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1
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Liu J, Zhang Y, Zhang M, Wang Q, Pang Y, Xie J. 6‴-Feruloylspinosin alleviates Aβ-induced toxicity by modulating relevant neurotransmitter and the AMPK/mTOR signaling pathway. Free Radic Biol Med 2025; 227:434-445. [PMID: 39653128 DOI: 10.1016/j.freeradbiomed.2024.12.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 11/24/2024] [Accepted: 12/06/2024] [Indexed: 12/15/2024]
Abstract
Alzheimer's disease (AD) is a gradually progressive neurodegenerative disease with a serious impact on patients' quality of life. However, single-targeted therapies are not currently effective, and there is a need to find pluripotent drugs with multiple properties. This study aimed to characterize the metabolism of neurotransmitters using a targeted metabolomics approach and to identify the major metabolic pathways mainly affected by 6‴-feruloylspinosin (6-FS). The mechanism of action of 6-FS in the treatment of AD was elucidated based on experimental validation. The metabolomics analysis revealed changes in 13 metabolic profiles by the LC-MS/MS, with significant changes in five amino acid-related neurotransmitters identified primarily. Based on the correlations, we found an effect of mTOR inhibition on the above neurotransmitter metabolism. Furthermore, pretreatment with 6-FS activated the AMPK/mTOR signaling pathway, promoting cellular autophagy, regulating oxidative stress homeostasis and inhibiting mitochondrial dysfunction. In short, these comprehensive analysis methods help clarify the preventive mechanism of 6-FS and potential targets in AD and provide the necessary support for developing natural products to prevent AD.
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Affiliation(s)
- Jinrui Liu
- College of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, 300134, China; School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yanqing Zhang
- College of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, 300134, China.
| | - Mei Zhang
- College of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, 300134, China
| | - Qing Wang
- College of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, 300134, China
| | - Yuxin Pang
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, China.
| | - Junbo Xie
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
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2
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Athari SZ, Kazmi S, Vatandoust SM, Mahmoudi J, Farajdokht F, Hajihosseinlou F, Ghaderi P, Majdi A, Sadigh-Eteghad S. Varenicline Attenuates Memory Impairment in Amyloid-Beta-Induced Rat Model of Alzheimer's Disease. Neurochem Res 2025; 50:86. [PMID: 39869225 DOI: 10.1007/s11064-025-04338-6] [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: 10/09/2024] [Revised: 01/08/2025] [Accepted: 01/10/2025] [Indexed: 01/28/2025]
Abstract
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by cognitive decline. Despite extensive research, therapeutic options remain limited. Varenicline, an α4β2 nicotinic acetylcholine receptor agonist, shows promise in enhancing cognitive function. This study aimed to evaluate varenicline's effect on memory and hippocampal activity in rat model of AD. Forty-eight adult male Wistar rats were randomly assigned to control, sham, AD, and varenicline (0.1, 1, and 3 mg/kg/po for 14 days) groups. AD was induced by intracerebroventricular (i.c.v.) injection of 4 µl amyloid-beta (Aβ)1-42 (1 µg/µl). Spatial learning and memory, hippocampal synaptic function, and CA1 electrophysiological activity were evaluated using appropriate methods. Barnes maze and T-maze behavioral tests revealed that varenicline, particularly at 1 mg/kg, significantly improved spatial memory compared to the AD group. Western blot analysis showed varenicline's ability to upregulate synaptic proteins PSD-95, synaptophysin, and GAP-43 in the hippocampus, with the most significant effects observed at 1 mg/kg. Electrophysiological recordings demonstrated that varenicline at 1 mg/kg enhanced hippocampal long-term potentiation (LTP), indicating improved synaptic plasticity. Single-unit recordings showed an increase in spike count with varenicline administration. These findings suggest that varenicline, particularly at 1 mg/kg, ameliorates memory deficits in AD rats possibly through modulation of synaptic proteins and enhancement of hippocampal LTP and electrical activity. Further investigations are warranted to elucidate varenicline's precise mechanisms of action in alleviating AD-induced cognitive deficits and its potential as a therapeutic intervention for AD-related cognitive impairment.
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Affiliation(s)
- Seyed Zanyar Athari
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sareh Kazmi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Javad Mahmoudi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fereshteh Farajdokht
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Pedram Ghaderi
- Department of Functional and Clinical Anatomy, Medical University of Innsbruck, Innsbruck, Austria
- Department of Otolaryngology, Medical University of Innsbruck, Innsbruck, Austria
| | - Alireza Majdi
- Research Group Experimental Oto-rhino-laryngology, Department of Neuroscience, Leuven Brain Institute, KU Leuven, Leuven, Belgium
| | - Saeed Sadigh-Eteghad
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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3
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Heneka MT, Morgan D, Jessen F. Passive anti-amyloid β immunotherapy in Alzheimer's disease-opportunities and challenges. Lancet 2024; 404:2198-2208. [PMID: 39549715 DOI: 10.1016/s0140-6736(24)01883-x] [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: 02/12/2024] [Revised: 08/30/2024] [Accepted: 09/05/2024] [Indexed: 11/18/2024]
Abstract
With the advent of the first disease-modifying, anti-amyloid β-directed passive immunotherapy for Alzheimer's disease, questions arise who, when, and how to treat. This paper describes shortly the pathogenic basis of and preclinical data, which have, more than two decades ago, initiated the development of this vaccination therapy. We discuss clinical trial results of aducanumab, lecanemab, and donanemab. We also review appropriate use recommendations of these novel treatments on patient selection and safety monitoring. Furthermore, estimations of numbers of patient who will qualify for treatment regarding inclusion and exclusion criteria and estimations on readiness of health-care systems for identifying the right patients and for providing the treatment are reported. In our view, we are experiencing a fundamental shift from syndrome-based Alzheimer's dementia care to early, biomarker-guided treatment of Alzheimer's disease. This shift requires substantial adjustments of infrastructure and resources, but also holds promise of eventually achieving substantial slowing of disease progression and delaying dementia.
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Affiliation(s)
- Michael T Heneka
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg; Departmnet of Medicine, UMass Chan Medical School, Worcester, MA, USA.
| | - David Morgan
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
| | - Frank Jessen
- Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany; German Center for Neurodegenerative Diseases, Bonn, Cologne, Germany; Excellence cluster on cellular stress response in aging associated disease, University of Cologne, Cologne, Germany
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4
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Akere MT, Zajac KK, Bretz JD, Madhavaram AR, Horton AC, Schiefer IT. Real-Time Analysis of Neuronal Cell Cultures for CNS Drug Discovery. Brain Sci 2024; 14:770. [PMID: 39199464 PMCID: PMC11352746 DOI: 10.3390/brainsci14080770] [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: 06/10/2024] [Revised: 07/23/2024] [Accepted: 07/27/2024] [Indexed: 09/01/2024] Open
Abstract
The ability to screen for agents that can promote the development and/or maintenance of neuronal networks creates opportunities for the discovery of novel agents for the treatment of central nervous system (CNS) disorders. Over the past 10 years, advances in robotics, artificial intelligence, and machine learning have paved the way for the improved implementation of live-cell imaging systems for drug discovery. These instruments have revolutionized our ability to quickly and accurately acquire large standardized datasets when studying complex cellular phenomena in real-time. This is particularly useful in the field of neuroscience because real-time analysis can allow efficient monitoring of the development, maturation, and conservation of neuronal networks by measuring neurite length. Unfortunately, due to the relative infancy of this type of analysis, standard practices for data acquisition and processing are lacking, and there is no standardized format for reporting the vast quantities of data generated by live-cell imaging systems. This paper reviews the current state of live-cell imaging instruments, with a focus on the most commonly used equipment (IncuCyte systems). We provide an in-depth analysis of the experimental conditions reported in publications utilizing these systems, particularly with regard to studying neurite outgrowth. This analysis sheds light on trends and patterns that will enhance the use of live-cell imaging instruments in CNS drug discovery.
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Affiliation(s)
- Millicent T. Akere
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA; (M.T.A.); (K.K.Z.); (J.D.B.); (A.R.M.); (A.C.H.)
| | - Kelsee K. Zajac
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA; (M.T.A.); (K.K.Z.); (J.D.B.); (A.R.M.); (A.C.H.)
| | - James D. Bretz
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA; (M.T.A.); (K.K.Z.); (J.D.B.); (A.R.M.); (A.C.H.)
| | - Anvitha R. Madhavaram
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA; (M.T.A.); (K.K.Z.); (J.D.B.); (A.R.M.); (A.C.H.)
| | - Austin C. Horton
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA; (M.T.A.); (K.K.Z.); (J.D.B.); (A.R.M.); (A.C.H.)
| | - Isaac T. Schiefer
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA; (M.T.A.); (K.K.Z.); (J.D.B.); (A.R.M.); (A.C.H.)
- Center for Drug Design and Development, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA
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5
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Zott B, Nästle L, Grienberger C, Unger F, Knauer MM, Wolf C, Keskin-Dargin A, Feuerbach A, Busche MA, Skerra A, Konnerth A. β-amyloid monomer scavenging by an anticalin protein prevents neuronal hyperactivity in mouse models of Alzheimer's Disease. Nat Commun 2024; 15:5819. [PMID: 38987287 PMCID: PMC11237084 DOI: 10.1038/s41467-024-50153-y] [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: 01/25/2023] [Accepted: 07/02/2024] [Indexed: 07/12/2024] Open
Abstract
Hyperactivity mediated by synaptotoxic β-amyloid (Aβ) oligomers is one of the earliest forms of neuronal dysfunction in Alzheimer's disease. In the search for a preventive treatment strategy, we tested the effect of scavenging Aβ peptides before Aβ plaque formation. Using in vivo two-photon calcium imaging and SF-iGluSnFR-based glutamate imaging in hippocampal slices, we demonstrate that an Aβ binding anticalin protein (Aβ-anticalin) can suppress early neuronal hyperactivity and synaptic glutamate accumulation in the APP23xPS45 mouse model of β-amyloidosis. Our results suggest that the sole targeting of Aβ monomers is sufficient for the hyperactivity-suppressing effect of the Aβ-anticalin at early disease stages. Biochemical and neurophysiological analyses indicate that the Aβ-anticalin-dependent depletion of naturally secreted Aβ monomers interrupts their aggregation to neurotoxic oligomers and, thereby, reverses early neuronal and synaptic dysfunctions. Thus, our results suggest that Aβ monomer scavenging plays a key role in the repair of neuronal function at early stages of AD.
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Affiliation(s)
- Benedikt Zott
- Institute of Neuroscience, Technical University of Munich, Munich, Germany.
- Department of Neuroradiology, MRI hospital of the Technical University of Munich, Munich, Germany.
- TUM Institute for Advanced Study, Garching, Germany.
