promoting the formation of more aggregated and nontoxic tau aggregates. To further investigate their therapeutic potential, we have extended our studies o disease-relevant brain-derived tau oligomers (BDTOs). Herein, using well-characterized BDTOs, isolated from brain tissues of different tauopathies, including Alzheimer's disease, progressive supranuclear palsy, and dementia with Lewy bodies, we found that curcumin derivatives modulate the aggregation state of BDTOs by reshaping them and rescue neurons from BDTO-associated toxicity. Interestingly, compound CL3 showed an effect on the aggregation pattern of BDTOs from different tauopathies, resulting in the formation of less neurotoxic larger tau aggregates with decreased hydrophobicity and seeding propensity. Our results lay the groundwork for potential investigations of the efficacy and beneficial effects of CL3 and other promising compounds for the treatment of tauopathies. Furthermore, CL3 may aid in the development of tau imaging agent for the detection of tau oligomeric strains and differential diagnosis of the tauopathies, thus enabling earlier interventions.
Collapse
Affiliation(s)
- Filippa Lo Cascio
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas, USA; Departments of Neurology, Neuroscience, and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Stephanie Garcia
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas, USA; Departments of Neurology, Neuroscience, and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Mauro Montalbano
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas, USA; Departments of Neurology, Neuroscience, and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Nicha Puangmalai
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas, USA; Departments of Neurology, Neuroscience, and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Salome McAllen
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas, USA; Departments of Neurology, Neuroscience, and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Andrea Pace
- Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies-STEBICEF, University of Palermo, Palermo, Italy
| | - Antonio Palumbo Piccionello
- Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies-STEBICEF, University of Palermo, Palermo, Italy
| | - Rakez Kayed
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas, USA; Departments of Neurology, Neuroscience, and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA.
| |
Collapse
|
|
37
|
Sinsky J, Majerova P, Kovac A, Kotlyar M, Jurisica I, Hanes J. Physiological Tau Interactome in Brain and Its Link to Tauopathies. J Proteome Res 2020; 19:2429-2442. [PMID: 32357304 DOI: 10.1021/acs.jproteome.0c00137] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Alzheimer's disease (AD) and most of the other tauopathies are incurable neurodegenerative diseases with unpleasant symptoms and consequences. The common hallmark of all of these diseases is tau pathology, but its connection with disease progress has not been completely understood so far. Therefore, uncovering novel tau-interacting partners and pathology affected molecular pathways can reveal the causes of diseases as well as potential targets for the development of AD treatment. Despite the large number of known tau-interacting partners, a limited number of studies focused on in vivo tau interactions in disease or healthy conditions are available. Here, we applied an in vivo cross-linking approach, capable of capturing weak and transient protein-protein interactions, to a unique transgenic rat model of progressive tau pathology similar to human AD. We have identified 175 potential novel and known tau-interacting proteins by MALDI-TOF mass spectrometry. Several of the most promising candidates for possible drug development were selected for validation by coimmunoprecipitation and colocalization experiments in animal and cellular models. Three proteins, Baiap2, Gpr37l1, and Nptx1, were confirmed as novel tau-interacting partners, and on the basis of their known functions and implications in neurodegenerative or psychiatric disorders, we proposed their potential role in tau pathology.