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
| | - Lea Nästle
- Chair of Biological Chemistry, Technical University of Munich, Freising, Germany
| | - Christine Grienberger
- Institute of Neuroscience, Technical University of Munich, Munich, Germany
- Department of Biology and Volen National Center of Complex Systems, Brandeis University, Waltham, MA, USA
| | - Felix Unger
- Institute of Neuroscience, Technical University of Munich, Munich, Germany
- Department of Neuroradiology, MRI hospital of the Technical University of Munich, Munich, Germany
- TUM Institute for Advanced Study, Garching, Germany
| | - Manuel M Knauer
- Institute of Neuroscience, Technical University of Munich, Munich, Germany
| | - Christian Wolf
- Institute of Neuroscience, Technical University of Munich, Munich, Germany
- Department of Neuroradiology, MRI hospital of the Technical University of Munich, Munich, Germany
| | | | - Anna Feuerbach
- Chair of Biological Chemistry, Technical University of Munich, Freising, Germany
| | - Marc Aurel Busche
- Institute of Neuroscience, Technical University of Munich, Munich, Germany
- UK Dementia Research Institute at UCL, University College London, London, United Kingdom
| | - Arne Skerra
- Chair of Biological Chemistry, Technical University of Munich, Freising, Germany.
| | - Arthur Konnerth
- Institute of Neuroscience, Technical University of Munich, Munich, Germany.
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
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Abidi SMS, Shukla AK, Randhawa S, Bathla M, Acharya A. Diosgenin loaded cellulose nanoonion impedes different stages of protein aggregation induced cell death via alleviating mitochondrial dysfunction and upregulation of autophagy. Int J Biol Macromol 2024; 266:131108. [PMID: 38531523 DOI: 10.1016/j.ijbiomac.2024.131108] [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: 10/20/2023] [Revised: 03/19/2024] [Accepted: 03/21/2024] [Indexed: 03/28/2024]
Abstract
Protein aggregation is a multifaceted phenomenon prevalent in the progression of neurodegenerative diseases, yielding aggregates of diverse sizes. Recently, increased attention has been directed towards early protein aggregates due to their pronounced toxicity, largely stemming from inflammation mediated by reactive oxygen species (ROS). This study advocates for a therapeutic approach focusing on inflammation control rather than mere ROS inhibition in the context of neurodegenerative disorders. Here, we introduced Camellia sinensis cellulose nanoonion (CS-CNO) as an innovative, biocompatible nanocarrier for encapsulating the phytosteroid diosgenin (DGN@CS-CNO). The resulting nano-assembly, manifesting as spherical entities with dimensions averaging ~180-220 nm, exhibits a remarkable capacity for the gradual and sustained release of approximately 39-44 % of DGN over a 60-hour time frame. DGN@CS-CNO displays a striking ability to inhibit or disassemble various phases of hen egg white lysozyme (HEWL) protein aggregates, including the early (HEWLEA) and late (HEWLLA) stages. In vitro experiments employing HEK293 cells underscore the potential of DGN@CS-CNO in mitigating cell death provoked by protein aggregation. This effect is achieved by ameliorating ROS-mediated inflammation and countering mitochondrial dysfunction, as evidenced by alterations in TNFα, TLR4, and MT-CO1 protein expression. Western blot analyses reveal that the gradual and sustained release of DGN from DGN@CS-CNO induces autophagy, a pivotal process in dismantling intracellular amyloid deposits. In summary, this study not only illuminates a path forward but also presents a compelling case for the utilization of phytosteroid as a formidable strategy against neuroinflammation incited by protein aggregation.
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Affiliation(s)
- Syed M S Abidi
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, H.P. 176061, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Ashish K Shukla
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, H.P. 176061, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Shiwani Randhawa
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, H.P. 176061, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Manik Bathla
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, H.P. 176061, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Amitabha Acharya
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, H.P. 176061, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India.
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7
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Li J, Chen D, Liu H, Xi Y, Luo H, Wei Y, Liu J, Liang H, Zhang Q. Identifying potential genetic epistasis implicated in Alzheimer's disease via detection of SNP-SNP interaction on quantitative trait CSF Aβ 42. Neurobiol Aging 2024; 134:84-93. [PMID: 38039940 DOI: 10.1016/j.neurobiolaging.2023.10.003] [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: 06/22/2023] [Revised: 10/06/2023] [Accepted: 10/10/2023] [Indexed: 12/03/2023]
Abstract
Although genome-wide association studies have identified multiple Alzheimer's disease (AD)-associated loci by selecting the main effects of individual single-nucleotide polymorphisms (SNPs), the interpretation of genetic variance in AD is limited. Based on the linear regression method, we performed genome-wide SNP-SNP interaction on cerebrospinal fluid Aβ42 to identify potential genetic epistasis implicated in AD, with age, gender, and diagnosis as covariates. A GPU-based method was used to address the computational challenges posed by the analysis of epistasis. We found 368 SNP pairs to be statistically significant, and highly significant SNP-SNP interactions were identified between the marginal main effects of SNP pairs, which explained a relatively high variance at the Aβ42 level. Our results replicated 100 previously reported AD-related genes and 5 gene-gene interaction pairs of the protein-protein interaction network. Our bioinformatics analyses provided preliminary evidence that the 5-overlapping gene-gene interaction pairs play critical roles in inducing synaptic loss and dysfunction, thereby leading to memory decline and cognitive impairment in AD-affected brains.
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Affiliation(s)
- Jin Li
- College of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, China
| | - Dandan Chen
- College of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, China; School of Automation Engineering, Northeast Electric Power University, Jilin, China
| | - Hongwei Liu
- College of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, China
| | - Yang Xi
- School of Computer Science, Northeast Electric Power University, Jilin, China
| | - Haoran Luo
- College of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, China
| | - Yiming Wei
- College of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, China
| | - Junfeng Liu
- School of Computer Science, Northeast Electric Power University, Jilin, China
| | - Hong Liang
- College of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, China.
| | - Qiushi Zhang
- School of Computer Science, Northeast Electric Power University, Jilin, China.
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8
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Balestri W, Sharma R, da Silva VA, Bobotis BC, Curle AJ, Kothakota V, Kalantarnia F, Hangad MV, Hoorfar M, Jones JL, Tremblay MÈ, El-Jawhari JJ, Willerth SM, Reinwald Y. Modeling the neuroimmune system in Alzheimer's and Parkinson's diseases. J Neuroinflammation 2024; 21:32. [PMID: 38263227 PMCID: PMC10807115 DOI: 10.1186/s12974-024-03024-8] [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: 10/26/2023] [Accepted: 01/16/2024] [Indexed: 01/25/2024] Open
Abstract
Parkinson's disease (PD) and Alzheimer's disease (AD) are neurodegenerative disorders caused by the interaction of genetic, environmental, and familial factors. These diseases have distinct pathologies and symptoms that are linked to specific cell populations in the brain. Notably, the immune system has been implicated in both diseases, with a particular focus on the dysfunction of microglia, the brain's resident immune cells, contributing to neuronal loss and exacerbating symptoms. Researchers use models of the neuroimmune system to gain a deeper understanding of the physiological and biological aspects of these neurodegenerative diseases and how they progress. Several in vitro and in vivo models, including 2D cultures and animal models, have been utilized. Recently, advancements have been made in optimizing these existing models and developing 3D models and organ-on-a-chip systems, holding tremendous promise in accurately mimicking the intricate intracellular environment. As a result, these models represent a crucial breakthrough in the transformation of current treatments for PD and AD by offering potential for conducting long-term disease-based modeling for therapeutic testing, reducing reliance on animal models, and significantly improving cell viability compared to conventional 2D models. The application of 3D and organ-on-a-chip models in neurodegenerative disease research marks a prosperous step forward, providing a more realistic representation of the complex interactions within the neuroimmune system. Ultimately, these refined models of the neuroimmune system aim to aid in the quest to combat and mitigate the impact of debilitating neuroimmune diseases on patients and their families.
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Affiliation(s)
- Wendy Balestri
- Department of Engineering, School of Science and Technology, Nottingham Trent University, Nottingham, UK
- Medical Technologies Innovation Facility, Nottingham Trent University, Nottingham, UK
| | - Ruchi Sharma
- Department of Mechanical Engineering, University of Victoria, Victoria, Canada
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
| | - Victor A da Silva
- Department of Mechanical Engineering, University of Victoria, Victoria, Canada
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
| | - Bianca C Bobotis
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
| | - Annabel J Curle
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Vandana Kothakota
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | | | - Maria V Hangad
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
- Department of Chemistry, University of Victoria, Victoria, BC, Canada
| | - Mina Hoorfar
- Department of Mechanical Engineering, University of Victoria, Victoria, Canada
| | - Joanne L Jones
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Marie-Ève Tremblay
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
- Neurosciences Axis, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada
- Department of Molecular Medicine, Université Laval, Québec City, QC, Canada
- Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada
- Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada
- Institute On Aging and Lifelong Health, University of Victoria, Victoria, BC, Canada
| | - Jehan J El-Jawhari
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, UK
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Stephanie M Willerth
- Department of Mechanical Engineering, University of Victoria, Victoria, Canada.
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
- Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada.
- School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.
| | - Yvonne Reinwald
- Department of Engineering, School of Science and Technology, Nottingham Trent University, Nottingham, UK.
- Medical Technologies Innovation Facility, Nottingham Trent University, Nottingham, UK.
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9
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Bigi A, Napolitano L, Vadukul DM, Chiti F, Cecchi C, Aprile FA, Cascella R. A single-domain antibody detects and neutralises toxic Aβ 42 oligomers in the Alzheimer's disease CSF. Alzheimers Res Ther 2024; 16:13. [PMID: 38238842 PMCID: PMC10795411 DOI: 10.1186/s13195-023-01361-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 11/29/2023] [Indexed: 01/22/2024]
Abstract
BACKGROUND Amyloid-β42 (Aβ42) aggregation consists of a complex chain of nucleation events producing soluble oligomeric intermediates, which are considered the major neurotoxic agents in Alzheimer's disease (AD). Cerebral lesions in the brain of AD patients start to develop 20 years before symptom onset; however, no preventive strategies, effective treatments, or specific and sensitive diagnostic tests to identify people with early-stage AD are currently available. In addition, the isolation and characterisation of neurotoxic Aβ42 oligomers are particularly difficult because of their transient and heterogeneous nature. To overcome this challenge, a rationally designed method generated a single-domain antibody (sdAb), named DesAb-O, targeting Aβ42 oligomers. METHODS We investigated the ability of DesAb-O to selectively detect preformed Aβ42 oligomers both in vitro and in cultured neuronal cells, by using dot-blot, ELISA immunoassay and super-resolution STED microscopy, and to counteract the toxicity induced by the oligomers, monitoring their interaction with neuronal membrane and the resulting mitochondrial impairment. We then applied this approach to CSF samples (CSFs) from AD patients as compared to age-matched control subjects. RESULTS DesAb-O was found to selectively detect synthetic Aβ42 oligomers both in vitro and in cultured cells, and to neutralise their associated neuronal dysfunction. DesAb-O can also identify Aβ42 oligomers present in the CSFs of AD patients with respect to healthy individuals, and completely prevent cell dysfunction induced by the administration of CSFs to neuronal cells. CONCLUSIONS Taken together, our data indicate a promising method for the improvement of an early diagnosis of AD and for the generation of novel therapeutic approaches based on sdAbs for the treatment of AD and other devastating neurodegenerative conditions.
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Affiliation(s)
- Alessandra Bigi
- Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, Florence, Italy
| | - Liliana Napolitano
- Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, Florence, Italy
| | - Devkee M Vadukul
- Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London, UK
| | - Fabrizio Chiti
- Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, Florence, Italy
| | - Cristina Cecchi
- Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, Florence, Italy
| | - Francesco A Aprile
- Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London, UK
- Institute of Chemical Biology, Molecular Sciences Research Hub, Imperial College London, London, UK
| | - Roberta Cascella
- Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, Florence, Italy.
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10
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Jin M, Wei Z, Ramalingam N, Xiao M, Xu A, Yu X, Song Q, Liu W, Zhao J, Zhang D, Selkoe DJ, Li S. Activation of β 2-adrenergic receptors prevents AD-type synaptotoxicity via epigenetic mechanisms. Mol Psychiatry 2023; 28:4877-4888. [PMID: 37365243 DOI: 10.1038/s41380-023-02145-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/28/2023]
Abstract
We previously reported that prolonged exposure to an enriched environment (EE) enhances hippocampal synaptic plasticity, with one of the significant mechanistic pathways being activation of β2-adrenergic receptor (β2-AR) signaling, thereby mitigating the synaptotoxic effects of soluble oligomers of amyloid β-protein (oAβ). However, the detailed mechanism remained elusive. In this work, we recorded field excitatory postsynaptic potentials (fEPSP) in the CA1 region of mouse hippocampal slices treated with or without toxic Aβ-species. We found that pharmacological activation of β2-AR, but not β1-AR, selectively mimicked the effects of EE in enhancing LTP and preventing oAβ-induced synaptic dysfunction. Mechanistic analyses showed that certain histone deacetylase (HDAC) inhibitors mimicked the benefits of EE, but this was not seen in β2-AR knockout mice, suggesting that activating β2-AR prevents oAβ-mediated synaptic dysfunction via changes in histone acetylation. EE or activation of β-ARs each decreased HDAC2, whereas Aβ oligomers increased HDAC2 levels in the hippocampus. Further, oAβ-induced inflammatory effects and neurite degeneration were prevented by either β2-AR agonists or certain specific HDAC inhibitors. These preclinical results suggest that activation of β2-AR is a novel potential therapeutic strategy to mitigate oAβ-mediated features of AD.
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Affiliation(s)
- Ming Jin
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Zhiyun Wei
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Nagendran Ramalingam
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Meng Xiao
- Department of Neurology, Xinxiang Medical University, Xinxiang, 453100, China
- Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, 518172, China
| | - Anqi Xu
- Department of Neurology, Xinxiang Medical University, Xinxiang, 453100, China
| | - Xiaohan Yu
- Department of Neurology, Xinxiang Medical University, Xinxiang, 453100, China
| | - Qingyang Song
- Department of Neurology, Xinxiang Medical University, Xinxiang, 453100, China
| | - Wen Liu
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Jianhua Zhao
- Department of Neurology, Xinxiang Medical University, Xinxiang, 453100, China
- Henan Key Laboratory of Neurorestoratology, Xinxiang, Henan, 453100, China
| | - Dainan Zhang
- Department of Neurology, Xinxiang Medical University, Xinxiang, 453100, China
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
| | - Dennis J Selkoe
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Shaomin Li
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
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11
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Saha J, Ford BJ, Wang X, Boyd S, Morgan SE, Rangachari V. Sugar distributions on gangliosides guide the formation and stability of amyloid-β oligomers. Biophys Chem 2023; 300:107073. [PMID: 37413816 PMCID: PMC10529042 DOI: 10.1016/j.bpc.2023.107073] [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: 03/24/2023] [Revised: 06/25/2023] [Accepted: 06/27/2023] [Indexed: 07/08/2023]
Abstract
Aggregation of Aβ peptides is a key contributor to the etiology of Alzheimer's disease. Being intrinsically disordered, monomeric Aβ is susceptible to conformational excursions, especially in the presence of important interacting partners such as membrane lipids, to adopt specific aggregation pathways. Furthermore, components such as gangliosides in membranes and lipid rafts are known to play important roles in the adoption of pathways and the generation of discrete neurotoxic oligomers. Yet, what roles do carbohydrates on gangliosides play in this process remains unknown. Here, using GM1, GM3, and GD3 ganglioside micelles as models, we show that the sugar distributions and cationic amino acids within Aβ N-terminal region modulate oligomerization of Aβ temporally, and dictate the stability and maturation of oligomers. These results demonstrate the selectivity of sugar distributions on the membrane surface toward oligomerization of Aβ and thus implicate cell-selective enrichment of oligomers.
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Affiliation(s)
- Jhinuk Saha
- Department of Chemistry and Biochemistry, School of Mathematics and Natural Sciences, 118, College Dr Hattiesburg, MS 39402, USA
| | - Brea J Ford
- Department of Chemistry and Biochemistry, School of Mathematics and Natural Sciences, 118, College Dr Hattiesburg, MS 39402, USA
| | | | - Sydney Boyd
- Department of Chemistry and Biochemistry, School of Mathematics and Natural Sciences, 118, College Dr Hattiesburg, MS 39402, USA
| | | | - Vijayaraghavan Rangachari
- Department of Chemistry and Biochemistry, School of Mathematics and Natural Sciences, 118, College Dr Hattiesburg, MS 39402, USA; Center for Molecular and Cellular Biosciences, University of Southern Mississippi, Hattiesburg, MS 39406, USA.
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12
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Khan F, Joshi A, Devkota HP, Subramaniyan V, Kumarasamy V, Arora J. Dietary glucosinolates derived isothiocyanates: chemical properties, metabolism and their potential in prevention of Alzheimer's disease. Front Pharmacol 2023; 14:1214881. [PMID: 37554984 PMCID: PMC10404612 DOI: 10.3389/fphar.2023.1214881] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 07/04/2023] [Indexed: 08/10/2023] Open
Abstract
Alzheimer's disease (AD) is the most prevalent form of dementia affecting millions of people worldwide. It is a progressive, irreversible, and incurable neurodegenerative disorder that disrupts the synaptic communication between millions of neurons, resulting in neuronal death and functional loss due to the abnormal accumulation of two naturally occurring proteins, amyloid β (Aβ) and tau. According to the 2018 World Alzheimer's Report, there is no single case of an Alzheimer's survivor; even 1 in 3 people die from Alzheimer's disease, and it is a growing epidemic across the globe fruits and vegetables rich in glucosinolates (GLCs), the precursors of isothiocyanates (ITCs), have long been known for their pharmacological properties and recently attracted increased interest for the possible prevention and treatment of neurodegenerative diseases. Epidemiological evidence from systematic research findings and clinical trials suggests that nutritional and functional dietary isothiocyanates interfere with the molecular cascades of Alzheimer's disease pathogenesis and prevent neurons from functional loss. The aim of this review is to explore the role of glucosinolates derived isothiocyanates in various molecular mechanisms involved in the progression of Alzheimer's disease and their potential in the prevention and treatment of Alzheimer's disease. It also covers the chemical diversity of isothiocyanates and their detailed mechanisms of action as reported by various in vitro and in vivo studies. Further clinical studies are necessary to evaluate their pharmacokinetic parameters and effectiveness in humans.
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Affiliation(s)
- Farhana Khan
- Laboratory of Bio-Molecular Technology, Department of Botany, Mohanlal Sukhadia University, Udaipur, Rajasthan, India
| | - Abhishek Joshi
- Laboratory of Bio-Molecular Technology, Department of Botany, Mohanlal Sukhadia University, Udaipur, Rajasthan, India
| | - Hari Prasad Devkota
- Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Vetriselvan Subramaniyan
- Department of Pharmacology, Center for Transdisciplinary Research, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
| | - Vinoth Kumarasamy
- Department of Parasitology and Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Jaya Arora
- Laboratory of Bio-Molecular Technology, Department of Botany, Mohanlal Sukhadia University, Udaipur, Rajasthan, India
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13
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Whitfield JF, Rennie K, Chakravarthy B. Alzheimer's Disease and Its Possible Evolutionary Origin: Hypothesis. Cells 2023; 12:1618. [PMID: 37371088 PMCID: PMC10297544 DOI: 10.3390/cells12121618] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/29/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
The enormous, 2-3-million-year evolutionary expansion of hominin neocortices to the current enormity enabled humans to take over the planet. However, there appears to have been a glitch, and it occurred without a compensatory expansion of the entorhinal cortical (EC) gateway to the hippocampal memory-encoding system needed to manage the processing of the increasing volume of neocortical data converging on it. The resulting age-dependent connectopathic glitch was unnoticed by the early short-lived populations. It has now surfaced as Alzheimer's disease (AD) in today's long-lived populations. With advancing age, processing of the converging neocortical data by the neurons of the relatively small lateral entorhinal cortex (LEC) inflicts persistent strain and high energy costs on these cells. This may result in their hyper-release of harmless Aβ1-42 monomers into the interstitial fluid, where they seed the formation of toxic amyloid-β oligomers (AβOs) that initiate AD. At the core of connectopathic AD are the postsynaptic cellular prion protein (PrPC). Electrostatic binding of the negatively charged AβOs to the positively charged N-terminus of PrPC induces hyperphosphorylation of tau that destroys synapses. The spread of these accumulating AβOs from ground zero is supported by Aβ's own production mediated by target cells' Ca2+-sensing receptors (CaSRs). These data suggest that an early administration of a strongly positively charged, AβOs-interacting peptide or protein, plus an inhibitor of CaSR, might be an effective AD-arresting therapeutic combination.