Collapse
Affiliation(s)
- Jakub Sinsky
- Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 84510, Slovakia
| | - Petra Majerova
- Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 84510, Slovakia.,AXON Neuroscience R&D Services SE, Dvorakovo nabrezie 10, Bratislava 811 02, Slovakia
| | - Andrej Kovac
- Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 84510, Slovakia.,AXON Neuroscience R&D Services SE, Dvorakovo nabrezie 10, Bratislava 811 02, Slovakia
| | - Max Kotlyar
- Krembil Research Institute, UHN, 60 Leonard Avenue, Toronto, Ontario M5T 0S8, Canada
| | - Igor Jurisica
- Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 84510, Slovakia.,Krembil Research Institute, UHN, 60 Leonard Avenue, Toronto, Ontario M5T 0S8, Canada.,Departments of Medical Biophysics and Computer Science, University of Toronto, 27 King's College Circle, Toronto, Ontario ON M5S, Canada
| | - Jozef Hanes
- Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava 84510, Slovakia.,AXON Neuroscience R&D Services SE, Dvorakovo nabrezie 10, Bratislava 811 02, Slovakia
| |
Collapse
|
|
38
|
Abstract
The microtubule-associated protein tau has been identified in several intraneuronal compartments, including in association with synapses. In Alzheimer's disease, frontotemporal dementia and related tauopathies, highly phosphorylated tau accumulates as intraneuronal protein aggregates that are likely responsible for the demise of neurons and the subsequent progressive cognitive decline. However, the molecular mechanisms underlying such tau-mediated damage in the tauopathies is not fully understood. Tauopathy induces loss of synapses, which is one of the earliest structural correlates of cognitive dysfunction and disease progression. Notably, altered post-translational modifications of tau, including increased phosphorylation and acetylation, augment the mislocalisation of tau to synapses, impair synaptic vesicle release and might influence the activity-dependent release of tau from neurons. Thus, disease-associated accumulation of modified tau at the synapse adversely affects critical neuronal processes that are linked to neuronal activity and synaptic function. These findings emphasise the importance of gaining a comprehensive understanding of the diverse roles of tau at distinct intraneuronal locations. An improved knowledge of the impact of synaptic tau under physiological and pathological conditions and how tau localisation impacts on neuronal function will provide valuable insights that may lead to the development of new therapies for the tauopathies.
Collapse
|
|
39
|
Zhang R, Zheng Y, Hu F, Meng X, Lv B, Lao K, Gao X, Zhang X, Gou X. Effect of (m)VD-hemopressin against Aβ1-42-induced oxidative stress and apoptosis in mouse hippocampal neurons. Peptides 2020; 124:170185. [PMID: 31730791 DOI: 10.1016/j.peptides.2019.170185] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 10/23/2019] [Accepted: 10/29/2019] [Indexed: 12/13/2022]
Abstract
Alzheimer's disease (AD) is a serious neurodegenerative disease. Senile plaques (SPs) composed of amyloid-β (Aβ) are typical features of AD. Aβ plays a key role in the disease and has the ability to induce other pathological characteristics of AD, including oxidative stress injury. (m)VD-hemopressin (VD), a peptide derived from mouse brain extracts, can bind cannabinoid 1 receptor (CB1R) as an agonist. Our previous report indicated that VD reverses memory impairment induced by Aβ1-42 in mice. This study aimed to clarify the mechanism by which VD protects hippocampal neurons against Aβ1-42-induced impairment. Our results showed that VD inhibited oxidative stress injury induced by Aβ1-42, as demonstrated by the VD-induced reversal of the upregulation of reactive oxygen species (ROS) and the intracellular lipid peroxidation product malondialdehyde (MDA) and the downregulation of the activities of the antioxidative enzymes catalase (CAT) and glutathione peroxidase (GSH-PX) in mouse hippocampal neurons. We also found that VD restored the decrease in cell growth and viability induced by Aβ1-42 and reversed Aβ1-42-induced apoptosis mediated by the apoptosis-associated proteins Bcl-2 and Bax. However, cotreatment with AM251 (an antagonist of CB1R) blocked the effects of VD. In brief, this study suggested that through CB1R, VD reversed the impairment of cell growth and viability, oxidative stress injury and apoptosis induced by Aβ1-42. Therefore, VD may be a promising agent for the treatment of diseases that involve oxidative stress injury and apoptosis induced by Aβ1-42, such as AD.
Collapse
Affiliation(s)
- Ruisan Zhang
- Shaanxi Key Laboratory of Brain Disorders, School of Basic Medical Science, Institute of Basic Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Xi'an Medical University, Xi'an, 710021, China
| | - Yongcai Zheng
- Shaanxi Key Laboratory of Brain Disorders, School of Basic Medical Science, Institute of Basic Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Xi'an Medical University, Xi'an, 710021, China
| | - Fengrui Hu
- Shaanxi Key Laboratory of Brain Disorders, School of Basic Medical Science, Institute of Basic Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Xi'an Medical University, Xi'an, 710021, China
| | - Xin Meng
- Shaanxi Key Laboratory of Brain Disorders, School of Basic Medical Science, Institute of Basic Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Xi'an Medical University, Xi'an, 710021, China
| | - Bosen Lv
- Shaanxi Key Laboratory of Brain Disorders, School of Basic Medical Science, Institute of Basic Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Xi'an Medical University, Xi'an, 710021, China
| | - Kejing Lao
- Shaanxi Key Laboratory of Brain Disorders, School of Basic Medical Science, Institute of Basic Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Xi'an Medical University, Xi'an, 710021, China
| | - Xingchun Gao
- Shaanxi Key Laboratory of Brain Disorders, School of Basic Medical Science, Institute of Basic Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Xi'an Medical University, Xi'an, 710021, China
| | - Xiaohua Zhang
- Shaanxi Key Laboratory of Brain Disorders, School of Basic Medical Science, Institute of Basic Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Xi'an Medical University, Xi'an, 710021, China
| | - Xingchun Gou
- Shaanxi Key Laboratory of Brain Disorders, School of Basic Medical Science, Institute of Basic Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Xi'an Medical University, Xi'an, 710021, China.
| |
Collapse
|
|
40
|
Mao Y, Fisher DW, Yang S, Keszycki RM, Dong H. Protein-protein interactions underlying the behavioral and psychological symptoms of dementia (BPSD) and Alzheimer's disease. PLoS One 2020; 15:e0226021. [PMID: 31951614 PMCID: PMC6968845 DOI: 10.1371/journal.pone.0226021] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Accepted: 11/19/2019] [Indexed: 12/25/2022] Open
Abstract
Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder currently affecting 45 million people worldwide, ranking as the 6th highest cause of death. Throughout the development and progression of AD, over 90% of patients display behavioral and psychological symptoms of dementia (BPSD), with some of these symptoms occurring before memory deficits and therefore serving as potential early predictors of AD-related cognitive decline. However, the biochemical links between AD and BPSD are not known. In this study, we explored the molecular interactions between AD and BPSD using protein-protein interaction (PPI) networks built from OMIM (Online Mendelian Inheritance in Man) genes that were related to AD and two distinct BPSD domains, the Affective Domain and the Hyperactivity, Impulsivity, Disinhibition, and Aggression (HIDA) Domain. Our results yielded 8 unique proteins for the Affective Domain (RHOA, GRB2, PIK3R1, HSPA4, HSP90AA1, GSK3beta, PRKCZ, and FYN), 5 unique proteins for the HIDA Domain (LRP1, EGFR, YWHAB, SUMO1, and EGR1), and 6 shared proteins between both BPSD domains (APP, UBC, ELAV1, YWHAZ, YWHAE, and SRC) and AD. These proteins might suggest specific targets and pathways that are involved in the pathogenesis of these BPSD domains in AD.
Collapse
Affiliation(s)
- Yimin Mao
- School of Information and Technology, Jiangxi University of Science and Technology, Jiangxi, China
- Applied Science Institute, Jiangxi University of Science and Technology, Jiangxi, China
| | - Daniel W. Fisher
- Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Shuxing Yang
- School of Information and Technology, Jiangxi University of Science and Technology, Jiangxi, China
| | - Rachel M. Keszycki
- Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Hongxin Dong
- Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
- * E-mail:
| |
Collapse
|
|
41
|
Gao Y, Yan Y, Fang Q, Zhang N, Kumar G, Zhang J, Song LJ, Yu J, Zhao L, Zhang HT, Ma CG. The Rho kinase inhibitor fasudil attenuates Aβ 1-42-induced apoptosis via the ASK1/JNK signal pathway in primary cultures of hippocampal neurons. Metab Brain Dis 2019; 34:1787-1801. [PMID: 31482248 DOI: 10.1007/s11011-019-00487-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 08/27/2019] [Indexed: 12/13/2022]
Abstract
Alzheimer's disease (AD), a chronic, progressive, neurodegenerative disorder, is the most common type of dementia. Beta amyloid (Aβ) peptide aggregation and phosphorylated tau protein accumulation are considered as one of the causes for AD. Our previous studies have demonstrated the neuroprotective effect of the Rho kinase inhibitor fasudil, but the mechanism remains elucidated. In the present study, we examined the effects of fasudil on Aβ1-42 aggregation and apoptosis and identified the intracellular signaling pathways involved in these actions in primary cultures of mouse hippocampal neurons. The results showed that fasudil increased neurite outgrowth (52.84%), decreased Aβ burden (46.65%), Tau phosphorylation (96.84%), and ROCK-II expression. In addition, fasudil reversed Aβ1-42-induced decreased expression of Bcl-2 and increases in caspase-3, cleaved-PARP, phospho-JNK(Thr183/Tyr185), and phospho-ASK1(Ser966). Further, fasudil decreased mitochondrial membrane potential and intracellular calcium overload in the neurons treated with Aβ1-42. These results suggest that inhibition of Rho kinase by fasudil reverses Aβ1-42-induced neuronal apoptosis via the ASK1/JNK signal pathway, calcium ions, and mitochondrial membrane potential. Fasudil could be a drug of choice for treatment of Alzheimer's disease.