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Affiliation(s)
- James F. Whitfield
- Human Health Therapeutics, National Research Council, Ottawa, ON K1A 0R6, Canada
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14
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Waigi EW, Webb RC, Moss MA, Uline MJ, McCarthy CG, Wenceslau CF. Soluble and insoluble protein aggregates, endoplasmic reticulum stress, and vascular dysfunction in Alzheimer's disease and cardiovascular diseases. GeroScience 2023; 45:1411-1438. [PMID: 36823398 PMCID: PMC10400528 DOI: 10.1007/s11357-023-00748-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 01/28/2023] [Indexed: 02/25/2023] Open
Abstract
Dementia refers to a particular group of symptoms characterized by difficulties with memory, language, problem-solving, and other thinking skills that affect a person's ability to perform everyday activities. Alzheimer's disease (AD) is the most common form of dementia, affecting about 6.2 million Americans aged 65 years and older. Likewise, cardiovascular diseases (CVDs) are a major cause of disability and premature death, impacting 126.9 million adults in the USA, a number that increases with age. Consequently, CVDs and cardiovascular risk factors are associated with an increased risk of AD and cognitive impairment. They share important age-related cardiometabolic and lifestyle risk factors, that make them among the leading causes of death. Additionally, there are several premises and hypotheses about the mechanisms underlying the association between AD and CVD. Although AD and CVD may be considered deleterious to health, the study of their combination constitutes a clinical challenge, and investigations to understand the mechanistic pathways for the cause-effect and/or shared pathology between these two disease constellations remains an active area of research. AD pathology is propagated by the amyloid β (Aβ) peptides. These peptides give rise to small, toxic, and soluble Aβ oligomers (SPOs) that are nonfibrillar, and it is their levels that show a robust correlation with the extent of cognitive impairment. This review will elucidate the interplay between the effects of accumulating SPOs in AD and CVDs, the resulting ER stress response, and their role in vascular dysfunction. We will also address the potential underlying mechanisms, including the possibility that SPOs are among the causes of vascular injury in CVD associated with cognitive decline. By revealing common mechanistic underpinnings of AD and CVD, we hope that novel experimental therapeutics can be designed to reduce the burden of these devastating diseases. Graphical abstract Alzheimer's disease (AD) pathology leads to the release of Aβ peptides, and their accumulation in the peripheral organs has varying effects on various components of the cardiovascular system including endoplasmic reticulum (ER) stress and vascular damage. Image created with BioRender.com.
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Affiliation(s)
- Emily W Waigi
- Cardiovascular Translational Research Cententer (CTRC), Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
| | - R Clinton Webb
- Cardiovascular Translational Research Cententer (CTRC), Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
- Biomedical Engineering Program, Univeristy of South Carolina, Columbia, SC, USA
| | - Melissa A Moss
- Biomedical Engineering Program, Univeristy of South Carolina, Columbia, SC, USA
- Department of Chemical Engineering, University of South Carolina, Columbia, SC, USA
| | - Mark J Uline
- Biomedical Engineering Program, Univeristy of South Carolina, Columbia, SC, USA
- Department of Chemical Engineering, University of South Carolina, Columbia, SC, USA
| | - Cameron G McCarthy
- Cardiovascular Translational Research Cententer (CTRC), Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
- Biomedical Engineering Program, Univeristy of South Carolina, Columbia, SC, USA
| | - Camilla Ferreira Wenceslau
- Cardiovascular Translational Research Cententer (CTRC), Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA.
- Biomedical Engineering Program, Univeristy of South Carolina, Columbia, SC, USA.
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15
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Seyedaghamiri F, Rajabi M, Mohaddes G. Targeting Novel microRNAs in Developing Novel Alzheimer's Disease Treatments. Neurochem Res 2023; 48:26-38. [PMID: 36048350 DOI: 10.1007/s11064-022-03734-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/18/2022] [Accepted: 08/21/2022] [Indexed: 01/11/2023]
Abstract
Alzheimer's disease (AD) is considered a multifactorial disease and a significant cause of dementia during aging. This neurodegenerative disease process is classically divided into two different pathologies cerebral accumulation of amyloid-β and hyperphosphorylated neurofibrillary tau tangles. In recent years, massive efforts have been made to treat AD by decreasing amyloid-β and tau in the brains of patients with AD, with no success. The dysfunction of a wide range of microRNAs promotes the generation and insufficient clearance of amyloid-β (Aβ) and increases tau plaques which are the pathophysiological markers of AD. Disturbance of these microRNAs is associated with mitochondrial dysfunction, oxidative damage, inflammation, apolipoprotein E4 (APOE4) pathogenic process, synaptic loss, and cognitive deficits induced by AD. Targeting a specific microRNA to restore AD-induced impairments at multiple stages might provide a promising approach for developing new drugs and therapeutic strategies for patients with AD. This review focuses on different mechanisms of microRNAs in AD pathophysiology.
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Affiliation(s)
| | - Mojgan Rajabi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, 51666-14756, Iran
| | - Gisou Mohaddes
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, 51666-14756, Iran.
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16
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Jin SX, Liu L, Li S, Meunier AL, Selkoe DJ. Aβ oligomers from human brain impair mossy fiber LTP in CA3 of hippocampus, but activating cAMP-PKA and cGMP-PKG prevents this. Neurobiol Dis 2022; 172:105816. [PMID: 35820646 PMCID: PMC9809147 DOI: 10.1016/j.nbd.2022.105816] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/29/2022] [Accepted: 07/07/2022] [Indexed: 01/05/2023] Open
Abstract
Early cognitive impairment in Alzheimer's disease may result in part from synaptic dysfunction caused by the accumulation oligomeric assemblies of amyloid β-protein (Aβ). Changes in hippocampal function seem critical for cognitive impairment in early Alzheimer's disease (AD). Diffusible oligomers of Aβ (oAβ) have been shown to block canonical long-term potentiation (LTP) in the CA1 area of hippocampus, but whether there is also a direct effect of oAβ on synaptic transmission and plasticity at synapses between mossy fibers (axons) from the dentate gyrus granule cells and CA3 pyramidal neurons (mf-CA3 synapses) is unknown. Studies in APP transgenic mice have suggested an age-dependent impairment of mossy fiber LTP. Here we report that although endogenous AD brain-derived soluble oAβ had no effect on mossy-fiber basal transmission, it strongly impaired paired-pulse facilitation in the mossy fiber pathway and presynaptic mossy fiber LTP (mf-LTP). Selective activation of both β1 and β2 adrenergic receptors and their downstream cAMP/PKA signaling pathway prevented oAβ-mediated inhibition of mf-LTP. Unexpectedly, activation of the cGMP/PKG signaling pathway also prevented oAβ-impaired mf-LTP. Our results reveal certain specific pharmacological targets to ameliorate human oAβ-mediated impairment at the mf-CA3 synapse.
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Affiliation(s)
| | | | | | | | - Dennis J. Selkoe
- Corresponding author at: Hale Building for Transformative Medicine, Rm 10002Q, 60 Fenwood Road, Boston, MA 02115, United States of America. (D.J. Selkoe)
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17
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Bioactive human Alzheimer brain soluble Aβ: pathophysiology and therapeutic opportunities. Mol Psychiatry 2022; 27:3182-3191. [PMID: 35484241 DOI: 10.1038/s41380-022-01589-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 04/11/2022] [Accepted: 04/14/2022] [Indexed: 12/16/2022]
Abstract
The accumulation of amyloid-β protein (Aβ) plays an early role in the pathogenesis of Alzheimer's disease (AD). The precise mechanism of how Aβ accumulation leads to synaptic dysfunction and cognitive impairment remains unclear but is likely due to small soluble oligomers of Aβ (oAβ). Most studies have used chemical synthetic or cell-secreted Aβ oligomers to study their pathogenic mechanisms, but the Aβ derived from human AD brain tissue is less well characterized. Here we review updated knowledge on the extraction and characterization of bioactive human AD brain oAβ and the mechanisms by which they cause hippocampal synaptic dysfunction. Human AD brain-derived oAβ can impair hippocampal long-term potentiation (LTP) and enhance long-term depression (LTD). Many studies suggest that oAβ may directly disrupt neuronal NMDA receptors, AMPA receptors and metabotropic glutamate receptors (mGluRs). oAβ also impairs astrocytic synaptic functions, including glutamate uptake, D-serine release, and NMDA receptor function. We also discuss oAβ-induced neuronal hyperexcitation. These results may suggest a multi-target approach for the treatment of AD, including both oAβ neutralization and reversal of glutamate-mediated excitotoxicity.
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18
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Yan XD, Qu XS, Yin J, Qiao J, Zhang J, Qi JS, Wu MN. Adiponectin Ameliorates Cognitive Behaviors and in vivo Synaptic Plasticity Impairments in 3xTg-AD Mice. J Alzheimers Dis 2021; 85:343-357. [PMID: 34806605 DOI: 10.3233/jad-215063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Cognitive deficit is mainly clinical characteristic of Alzheimer's disease (AD). Recent reports showed adiponectin and its analogues could reverse cognitive impairments, lower amyloid-β protein (Aβ) deposition, and exert anti-inflammatory effects in different APP/PS1 AD model mice mainly exhibiting amyloid plaque pathology. However, the potential in vivo electrophysiological mechanism of adiponectin protecting against cognitive deficits in AD and the neuroprotective effects of adiponectin on 3xTg-AD mice including both plaque and tangle pathology are still unclear. OBJECTIVE To observe the effects of adiponectin treatment on cognitive deficits in 3xTg-AD mice, investigate its potential in vivo electrophysiological mechanism, and testify its anti-inflammatory effects. METHODS Barnes maze test, Morris water maze test, and fear conditioning test were used to evaluate the memory-ameliorating effects of adiponectin on 3xTg-AD mice. In vivo hippocampal electrophysiological recording was used to observe the change of basic synaptic transmission, long-term potentiation, and long-term depression. Immunohistochemistry staining and western blot were used to observe the activation of microglia and astroglia, and the expression levels of proinflammatory factors and anti-inflammtory factor IL-10. RESULTS Adiponectin treatment could alleviate spatial memory and conditioned fear memory deficits observed in 3xTg-AD mice, improve in vivo LTP depression and LTD facilitation, inhibit overactivation of microglia and astroglia, decrease the expression of proinflammatory factors NF- κB and IL-1β, and increase the expression level of IL-10 in the hippocampus of 3xTg-AD mice. CONCLUSION Adiponectin could ameliorate cognitive deficits in 3xTg-AD mice through improving in vivo synaptic plasticity impairments and alleviating neuroinflammation in the hippocampus of 3xTg-AD mice.
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Affiliation(s)
- Xu-Dong Yan
- Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Xue-Song Qu
- Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China.,Pomology Institute of Shanxi Agricultural University, Taiyuan, China
| | - Jing Yin
- Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Jin Qiao
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, China
| | - Jun Zhang
- Functional Laboratory Center, Shanxi Medical University, Taiyuan, China
| | - Jin-Shun Qi
- Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Mei-Na Wu
- Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China
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19
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Liu L, Kwak H, Lawton TL, Jin SX, Meunier AL, Dang Y, Ostaszewski B, Pietras AC, Stern AM, Selkoe DJ. An ultra-sensitive immunoassay detects and quantifies soluble Aβ oligomers in human plasma. Alzheimers Dement 2021; 18:1186-1202. [PMID: 34550630 DOI: 10.1002/alz.12457] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 07/02/2021] [Accepted: 07/30/2021] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Evidence strongly suggests that soluble oligomers of amyloid beta protein (oAβ) help initiate the pathogenic cascade of Alzheimer's disease (AD). To date, there have been no validated assays specific for detecting and quantifying oAβ in human blood. METHODS We developed an ultrasensitive oAβ immunoassay using a novel capture antibody (71A1) with N-terminal antibody 3D6 for detection that specifically quantifies soluble oAβ in the human brain, cerebrospinal fluid (CSF), and plasma. RESULTS Two new antibodies (71A1; 1G5) are oAβ-selective, label Aβ plaques in non-fixed AD brain sections, and potently neutralize the synaptotoxicity of AD brain-derived oAβ. The 71A1/3D6 assay showed excellent dilution linearity in CSF and plasma without matrix effects, good spike recovery, and specific immunodepletion. DISCUSSION We have created a sensitive, high throughput, and inexpensive method to quantify synaptotoxic oAβ in human plasma for analyzing large cohorts of aged and AD subjects to assess the dynamics of this key pathogenic species and response to therapy.