Collapse
Affiliation(s)
- Ye Gao
- Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Medical School of Shanxi Datong University, Datong, China
| | - Yuqing Yan
- Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Medical School of Shanxi Datong University, Datong, China.
| | - Qingli Fang
- Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Medical School of Shanxi Datong University, Datong, China
| | - Nianping Zhang
- Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Medical School of Shanxi Datong University, Datong, China
| | - Gajendra Kumar
- Department of Biomedical Sciences, City University of Hong Kong, Tat Chee Avenue, Hong Kong
- Bio-Signal technologies (HK) Limited, 9th Floor, Amtel Building,148 Des Voeux Road Central, Central, Hong Kong
| | - Jihong Zhang
- Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Medical School of Shanxi Datong University, Datong, China
| | - Li-Juan Song
- The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine/Research Center of Neurobiology, Shanxi University of Chinese Medicine, Taiyuan, China
| | - Jiezhong Yu
- Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Medical School of Shanxi Datong University, Datong, China
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Linhu Zhao
- Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Medical School of Shanxi Datong University, Datong, China
| | - Han-Ting Zhang
- Departments of Neuroscience and Behavioral Medicine & Psychiatry, the Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, 26506, USA.
| | - Cun-Gen Ma
- Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Medical School of Shanxi Datong University, Datong, China.
- The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine/Research Center of Neurobiology, Shanxi University of Chinese Medicine, Taiyuan, China.
| |
Collapse
|
|
42
|
Kobayashi S, Tanaka T, Soeda Y, Takashima A. Enhanced Tau Protein Translation by Hyper-Excitation. Front Aging Neurosci 2019; 11:322. [PMID: 31824301 PMCID: PMC6879554 DOI: 10.3389/fnagi.2019.00322] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 11/05/2019] [Indexed: 12/04/2022] Open
Abstract
Tau is a microtubule-associated protein, localizing mainly in the axon of mature neurons. Phenotypic analysis of Tau knockout mice has revealed an impairment of synaptic plasticity but without gross changes in brain morphology. Since we previously described the presence of tau mRNA in the somatodendritic compartment, including the postsynapse, and demonstrated that it could be locally translated in response to glutamate, it appears that the regulated translation of synaptic tau can have a direct impact on synaptic function. Using SH-SY5Y cells, we herein confirm that glutamate dose-dependently regulates the translation of tau protein without altering tau mRNA levels. This is supported by the finding that cycloheximide blocks glutamate-stimulated increases in tau protein levels. Our observation that neural excitation can directly upregulate tau mRNA translation helps explain the pathological accumulation of tau in the somatodendrite.
Collapse
Affiliation(s)
- Shunsuke Kobayashi
- Department of Biochemistry, School of Pharmacy, Nihon University, Funabashi, Japan
| | - Toru Tanaka
- Department of Biochemistry, School of Pharmacy, Nihon University, Funabashi, Japan
| | - Yoshiyuki Soeda
- Laboratory for Alzheimer's Disease, Department of Life Science, Faculty of Science, Gakushuin University, Tokyo, Japan
| | - Akihiko Takashima
- Laboratory for Alzheimer's Disease, Department of Life Science, Faculty of Science, Gakushuin University, Tokyo, Japan
| |
Collapse
|
|
43
|
Li Y, Ding R, Ren X, Wen G, Dong Z, Yao H, Tan Y, Yu H, Wang X, Zhan X, Yao J, Lu Y, Zhang G, Wu X. Long-term ketamine administration causes Tau protein phosphorylation and Tau protein-dependent AMPA receptor reduction in the hippocampus of mice. Toxicol Lett 2019; 315:107-115. [PMID: 31470060 DOI: 10.1016/j.toxlet.2019.08.023] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 07/19/2019] [Accepted: 08/25/2019] [Indexed: 12/13/2022]
Abstract
As a recreational drug of abuse and an injectable anesthetic, ketamine has been shown to cause cognitive dysfunction and induce psychotic states. Although the specific mechanism is still unclear, it may be linked to synaptic receptors, including the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor. Recent evidence suggests that Tau protein phosphorylation and targeted delivery to the postsynaptic area is involved in maintaining neuronal plasticity, indicating that the neurotoxicity induced by ketamine may be related to the transfer of Tau protein after phosphorylation. In this study, we established a model of long-term (6 months) ketamine administration in wild-type (C57BL/6) and Tau knockout mice to investigate the effects of different doses of ketamine administration on Tau protein expression and phosphorylation in the mouse hippocampus. We also investigated changes in AMPA receptor expression in the synaptic membrane of wild-type and Tau knockout mice. Our results showed that long-term ketamine administration led to excessive Tau protein phosphorylation at Ser202/Thr205 and Ser396, but not at Ser199, Ser262 and Ser404. Most importantly, long-term ketamine administration decreased AMPA receptor levels in the hippocampal cell membrane in a Tau protein-dependent manner. Our results reveal the role of Tau protein phosphorylation in the mechanism of ketamine neurotoxicity, suggesting that the changes of membrane AMPA receptor and synaptic function induced by ketamine are mediated by abnormal phosphorylation of Tau protein at specific sites.
Collapse
Affiliation(s)
- Yanning Li
- School of Forensic Medicine, China Medical University, Shenyang 110122, PR China; Department of Forensic Medicine, School of Basic Medicine, Gannan Medical University, Ganzhou 341000, PR China
| | - Runtao Ding
- School of Forensic Medicine, China Medical University, Shenyang 110122, PR China
| | - Xinghua Ren
- School of Forensic Medicine, China Medical University, Shenyang 110122, PR China
| | - Gehua Wen
- School of Forensic Medicine, China Medical University, Shenyang 110122, PR China
| | - Zhibin Dong
- School of Forensic Medicine, China Medical University, Shenyang 110122, PR China
| | - Hui Yao
- School of Forensic Medicine, China Medical University, Shenyang 110122, PR China
| | - Yaqing Tan
- School of Forensic Medicine, China Medical University, Shenyang 110122, PR China
| | - Hao Yu
- School of Forensic Medicine, China Medical University, Shenyang 110122, PR China
| | - Xiaolong Wang
- School of Forensic Medicine, China Medical University, Shenyang 110122, PR China
| | - Xiaoni Zhan
- School of Forensic Medicine, China Medical University, Shenyang 110122, PR China
| | - Jun Yao
- School of Forensic Medicine, China Medical University, Shenyang 110122, PR China
| | - Yan Lu
- Key Laboratory of Health Ministry in Congenital Malformation, the Affiliated Shengjing Hospital of China Medical University, Shenyang 110004, PR China
| | - Guohua Zhang
- School of Forensic Medicine, China Medical University, Shenyang 110122, PR China.
| | - Xu Wu
- School of Forensic Medicine, China Medical University, Shenyang 110122, PR China.
| |
Collapse
|
|
44
|
Lee KY, Chang HC, Seah C, Lee LJ. Deprivation of Muscleblind-Like Proteins Causes Deficits in Cortical Neuron Distribution and Morphological Changes in Dendritic Spines and Postsynaptic Densities. Front Neuroanat 2019; 13:75. [PMID: 31417371 PMCID: PMC6682673 DOI: 10.3389/fnana.2019.00075] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 07/11/2019] [Indexed: 02/06/2023] Open
Abstract
Myotonic dystrophy (Dystrophia Myotonica; DM) is the most common adult-onset muscular dystrophy and its brain symptoms seriously affect patients’ quality of life. It is caused by extended (CTG)n expansions at 3′-UTR of DMPK gene (DM type 1, DM1) or (CCTG)n repeats in the intron 1 of CNBP gene (DM type 2, DM2) and the sequestration of Muscleblind-like (MBNL) family proteins by transcribed (CUG)n RNA hairpin is the main pathogenic mechanism for DM. The MBNL proteins are splicing factors regulating posttranscriptional RNA during development. Previously, Mbnl knockout (KO) mouse lines showed molecular and phenotypic evidence that recapitulate DM brains, however, detailed morphological study has not yet been accomplished. In our studies, control (Mbnl1+/+; Mbnl2cond/cond; Nestin-Cre−/−), Mbnl2 conditional KO (2KO, Mbnl1+/+; Mbnl2cond/cond; Nestin-Cre+/−) and Mbnl1/2 double KO (DKO, Mbnl1ΔE3/ΔE3; Mbnl2cond/cond; Nestin-Cre+/−) mice were generated by crossing three individual lines. Immunohistochemistry for evaluating density and distribution of cortical neurons; Golgi staining for depicting the dendrites/dendritic spines; and electron microscopy for analyzing postsynaptic ultrastructure were performed. We found distributional defects in cortical neurons, reduction in dendritic complexity, immature dendritic spines and alterations of postsynaptic densities (PSDs) in the mutants. In conclusion, loss of function of Mbnl1/2 caused fundamental defects affecting neuronal distribution, dendritic morphology and postsynaptic architectures that are reminiscent of predominantly immature and fetal phenotypes in DM patients.