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Affiliation(s)
- Lei Liu
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, Massachusetts, 02115, USA
| | - Hyunchang Kwak
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, Massachusetts, 02115, USA
| | - Trebor L Lawton
- Abyssinia Biologics, LLC, 23 Cedar Point Rd, Durham, New Hampshire, 03824, USA
| | - Shan-Xue Jin
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, Massachusetts, 02115, USA
| | - Angela L Meunier
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, Massachusetts, 02115, USA
| | - Yifan Dang
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, Massachusetts, 02115, USA
| | - Beth Ostaszewski
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, Massachusetts, 02115, USA
| | - Alison C Pietras
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, Massachusetts, 02115, USA
| | - Andrew M Stern
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, Massachusetts, 02115, USA
| | - Dennis J Selkoe
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, Massachusetts, 02115, USA
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20
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Oxidative Stress and Beta Amyloid in Alzheimer's Disease. Which Comes First: The Chicken or the Egg? Antioxidants (Basel) 2021; 10:antiox10091479. [PMID: 34573112 PMCID: PMC8468973 DOI: 10.3390/antiox10091479] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/13/2021] [Accepted: 09/15/2021] [Indexed: 02/07/2023] Open
Abstract
The pathogenesis of Alzheimer's disease involves β amyloid (Aβ) accumulation known to induce synaptic dysfunction and neurodegeneration. The brain's vulnerability to oxidative stress (OS) is considered a crucial detrimental factor in Alzheimer's disease. OS and Aβ are linked to each other because Aβ induces OS, and OS increases the Aβ deposition. Thus, the answer to the question "which comes first: the chicken or the egg?" remains extremely difficult. In any case, the evidence for the primary occurrence of oxidative stress in AD is attractive. Thus, evidence indicates that a long period of gradual oxidative damage accumulation precedes and results in the appearance of clinical and pathological AD symptoms, including Aβ deposition, neurofibrillary tangle formation, metabolic dysfunction, and cognitive decline. Moreover, oxidative stress plays a crucial role in the pathogenesis of many risk factors for AD. Alzheimer's disease begins many years before its symptoms, and antioxidant treatment can be an important therapeutic target for attacking the disease.
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21
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Chuang Y, Van I, Zhao Y, Xu Y. Icariin ameliorate Alzheimer's disease by influencing SIRT1 and inhibiting Aβ cascade pathogenesis. J Chem Neuroanat 2021; 117:102014. [PMID: 34407393 DOI: 10.1016/j.jchemneu.2021.102014] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 08/09/2021] [Accepted: 08/09/2021] [Indexed: 12/23/2022]
Abstract
Of all types of dementia, Alzheimer's disease is the type that has the highest proportion of cases and is the cause of substantial medical and economic burden. The mechanism of Alzheimer's disease is closely associated with the aggregation of amyloid-β protein and causes neurotoxicity and extracellular accumulation in the brain and to intracellular neurofibrillary tangles caused by tau protein hyperphosphorylation in the brain tissue. Previous studies have demonstrated that sirtuin1 downregulation is involved in the pathological mechanism of Alzheimer's disease. The decrease of sirtuin1 level would cause Alzheimer's disease by means of promoting the amyloidogenic pathway to generate amyloid-β species and thereby triggering amyloid-β cascade reaction, such as tau protein hyperphosphorylation, neuron autophagy, neuroinflammation, oxidative stress, and neuron apoptosis. Currently, there is no effective treatment for Alzheimer's disease, it is necessary to develop new treatment strategies. According to the theory of traditional Chinese medicine and based on the mechanism of the disease, tonifying the kidneys is one of the principles for the treatment of Alzheimer's disease and Epimedium is a well-known Chinese medicine for tonifying kidney. Therefore, investigating the influence of the components of Epimedium on the pathological characteristics of Alzheimer's disease may provide a reference for the treatment of Alzheimer's disease in the future. In this article, we summarise the effects and mechanism of icariin, the main ingredient extracted from Epimedium, in ameliorating Alzheimer's disease by regulating sirtuin1 to inhibit amyloid-β protein and improve other amyloid-β cascade pathogenesis.
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Affiliation(s)
- Yaochen Chuang
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, 999078, China; Kiang Wu Nursing College of Macau, Macao, 999078, China
| | - Iatkio Van
- Kiang Wu Nursing College of Macau, Macao, 999078, China.
| | - Yonghua Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China
| | - Youhua Xu
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, 999078, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, 999078, China.
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22
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Diociaiuti M, Bonanni R, Cariati I, Frank C, D’Arcangelo G. Amyloid Prefibrillar Oligomers: The Surprising Commonalities in Their Structure and Activity. Int J Mol Sci 2021; 22:ijms22126435. [PMID: 34208561 PMCID: PMC8235680 DOI: 10.3390/ijms22126435] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 06/10/2021] [Accepted: 06/14/2021] [Indexed: 12/12/2022] Open
Abstract
It has been proposed that a “common core” of pathologic pathways exists for the large family of amyloid-associated neurodegenerations, including Alzheimer’s, Parkinson’s, type II diabetes and Creutzfeldt–Jacob’s Disease. Aggregates of the involved proteins, independently from their primary sequence, induced neuron membrane permeabilization able to trigger an abnormal Ca2+ influx leading to synaptotoxicity, resulting in reduced expression of synaptic proteins and impaired synaptic transmission. Emerging evidence is now focusing on low-molecular-weight prefibrillar oligomers (PFOs), which mimic bacterial pore-forming toxins that form well-ordered oligomeric membrane-spanning pores. At the same time, the neuron membrane composition and its chemical microenvironment seem to play a pivotal role. In fact, the brain of AD patients contains increased fractions of anionic lipids able to favor cationic influx. However, up to now the existence of a specific “common structure” of the toxic aggregate, and a “common mechanism” by which it induces neuronal damage, synaptotoxicity and impaired synaptic transmission, is still an open hypothesis. In this review, we gathered information concerning this hypothesis, focusing on the proteins linked to several amyloid diseases. We noted commonalities in their structure and membrane activity, and their ability to induce Ca2+ influx, neurotoxicity, synaptotoxicity and impaired synaptic transmission.
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Affiliation(s)
- Marco Diociaiuti
- Centro Nazionale Malattie Rare, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
- Correspondence:
| | - Roberto Bonanni
- Department of Systems Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (G.D.)
| | - Ida Cariati
- PhD in Medical-Surgical Biotechnologies and Translational Medicine, Department of Clinical Sciences and Translational Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy;
| | - Claudio Frank
- UniCamillus-Saint Camillus International University of Health Sciences, Via di Sant’Alessandro 8, 00131 Rome, Italy;
| | - Giovanna D’Arcangelo
- Department of Systems Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (G.D.)
- Centre of Space Bio-Medicine, “Tor Vergata” University of Rome, Via Montpellier 1, 00133 Rome, Italy
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23
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A review on α-mangostin as a potential multi-target-directed ligand for Alzheimer's disease. Eur J Pharmacol 2021; 897:173950. [PMID: 33607107 DOI: 10.1016/j.ejphar.2021.173950] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 02/03/2021] [Accepted: 02/12/2021] [Indexed: 12/20/2022]
Abstract
Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive memory loss, declining language skills and other cognitive disorders. AD has brought great mental and economic burden to patients, families and society. However due to the complexity of AD's pathology, drugs developed for the treatment of AD often fail in clinical or experimental trials. The main problems of current anti-AD drugs are low efficacy due to mono-target method or side effects, especially high hepatotoxicity. To tackle these two main problems, multi-target-directed ligand (MTDL) based on "one molecule, multiple targets" has been studied. MTDLs can regulate multiple biological targets at the same time, so it has shown higher efficacy, better safety. As a natural active small molecule, α-mangostin (α-M) has shown potential multi-factor anti-AD activities in a series of studies, furthermore it also has a certain hepatoprotective effect. The good availability of α-M also provides support for its application in clinical research. In this work, multiple activities of α-M related to AD therapy were reviewed, which included anti-cholinesterase, anti-amyloid-cascade, anti-inflammation, anti-oxidative stress, low toxicity, hepatoprotective effects and drug formulation. It shows that α-M is a promising candidate for the treatment of AD.
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24
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Kumar S, Kapadia A, Theil S, Joshi P, Riffel F, Heneka MT, Walter J. Novel Phosphorylation-State Specific Antibodies Reveal Differential Deposition of Ser26 Phosphorylated Aβ Species in a Mouse Model of Alzheimer's Disease. Front Mol Neurosci 2021; 13:619639. [PMID: 33519377 PMCID: PMC7844098 DOI: 10.3389/fnmol.2020.619639] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 12/15/2020] [Indexed: 12/15/2022] Open
Abstract
Aggregation and deposition of amyloid-β (Aβ) peptides in extracellular plaques and in the cerebral vasculature are prominent neuropathological features of Alzheimer's disease (AD) and closely associated with the pathogenesis of AD. Amyloid plaques in the brains of most AD patients and transgenic mouse models exhibit heterogeneity in the composition of Aβ deposits, due to the occurrence of elongated, truncated, and post-translationally modified Aβ peptides. Importantly, changes in the deposition of these different Aβ variants are associated with the clinical disease progression and considered to mark sequential phases of plaque and cerebral amyloid angiopathy (CAA) maturation at distinct stages of AD. We recently showed that Aβ phosphorylated at serine residue 26 (pSer26Aβ) has peculiar characteristics in aggregation, deposition, and neurotoxicity. In the current study, we developed and thoroughly validated novel monoclonal and polyclonal antibodies that recognize Aβ depending on the phosphorylation-state of Ser26. Our results demonstrate that selected phosphorylation state-specific antibodies were able to recognize Ser26 phosphorylated and non-phosphorylated Aβ with high specificity in enzyme-linked immunosorbent assay (ELISA) and Western Blotting (WB) assays. Furthermore, immunofluorescence analyses with these antibodies demonstrated the occurrence of pSer26Aβ in transgenic mouse brains that show differential deposition as compared to non-phosphorylated Aβ (npAβ) or other modified Aβ species. Notably, pSer26Aβ species were faintly detected in extracellular Aβ plaques but most prominently found intraneuronally and in cerebral blood vessels. In conclusion, we developed new antibodies to specifically differentiate Aβ peptides depending on the phosphorylation state of Ser26, which are applicable in ELISA, WB, and immunofluorescence staining of mouse brain tissues. These site- and phosphorylation state-specific Aβ antibodies represent novel tools to examine phosphorylated Aβ species to further understand and dissect the complexity in the age-related and spatio-temporal deposition of different Aβ variants in transgenic mouse models and human AD brains.