Collapse
Affiliation(s)
- Kuang-Yung Lee
- Department of Neurology, Chang Gung Memorial Hospital, Keelung, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ho-Ching Chang
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Carol Seah
- Department of Neurology, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Li-Jen Lee
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.,Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.,Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan
| |
Collapse
|
|
45
|
Friel H. Biopharmaceutical Monotargeting versus 'Universal Targeting' of Late-Onset Alzheimer's Disease Using Mixtures of Pleiotropic Natural Compounds. J Alzheimers Dis Rep 2019; 3:219-232. [PMID: 31435619 PMCID: PMC6700529 DOI: 10.3233/adr-190127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
A five-year close reading of the scientific literature on late-onset Alzheimer’s disease (AD) has prompted the invention of a novel therapeutic method that biomechanistically targets the targetable disease-process targets of AD with one or another mixture of non-toxic pleiotropic natural compounds. The featured mixture herein is comprised of curcumin, resveratrol, and EGCG. The mixture’s targets include central pathological elements of AD (including amyloid, tau, synaptic dysfunction, oxidative stress, mitochondrial dysfunction, and aberrant neuroinflammation), modifiable risk factors, comorbidities, and epigenetic elements. The featured mixture and other such mixtures are suitable for long-term use, and may be applied to any stage of AD, including primary and secondary prevention. Such mixtures also would be amenable for use as pre-treatment, co-treatment, and post-treatment applications with certain biopharmaceutical agents. The targeting focus here is the major credible hypotheses of AD. The focus of future such articles will include other AD-related targets, modifiable risk factors and comorbidities, APOE4, epigenetic factors, bioavailability, dose response, and implications for clinical testing. The “universal targeting” method described herein—that is, “targeting the targetable targets” of AD using certain mixtures of natural compounds—is reprogrammable and thus is applicable to other chronic neurological conditions, including Parkinson’s disease, vascular dementia, ischemic-stroke prevention and recovery, and sports-related head injuries and sequelae leading to chronic traumatic encephalopathy.
Collapse
|
|
46
|
Vogels T, Murgoci AN, Hromádka T. Intersection of pathological tau and microglia at the synapse. Acta Neuropathol Commun 2019; 7:109. [PMID: 31277708 PMCID: PMC6612163 DOI: 10.1186/s40478-019-0754-y] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 06/19/2019] [Indexed: 02/07/2023] Open
Abstract
Tauopathies are a heterogenous class of diseases characterized by cellular accumulation of aggregated tau and include diseases such as Alzheimer’s disease (AD), progressive supranuclear palsy and chronic traumatic encephalopathy. Tau pathology is strongly linked to neurodegeneration and clinical symptoms in tauopathy patients. Furthermore, synapse loss is an early pathological event in tauopathies and is the strongest correlate of cognitive decline. Tau pathology is additionally associated with chronic neuroinflammatory processes, such as reactive microglia, astrocytes, and increased levels of pro-inflammatory molecules (e.g. complement proteins, cytokines). Recent studies show that as the principal immune cells of the brain, microglia play a particularly important role in the initiation and progression of tau pathology and associated neurodegeneration. Furthermore, AD risk genes such as Triggering receptor expressed on myeloid cells 2 (TREM2) and Apolipoprotein E (APOE) are enriched in the innate immune system and modulate the neuroinflammatory response of microglia to tau pathology. Microglia can play an active role in synaptic dysfunction by abnormally phagocytosing synaptic compartments of neurons with tau pathology. Furthermore, microglia are involved in synaptic spreading of tau – a process which is thought to underlie the progressive nature of tau pathology propagation through the brain. Spreading of pathological tau is also the predominant target for tau-based immunotherapy. Active tau vaccines, therapeutic tau antibodies and other approaches targeting the immune system are actively explored as treatment options for AD and other tauopathies. This review describes the role of microglia in the pathobiology of tauopathies and the mechanism of action of potential therapeutics targeting the immune system in tauopathies.
Collapse
|
|
47
|
Wan W, Cao L, Kalionis B, Murthi P, Xia S, Guan Y. Iron Deposition Leads to Hyperphosphorylation of Tau and Disruption of Insulin Signaling. Front Neurol 2019; 10:607. [PMID: 31275224 PMCID: PMC6593079 DOI: 10.3389/fneur.2019.00607] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 05/22/2019] [Indexed: 12/22/2022] Open
Abstract
Iron deposition in the brain is an early issue in Alzheimer's disease (AD). However, the pathogenesis of iron-induced pathological changes in AD remains elusive. Insulin resistance in brains is an essential feature of AD. Previous studies determined that insulin resistance is involved in the development of pathologies in AD. Tau pathology is one of most important hallmarks in AD and is associated with the impairment of cognition and clinical grades of the disease. In the present study, we observed that ferrous (Fe2+) chloride led to aberrant phosphorylation of tau, and decreased tyrosine phosphorylation levels of insulin receptor β (IRβ), insulin signal substrate 1 (IRS-1) and phosphoinositide 3-kinase p85α (PI3K p85α), in primary cultured neurons. In the in vivo studies using mice with supplemented dietary iron, learning and memory was impaired. As well, hyperphosphorylation of tau and disrupted insulin signaling in the brain was induced in iron-overloaded mice. Furthermore, in our in vitro work we identified the activation of insulin signaling following exogenous supplementation of insulin. This was further attenuated by iron-induced hyperphosphorylation of tau in primary neurons. Together, these data suggest that dysfunctional insulin signaling participates in iron-induced abnormal phosphorylation of tau in AD. Our study highlights the promising role of insulin signaling in pathological lesions induced by iron overloading.
Collapse
Affiliation(s)
- Wenbin Wan
- Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lan Cao
- State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Bill Kalionis
- Department of Maternal-Fetal Medicine, Pregnancy Research Centre, University of Melbourne, Parkville, VIC, Australia.,Department of Obstetrics and Gynecology, Royal Women's Hospital, Parkville, VIC, Australia
| | - Padma Murthi
- Department of Obstetrics and Gynecology, University of Melbourne, Parkville, VIC, Australia
| | - Shijin Xia
- Shanghai Institute of Geriatrics, Huadong Hospital, Fudan University, Shanghai, China
| | - Yangtai Guan
- Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
48
|
Shi Y, Fang YY, Wei YP, Jiang Q, Zeng P, Tang N, Lu Y, Tian Q. Melatonin in Synaptic Impairments of Alzheimer's Disease. J Alzheimers Dis 2019; 63:911-926. [PMID: 29710712 DOI: 10.3233/jad-171178] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Alzheimer's disease (AD) underlies dementia for millions of people worldwide with no effective treatment. The dementia of AD is thought stem from the impairments of the synapses because of their critical roles in cognition. Melatonin is a neurohormone mainly released by the pineal gland in a circadian manner and it regulates brain functions in various manners. It is reported that both the melatonin deficit and synaptic impairments are present in the very early stage of AD and strongly contribute to the progress of AD. In the mammalian brains, the effects of melatonin are mainly relayed by two of its receptors, melatonin receptor type 1a (MT1) and 1b (MT2). To have a clear idea on the roles of melatonin in synaptic impairments of AD, this review discussed the actions of melatonin and its receptors in the stabilization of synapses, modulation of long-term potentiation, as well as their contributions in the transmissions of glutamatergic, GABAergic and dopaminergic synapses, which are the three main types of synapses relevant to the synaptic strength. The synaptic protective roles of melatonin in AD treatment were also summarized. Regarding its protective roles against amyloid-β neurotoxicity, tau hyperphosphorylation, oxygenation, inflammation as well as synaptic dysfunctions, melatonin may be an ideal therapeutic agent against AD at early stage.