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Affiliation(s)
- Sathish Kumar
- Department of Neurology, University of Bonn Medical Center, Bonn, Germany
| | - Akshay Kapadia
- Department of Neurology, University of Bonn Medical Center, Bonn, Germany
| | - Sandra Theil
- Department of Neurology, University of Bonn Medical Center, Bonn, Germany
| | - Pranav Joshi
- Department of Neurology, University of Bonn Medical Center, Bonn, Germany
| | - Florian Riffel
- Department of Neurology, University of Bonn Medical Center, Bonn, Germany
| | - Michael T. Heneka
- Department of Neurodegenerative Diseases and Geropsychiatry, Neurology, University of Bonn Medical Center, Bonn, Germany
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Jochen Walter
- Department of Neurology, University of Bonn Medical Center, Bonn, Germany
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25
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Quartey MO, Nyarko JNK, Maley JM, Barnes JR, Bolanos MAC, Heistad RM, Knudsen KJ, Pennington PR, Buttigieg J, De Carvalho CE, Leary SC, Parsons MP, Mousseau DD. The Aβ(1-38) peptide is a negative regulator of the Aβ(1-42) peptide implicated in Alzheimer disease progression. Sci Rep 2021; 11:431. [PMID: 33432101 PMCID: PMC7801637 DOI: 10.1038/s41598-020-80164-w] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 12/17/2020] [Indexed: 12/14/2022] Open
Abstract
The pool of β-Amyloid (Aβ) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for Aβ peptides. We examined how a naturally occurring variant, e.g. Aβ(1-38), interacts with the AD-related variant, Aβ(1-42), and the predominant physiological variant, Aβ(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that Aβ(1-38) interacts differently with Aβ(1-40) and Aβ(1-42) and, in general, Aβ(1-38) interferes with the conversion of Aβ(1-42) to a β-sheet-rich aggregate. Functionally, Aβ(1-38) reverses the negative impact of Aβ(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an Aβ(1-42) phenotype in Caenorhabditis elegans. Aβ(1-38) also reverses any loss of MTT conversion induced by Aβ(1-40) and Aβ(1-42) in HT-22 hippocampal neurons and APOE ε4-positive human fibroblasts, although the combination of Aβ(1-38) and Aβ(1-42) inhibits MTT conversion in APOE ε4-negative fibroblasts. A greater ratio of soluble Aβ(1-42)/Aβ(1-38) [and Aβ(1-42)/Aβ(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that Aβ(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant Aβ(1-42).
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Affiliation(s)
- Maa O Quartey
- Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, GB41 HSB, 107 Wiggins Rd., Saskatoon, SK, S7N 5E5, Canada
| | - Jennifer N K Nyarko
- Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, GB41 HSB, 107 Wiggins Rd., Saskatoon, SK, S7N 5E5, Canada
| | - Jason M Maley
- Saskatchewan Structural Sciences Centre, University of Saskatchewan, Saskatoon, SK, Canada
| | - Jocelyn R Barnes
- Division of BioMedical Sciences (Neurosciences), Memorial University of Newfoundland, St. John's, NL, Canada
| | | | - Ryan M Heistad
- Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, GB41 HSB, 107 Wiggins Rd., Saskatoon, SK, S7N 5E5, Canada
| | - Kaeli J Knudsen
- Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, GB41 HSB, 107 Wiggins Rd., Saskatoon, SK, S7N 5E5, Canada
| | - Paul R Pennington
- Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, GB41 HSB, 107 Wiggins Rd., Saskatoon, SK, S7N 5E5, Canada
| | - Josef Buttigieg
- Department of Biology, University of Regina, Regina, SK, Canada
| | | | - Scot C Leary
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Matthew P Parsons
- Division of BioMedical Sciences (Neurosciences), Memorial University of Newfoundland, St. John's, NL, Canada
| | - Darrell D Mousseau
- Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, GB41 HSB, 107 Wiggins Rd., Saskatoon, SK, S7N 5E5, Canada.
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26
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Zhao L, Liu JW, Kan BH, Shi HY, Yang LP, Liu XY. Acupuncture accelerates neural regeneration and synaptophysin production after neural stem cells transplantation in mice. World J Stem Cells 2020; 12:1576-1590. [PMID: 33505601 PMCID: PMC7789117 DOI: 10.4252/wjsc.v12.i12.1576] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 09/23/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Synaptophysin plays a key role in synaptic development and plasticity of neurons and is closely related to the cognitive process of Alzheimer's disease (AD) patients. Exogenous neural stem cells (NSCs) improve the damaged nerve function. The effects of Sanjiao acupuncture on cognitive impairment may be related to the regulation of the NSC microenvironment. AIM To explore the anti-dementia mechanism of acupuncture by regulating the NSC microenvironment. METHODS NSCs were isolated from pregnant senescence-accelerated mouse resistant 1 (SAMR1) mice, labeled with BrdU, and injected into the hippocampus of senescence-accelerated mouse prone 8 (SAMP8) mice. Eight-month-old senescence-accelerated mice (SAM) were randomly divided into six groups: SAMR1 (RC), SAMP8 (PC), sham transplantation (PS), NSC transplantation (PT), NSC transplantation with acupuncture (PTA), and NSC transplantation with non-acupoint acupuncture (PTN). Morris water maze test was used to study the learning and memory ability of mice after NSC transplantation. Hematoxylin-eosin staining and immunofluorescence were used to observe the his-topathological changes and NSC proliferation in mice. A co-culture model of hippocampal slices and NSCs was established in vitro, and the synaptophysin expression in the hippocampal microenvironment of mice was observed by flow cytometry after acupuncture treatment. RESULTS Morris water maze test showed significant cognitive impairment of learning and memory in 8-mo-old SAMP8, which improved in all the NSC transplantation groups. The behavioral change in the PTA group was stronger than those in the other two groups (P < 0.05). Histopathologically, the hippocampal structure was clear, the cell arrangement was dense and orderly, and the necrosis of cells in CA1 and CA3 areas was significantly reduced in the PTA group when compared with the PC group. The BrdU-positive proliferating cells were found in NSC hippocampal transplantation groups, and the number increased significantly in the PTA group than in the PT and PTN groups (P < 0.05). Flow cytometry showed that after co-culture of NSCs with hippocampal slices in vitro, the synaptophysin expression in the PC group decreased in comparison to the RC group, that in PT, PTA, and PTN groups increased as compared to the PC group, and that in the PTA group increased significantly as compared to the PTN group with acupoint-related specificity (P < 0.05). CONCLUSION Acupuncture may promote nerve regeneration and synaptogenesis in SAMP8 mice by regulating the microenvironment of NSC transplantation to improve the nerve activity and promote the recovery of AD-damaged cells.
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Affiliation(s)
- 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.
| | - Jian-Wei Liu
- Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Bo-Hong Kan
- 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
| | - Hui-Yan Shi
- 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
| | - Lin-Po Yang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
| | - Xin-Yu Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
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27
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Qu W, Yuan B, Liu J, Liu Q, Zhang X, Cui R, Yang W, Li B. Emerging role of AMPA receptor subunit GluA1 in synaptic plasticity: Implications for Alzheimer's disease. Cell Prolif 2020; 54:e12959. [PMID: 33188547 PMCID: PMC7791177 DOI: 10.1111/cpr.12959] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/23/2020] [Accepted: 10/24/2020] [Indexed: 02/06/2023] Open
Abstract
It is well established that GluA1 mediated synaptic plasticity plays a central role in the early development of AD. The complex cellular and molecular mechanisms that enable GluA1‐related synaptic regulation remain to fully understood. Particularly, understanding the mechanisms that disrupt GluA1 related synaptic plasticity is central to the development of disease‐modifying therapies which are sorely needed as the incidence of AD rises. We surmise that the published evidence establishes deficits in synaptic plasticity as a central factor of AD aetiology. We additionally highlight potential therapeutic strategies for the treatment of AD, and we delve into the roles of GluA1 in learning and memory. Particularly, we review the current understanding of the molecular interactions that confer the actions of this ubiquitous excitatory receptor subunit including post‐translational modification and accessory protein recruitment of the GluA1 subunit. These are proposed to regulate receptor trafficking, recycling, channel conductance and synaptic transmission and plasticity.
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Affiliation(s)
- Wenrui Qu
- Department of Hand Surgery, The Second Hospital of Jilin University, Changchun, China.,Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Baoming Yuan
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, China
| | - Jun Liu
- Department of Hand Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Qianqian Liu
- Department of Hand Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Xi Zhang
- Department of Burn Surgery, The First Hospital of Jilin University, Changchun, China
| | - Ranji Cui
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Wei Yang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Bingjin Li
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
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28
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Elmazoglu Z, Rangel-López E, Medina-Campos ON, Pedraza-Chaverri J, Túnez I, Aschner M, Santamaría A, Karasu Ç. Cannabinoid-profiled agents improve cell survival via reduction of oxidative stress and inflammation, and Nrf2 activation in a toxic model combining hyperglycemia+Aβ 1-42 peptide in rat hippocampal neurons. Neurochem Int 2020; 140:104817. [PMID: 32781098 PMCID: PMC7572748 DOI: 10.1016/j.neuint.2020.104817] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 06/29/2020] [Accepted: 07/20/2020] [Indexed: 12/15/2022]
Abstract
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder linked to various converging toxic mechanisms. Evidence suggests that hyperglycemia induces oxidative stress, mitochondrial dysfunction, inflammation and excitotoxicity, all of which play important roles in the onset and progression of AD pathogenesis. The endocannabinoid system (ECS) orchestrates major physiological responses, including neuronal plasticity, neuroprotection, and redox homeostasis, to name a few. The multi-targeted effectiveness of the ECS emerges as a potential approach to treat AD. Here we characterized the protective properties of the endocannabinoids arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), the synthetic cannabinoids CP 55-940 and WIN 55,212-2, and the fatty acid amide hydrolase (FAAH) inhibitor URB597, on a combined hyperglycemia + oligomeric amyloid β peptide (Aβ1-42) neurotoxic model in primary hippocampal neurons which exhibit several AD features. Cells were treated with cannabinoid agents at increased concentrations (1 nM-1 μM) for 6 h, and then co-treated with 150 mM glucose (GLU, 24 h), followed by incubation with 500 nM Aβ1-42 (24 h). Cell viability/survival, reactive oxygen species (ROS) levels, antioxidant enzyme (SOD, CAT, GPx and GRx) activities, biological products of oxidative damage (AGE and HNE adducts) and nitrosative stress (3-NT), several endpoints of inflammation (iNOS, IL-1β and TNF-α), amyloid quantification, mitochondrial membrane potential, and the involvement of the Nrf2 pathway, were all evaluated. The combined high glucose + amyloid beta 1-42 (GLU + Aβ1-42) condition decreased cell viability and mitochondrial membrane potential, while augmenting oxidative damage and inflammation. All agents tested preserved cell viability and stimulated mitochondrial membrane potential, while reducing all the evaluated toxic endpoints in a differential manner, with URB597 showing the highest efficacy. The neuroprotective efficacy of all cannabinoid agents, except for URB597, led to partial recruitment of specific antioxidant activity and Nrf2 pathway regulation. Our results support the neuroprotective potential of these agents at low concentrations against the damaging effects of GLU + Aβ1-42, affording new potential modalities for the design of AD therapies.