Collapse
Affiliation(s)
- Yan Shi
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, China
| | - Ying-Yan Fang
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, China
| | - Yu-Ping Wei
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Jiang
- Integrated TCM and Western Medicine Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Zeng
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, China
| | - Na Tang
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, China
| | - Youming Lu
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, China
| | - Qing Tian
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
49
|
Wegmann S, Bennett RE, Delorme L, Robbins AB, Hu M, McKenzie D, Kirk MJ, Schiantarelli J, Tunio N, Amaral AC, Fan Z, Nicholls S, Hudry E, Hyman BT. Experimental evidence for the age dependence of tau protein spread in the brain. SCIENCE ADVANCES 2019; 5:eaaw6404. [PMID: 31249873 PMCID: PMC6594764 DOI: 10.1126/sciadv.aaw6404] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 05/16/2019] [Indexed: 05/24/2023]
Abstract
The incidence of Alzheimer's disease (AD), which is characterized by progressive cognitive decline that correlates with the spread of tau protein aggregation in the cortical mantle, is strongly age-related. It could be that age predisposes the brain for tau misfolding and supports the propagation of tau pathology. We tested this hypothesis using an experimental setup that allowed for exploration of age-related factors of tau spread and regional vulnerability. We virally expressed human tau locally in entorhinal cortex (EC) neurons of young or old mice and monitored the cell-to-cell tau protein spread by immunolabeling. Old animals showed more tau spreading in the hippocampus and adjacent cortical areas and accumulated more misfolded tau in EC neurons. No misfolding, at any age, was observed in the striatum, a brain region mostly unaffected by tangles. Age and brain region dependent tau spreading and misfolding likely contribute to the profound age-related risk for sporadic AD.
Collapse
Affiliation(s)
- Susanne Wegmann
- German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Rachel E. Bennett
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Louis Delorme
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Ashley B. Robbins
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Miwei Hu
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Danny McKenzie
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Molly J. Kirk
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Nahel Tunio
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Ana C. Amaral
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Zhanyun Fan
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Samantha Nicholls
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Eloise Hudry
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Bradley T. Hyman
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
50
|
Saha P, Sen N. Tauopathy: A common mechanism for neurodegeneration and brain aging. Mech Ageing Dev 2019; 178:72-79. [PMID: 30668956 DOI: 10.1016/j.mad.2019.01.007] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 01/09/2019] [Accepted: 01/18/2019] [Indexed: 01/07/2023]
Abstract
Tau, a microtubule-associated protein promotes assembly and stability of microtubules which is related to axoplasmic flow and critical neuronal activities upon physiological conditions. Under neurodegenerative condition such as in Alzheimer's Disease (AD), tau-microtubule binding dynamics and equilibrium are severely affected due to its aberrant post-translational modifications including acetylation and hyperphosphorylation. This event results in its conformational changes to form neurofibrillary tangles (NFT) after aggregation in the cytosol. The formation of NFT is more strongly correlated with cognitive decline than the distribution of senile plaque, which is formed by polymorphous beta-amyloid (Aβ) protein deposits, another pathological hallmark of AD. In neurodegenerative conditions, other than AD, the disease manifestation is correlated with mutations of the MAPT gene. In Primary age-related tauopathy (PART), which is commonly observed in the brains of aged individuals, tau deposition is directly correlated with cognitive deficits even in the absence of Aβ deposition. Thus, tauopathy has been considered as an essential hallmark in neurodegeneration and normal brain aging. In this review, we highlighted the recent progress about the tauopathies in the light of its posttranslational modifications and its implication in AD and the aged brain.
Collapse
Affiliation(s)
- Pampa Saha
- Department of Neurological Surgery, University of Pittsburgh, 200 Lothrop Street, Scaife Hall, Pittsburgh, 15213, United States
| | - Nilkantha Sen
- Department of Neurological Surgery, University of Pittsburgh, 200 Lothrop Street, Scaife Hall, Pittsburgh, 15213, United States.
| |
Collapse
|