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Affiliation(s)
- Zubeyir Elmazoglu
- Cellular Stress Response and Signal Transduction Research Laboratory, Faculty of Medicine, Department of Medical Pharmacology, Gazi University, Beşevler, 06500, Ankara, Turkey
| | - Edgar Rangel-López
- Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, 14269, Mexico
| | - Omar Noel Medina-Campos
- Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
| | - José Pedraza-Chaverri
- Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
| | - Isaac Túnez
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina y Enfermería, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Córdoba, 14004, Spain
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, United States
| | - Abel Santamaría
- Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, 14269, Mexico.
| | - Çimen Karasu
- Cellular Stress Response and Signal Transduction Research Laboratory, Faculty of Medicine, Department of Medical Pharmacology, Gazi University, Beşevler, 06500, Ankara, Turkey.
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29
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Jaunmuktane Z, Brandner S. Invited Review: The role of prion-like mechanisms in neurodegenerative diseases. Neuropathol Appl Neurobiol 2020; 46:522-545. [PMID: 31868945 PMCID: PMC7687189 DOI: 10.1111/nan.12592] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/30/2019] [Accepted: 12/17/2019] [Indexed: 12/12/2022]
Abstract
The prototype of transmissible neurodegenerative proteinopathies is prion diseases, characterized by aggregation of abnormally folded conformers of the native prion protein. A wealth of mechanisms has been proposed to explain the conformational conversion from physiological protein into misfolded, pathological form, mode of toxicity, propagation from cell-to-cell and regional spread. There is increasing evidence that other neurodegenerative diseases, most notably Alzheimer's disease (Aβ and tau), Parkinson's disease (α-synuclein), frontotemporal dementia (TDP43, tau or FUS) and motor neurone disease (TDP43), exhibit at least some of the misfolded prion protein properties. In this review, we will discuss to what extent each of the properties of misfolded prion protein is known to occur for Aβ, tau, α-synuclein and TDP43, with particular focus on self-propagation through seeding, conformational strains, selective cellular and regional vulnerability, stability and resistance to inactivation, oligomers, toxicity and summarize the most recent literature on transmissibility of neurodegenerative disorders.
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Affiliation(s)
- Z. Jaunmuktane
- Division of NeuropathologyNational Hospital for Neurology and NeurosurgeryUniversity College London NHS Foundation Trust
- Department of Clinical and Movement Neurosciences and Queen Square Brain Bank for Neurological Disorders
| | - S. Brandner
- Division of NeuropathologyNational Hospital for Neurology and NeurosurgeryUniversity College London NHS Foundation Trust
- Department of Neurodegenerative diseaseQueen Square Institute of NeurologyUniversity College LondonLondonUK
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30
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Liquiritigenin Decreases Aβ Levels and Ameliorates Cognitive Decline by Regulating Microglia M1/M2 Transformation in AD Mice. Neurotox Res 2020; 39:349-358. [PMID: 32990912 DOI: 10.1007/s12640-020-00284-z] [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] [Received: 05/11/2020] [Revised: 08/20/2020] [Accepted: 09/02/2020] [Indexed: 10/23/2022]
Abstract
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is currently incurable. Amyloid β protein (Aβ) deposition is the main pathogenesis of AD, and many studies have shown that Aβ accumulation is toxic to neurons, leading to the inflammatory reaction, neuronal apoptosis, and neurofibrillary tangles. Thus, reducing Aβ levels might be a potential therapeutic strategy for AD. Liquiritigenin (LG), a dihydroflavone monomer compound extracted from natural plant licorice, has a variety of biological activities such as antioxidant, anti-tumor, anti-inflammatory and anti-virus. However, the exact function of LG in the pathogenesis of AD is elusive. Here, we reported that LG could significantly attenuate neuronal apoptosis in Aβ-induced N2A cells and APP/PS1 transgenic mice. Our in vivo and in vitro studies revealed that LG could alleviate the inflammation response, reflected by the reduction of NLRP3 and cleaved caspase-1. Meanwhile, we also found that LG was able to shift M1 type microglia towards M2 type microglia in Aβ-induced BV2 cells and AD mice. Furthermore, LG could reduce the Aβ levels by decreasing APP processing and accelerating Aβ clearance in AD mice. More importantly, daily treatment of LG (30 mg/kg day) for 90 days dramatically ameliorated the spatial learning and memory of AD mice. Taken together, these results suggest that LG can reduce the Aβ levels by regulating the M1/M2 transformation of microglia, thereby reversing memory decline during AD development, suggesting that LG may be a potential therapeutic agent for treating AD.
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31
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Johnson ECB, Ho K, Yu GQ, Das M, Sanchez PE, Djukic B, Lopez I, Yu X, Gill M, Zhang W, Paz JT, Palop JJ, Mucke L. Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer's disease mutations but not by inhibition of BACE1. Mol Neurodegener 2020; 15:53. [PMID: 32921309 PMCID: PMC7489007 DOI: 10.1186/s13024-020-00393-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 07/08/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is the most frequent and costly neurodegenerative disorder. Although diverse lines of evidence suggest that the amyloid precursor protein (APP) is involved in its causation, the precise mechanisms remain unknown and no treatments are available to prevent or halt the disease. A favorite hypothesis has been that APP contributes to AD pathogenesis through the cerebral accumulation of the amyloid-β peptide (Aβ), which is derived from APP through sequential proteolytic cleavage by BACE1 and γ-secretase. However, inhibitors of these enzymes have failed in clinical trials despite clear evidence for target engagement. METHODS To further elucidate the roles of APP and its metabolites in AD pathogenesis, we analyzed transgenic mice overexpressing wildtype human APP (hAPP) or hAPP carrying mutations that cause autosomal dominant familial AD (FAD), as well as App knock-in mice that do not overexpress hAPP but have two mouse App alleles with FAD mutations and a humanized Aβ sequence. RESULTS Although these lines of mice had marked differences in cortical and hippocampal levels of APP, APP C-terminal fragments, soluble Aβ, Aβ oligomers and age-dependent amyloid deposition, they all developed cognitive deficits as well as non-convulsive epileptiform activity, a type of network dysfunction that also occurs in a substantive proportion of humans with AD. Pharmacological inhibition of BACE1 effectively reduced levels of amyloidogenic APP C-terminal fragments (C99), soluble Aβ, Aβ oligomers, and amyloid deposits in transgenic mice expressing FAD-mutant hAPP, but did not improve their network dysfunction and behavioral abnormalities, even when initiated at early stages before amyloid deposits were detectable. CONCLUSIONS hAPP transgenic and App knock-in mice develop similar pathophysiological alterations. APP and its metabolites contribute to AD-related functional alterations through complex combinatorial mechanisms that may be difficult to block with BACE inhibitors and, possibly, also with other anti-Aβ treatments.
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Affiliation(s)
- Erik C. B. Johnson
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
- Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158 USA
| | - Kaitlyn Ho
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
| | - Gui-Qiu Yu
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
| | - Melanie Das
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
| | - Pascal E. Sanchez
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
| | - Biljana Djukic
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
| | - Isabel Lopez
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
| | - Xinxing Yu
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
| | - Michael Gill
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
| | - Weiping Zhang
- NHC Key Laboratory of Hormones and Development, Tianjin Institute of Endocrinology, Tianjin Medical University Metabolic Diseases Hospital, Tianjin, China
| | - Jeanne T. Paz
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
- Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158 USA
| | - Jorge J. Palop
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
- Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158 USA
| | - Lennart Mucke
- Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158 USA
- Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158 USA
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Li S, Selkoe DJ. A mechanistic hypothesis for the impairment of synaptic plasticity by soluble Aβ oligomers from Alzheimer's brain. J Neurochem 2020; 154:583-597. [PMID: 32180217 PMCID: PMC7487043 DOI: 10.1111/jnc.15007] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/28/2020] [Accepted: 03/02/2020] [Indexed: 12/18/2022]
Abstract
It is increasingly accepted that early cognitive impairment in Alzheimer's disease results in considerable part from synaptic dysfunction caused by the accumulation of a range of oligomeric assemblies of amyloid β-protein (Aβ). Most studies have used synthetic Aβ peptides to explore the mechanisms of memory deficits in rodent models, but recent work suggests that Aβ assemblies isolated from human (AD) brain tissue are far more potent and disease-relevant. Although reductionist experiments show Aβ oligomers to impair synaptic plasticity and neuronal viability, the responsible mechanisms are only partly understood. Glutamatergic receptors, GABAergic receptors, nicotinic receptors, insulin receptors, the cellular prion protein, inflammatory mediators, and diverse signaling pathways have all been suggested. Studies using AD brain-derived soluble Aβ oligomers suggest that only certain bioactive forms (principally small, diffusible oligomers) can disrupt synaptic plasticity, including by binding to plasma membranes and changing excitatory-inhibitory balance, perturbing mGluR, PrP, and other neuronal surface proteins, down-regulating glutamate transporters, causing glutamate spillover, and activating extrasynaptic GluN2B-containing NMDA receptors. We synthesize these emerging data into a mechanistic hypothesis for synaptic failure in Alzheimer's disease that can be modified as new knowledge is added and specific therapeutics are developed.
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Affiliation(s)
- Shaomin Li
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Dennis J Selkoe
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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Bai Y, Ma X. Chlorzoxazone exhibits neuroprotection against Alzheimer's disease by attenuating neuroinflammation and neurodegeneration in vitro and in vivo. Int Immunopharmacol 2020; 88:106790. [PMID: 32795892 DOI: 10.1016/j.intimp.2020.106790] [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: 04/15/2020] [Revised: 06/21/2020] [Accepted: 07/06/2020] [Indexed: 11/25/2022]
Abstract
Alzheimer's disease (AD), a complex and an age-related brain disease, is induced by the accumulation of amyloid beta (Aβ) and neuroinflammation. Chlorzoxazone (CZ) is a classical FDA-approved drug, and shows anti-inflammatory effects. However, up until now, its regulatory role in AD has not been investigated. Therefore, in this study we attempted to explore if CZ could be an effective therapeutic strategy for AD treatment. At first, the in vitro study was performed to mimic AD using Aβ. We found that Aβ caused p65 nuclear translocation in both primary microglial cells and astrocytes, which were, however, restrained by CZ treatments. Meanwhile, CZ incubation markedly decreased the expression of pro-inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β). Aβ deposition was also markedly reduced in glial cells treated with CZ. Importantly, we found that glial activation and its-related pro-inflammation induced by Aβ led to obvious neurodegeneration and neuroinflammation, which were effectively attenuated by CZ pre-treatment in the isolated primary cortical neurons. Then, the in vivo study was performed using APP/PS1 mice with AD. Behavior tests showed that CZ administration effectively improved cognitive deficits in AD mice. Neuron death in hippocampus of AD mice was also inhibited by CZ. Aβ accumulation in brain was markedly decreased in CZ-treated AD mice. We finally found that hippocampal glial activation in AD mice was obviously blocked by CZ supplementation, along with remarkable decreases in TNF-α, IL-1β and p65 nuclear translocation. Together, these findings above demonstrated that CZ could inhibit glial activation and inflammatory response, contributing to the suppression of neurodegeneration and neuroinflammation. Therefore, CZ may be an effective therapeutic strategy for AD treatment.
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Affiliation(s)
- Yanyan Bai
- Department of Neurology, The First Hospital of Yulin, Yulin 719000, China
| | - Xinshun Ma
- Department of Neurology, The First Hospital of Yulin, Yulin 719000, China.
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Harris SS, Wolf F, De Strooper B, Busche MA. Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer’s Disease. Neuron 2020; 107:417-435. [DOI: 10.1016/j.neuron.2020.06.005] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/24/2020] [Accepted: 06/01/2020] [Indexed: 02/07/2023]
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35
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Heckmann BL, Teubner BJW, Boada-Romero E, Tummers B, Guy C, Fitzgerald P, Mayer U, Carding S, Zakharenko SS, Wileman T, Green DR. Noncanonical function of an autophagy protein prevents spontaneous Alzheimer's disease. SCIENCE ADVANCES 2020; 6:eabb9036. [PMID: 32851186 PMCID: PMC7428329 DOI: 10.1126/sciadv.abb9036] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 07/02/2020] [Indexed: 05/02/2023]
Abstract
Noncanonical functions of autophagy proteins have been implicated in neurodegenerative conditions, including Alzheimer's disease (AD). The WD domain of the autophagy protein Atg16L is dispensable for canonical autophagy but required for its noncanonical functions. Two-year-old mice lacking this domain presented with robust β-amyloid (Aβ) pathology, tau hyperphosphorylation, reactive microgliosis, pervasive neurodegeneration, and severe behavioral and memory deficiencies, consistent with human disease. Mechanistically, we found this WD domain was required for the recycling of Aβ receptors in primary microglia. Pharmacologic suppression of neuroinflammation reversed established memory impairment and markers of disease pathology in this novel AD model. Therefore, loss of the Atg16L WD domain drives spontaneous AD in mice, and inhibition of neuroinflammation is a potential therapeutic approach for treating neurodegeneration and memory loss. A decline in expression of ATG16L in the brains of human patients with AD suggests the possibility that a similar mechanism may contribute in human disease.
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Affiliation(s)
- Bradlee L. Heckmann
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Brett J. W. Teubner
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Emilio Boada-Romero
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Bart Tummers
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Clifford Guy
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Patrick Fitzgerald
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Ulrike Mayer
- School of Biological Sciences, University of East Anglia, Norwich, Norfolk, UK
| | - Simon Carding
- Quadram Institute of Bioscience, Norwich, Norfolk, UK
| | - Stanislav S. Zakharenko
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Thomas Wileman
- Quadram Institute of Bioscience, Norwich, Norfolk, UK
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, UK
| | - Douglas R. Green
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA
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36
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Mancuso C, Gaetani S. Editorial: Alzheimer's Disease: Original Mechanisms and Translational Impact. Front Pharmacol 2020; 11:157. [PMID: 32174838 PMCID: PMC7054435 DOI: 10.3389/fphar.2020.00157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 02/06/2020] [Indexed: 12/05/2022] Open
Affiliation(s)
- Cesare Mancuso
- Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy.,Institute of Pharmacology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Silvana Gaetani
- Department of Physiology and Pharmacology "V. Erspamer," Sapienza University of Rome, Rome, Italy
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Beta amyloid aggregates induce sensitised TLR4 signalling causing long-term potentiation deficit and rat neuronal cell death. Commun Biol 2020; 3:79. [PMID: 32071389 PMCID: PMC7028984 DOI: 10.1038/s42003-020-0792-9] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 01/24/2020] [Indexed: 01/26/2023] Open
Abstract
The molecular events causing memory loss and neuronal cell death in Alzheimer’s disease (AD) over time are still unknown. Here we found that picomolar concentrations of soluble oligomers of synthetic beta amyloid (Aβ42) aggregates incubated with BV2 cells or rat astrocytes caused a sensitised response of Toll-like receptor 4 (TLR4) with time, leading to increased production of TNF-α. Aβ aggregates caused long term potentiation (LTP) deficit in hippocampal slices and predominantly neuronal cell death in co-cultures of astrocytes and neurons, which was blocked by TLR4 antagonists. Soluble Aβ aggregates cause LTP deficit and neuronal death via an autocrine/paracrine mechanism due to TLR4 signalling. These findings suggest that the TLR4-mediated inflammatory response may be a key pathophysiological process in AD. Hughes et al. investigate the TLR4-mediated inflammatory response in Alzheimer’s disease and show that picomolar concentrations of soluble amyloid beta aggregates lead to a sensitised response of TLR4 with time, resulting in increased TNF-α production. They suggest the use of near physiological concentration of soluble aggregates can cause long-term potentiation deficit and neuronal death through an autocrine/paracrine mechanism due to TLR4 signalling.
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Guillemaud O, Ceyzériat K, Saint-Georges T, Cambon K, Petit F, Ben Haim L, Carrillo-de Sauvage MA, Guillermier M, Bernier S, Hérard AS, Joséphine C, Bémelmans AP, Brouillet E, Hantraye P, Bonvento G, Escartin C. Complex roles for reactive astrocytes in the triple transgenic mouse model of Alzheimer disease. Neurobiol Aging 2020; 90:135-146. [PMID: 32171592 DOI: 10.1016/j.neurobiolaging.2020.02.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 02/06/2020] [Accepted: 02/12/2020] [Indexed: 12/29/2022]
Abstract
In Alzheimer disease (AD), astrocytes undergo complex changes and become reactive. The consequences of this reaction are still unclear. To evaluate the net impact of reactive astrocytes in AD, we developed viral vectors targeting astrocytes that either activate or inhibit the Janus kinase-signal transducer and activator of transcription 3 (JAK2-STAT3) pathway, a central cascade controlling astrocyte reaction. We aimed to evaluate whether reactive astrocytes contribute to tau as well as amyloid pathologies in the hippocampus of 3xTg-AD mice, an AD model that develops tau hyper-phosphorylation and amyloid deposition. JAK2-STAT3 pathway-mediated modulation of reactive astrocytes in 25% of the hippocampus of 3xTg-AD mice did not significantly influence tau phosphorylation or amyloid processing and deposition at early, advanced, and terminal disease stage. Interestingly, inhibition of the JAK2-STAT3 pathway in hippocampal astrocytes did not improve spatial memory in the Y maze but it did reduce anxiety in the elevated plus maze. Our unique approach to specifically manipulate reactive astrocytes in situ show they may impact behavioral outcomes without influencing tau or amyloid pathology.
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Affiliation(s)
- Océane Guillemaud
- Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France
| | - Kelly Ceyzériat
- Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France
| | - Thomas Saint-Georges
- Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France
| | - Karine Cambon
- Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France
| | - Fanny Petit
- Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France
| | - Lucile Ben Haim
- Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France
| | | | - Martine Guillermier
- Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France
| | - Sueva Bernier
- Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France
| | - Anne-Sophie Hérard
- Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France
| | - Charlène Joséphine
- Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France
| | - Alexis Pierre Bémelmans
- Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France
| | - Emmanuel Brouillet
- Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France
| | - Philippe Hantraye
- Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France
| | - Gilles Bonvento
- Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France
| | - Carole Escartin
- Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France.
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Wei Z, Meng X, El Fatimy R, Sun B, Mai D, Zhang J, Arora R, Zeng A, Xu P, Qu S, Krichevsky AM, Selkoe DJ, Li S. Environmental enrichment prevents Aβ oligomer-induced synaptic dysfunction through mirna-132 and hdac3 signaling pathways. Neurobiol Dis 2020; 134:104617. [PMID: 31669733 PMCID: PMC7243177 DOI: 10.1016/j.nbd.2019.104617] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 09/04/2019] [Accepted: 09/17/2019] [Indexed: 12/21/2022] Open
Abstract
As the most common cause of progressive cognitive decline in humans, Alzheimer's disease (AD) has been intensively studied, but the mechanisms underlying its profound synaptic dysfunction remain unclear. Here we confirm that exposing wild-type mice to an enriched environment (EE) facilitates signaling in the hippocampus that promotes long-term potentiation (LTP). Exposing the hippocampus of mice kept in standard housing to soluble Aβ oligomers impairs LTP, but EE can fully prevent this. Mechanistically, the key molecular features of the EE benefit are an upregulation of miRNA-132 and an inhibition of histone deacetylase (HDAC) signaling. Specifically, soluble Aβ oligomers decreased miR-132 expression and increased HDAC3 levels in cultured primary neurons. Further, we provide evidence that HDAC3 is a direct target of miR-132. Overexpressing miR-132 or injecting an HDAC3 inhibitor into mice in standard housing mimics the benefits of EE in enhancing hippocampal LTP and preventing hippocampal impairment by Aβ oligomers in vivo. We conclude that EE enhances hippocampal synaptic plasticity by upregulating miRNA-132 and reducing HDAC3 signaling in a way that counteracts the synaptotoxicity of human Aβ oligomers. Our findings provide a rationale for prolonged exposure to cognitive novelty and/or epigenetic modulation to lessen the progressive effects of Aβ accumulation during human brain aging.
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Affiliation(s)
- Zhiyun Wei
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of America; Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xingjun Meng
- Central Laboratory and Department of Neurology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan 528300, Guangdong, China
| | - Rachid El Fatimy
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of America
| | - Bowen Sun
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of America
| | - Dongmei Mai
- Central Laboratory and Department of Neurology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan 528300, Guangdong, China
| | - Junfang Zhang
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of America; Department of Physiology and Pharmacology, School of Medicine, Ningbo University, Ningbo, HMS Initiative for RNA Medicine, Zhejiang, China
| | - Ramil Arora
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of America
| | - Ailiang Zeng
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of America
| | - Pingyi Xu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shaogang Qu
- Central Laboratory and Department of Neurology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan 528300, Guangdong, China
| | - Anna M Krichevsky
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of America
| | - Dennis J Selkoe
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of America
| | - Shaomin Li
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, United States of America.
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40
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Li S, Hayden EY, Garcia VJ, Fuchs DT, Sheyn J, Daley DA, Rentsendorj A, Torbati T, Black KL, Rutishauser U, Teplow DB, Koronyo Y, Koronyo-Hamaoui M. Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer's-Related Aβ 42 Oligomers and Protect Synapses. Front Immunol 2020; 11:49. [PMID: 32082319 PMCID: PMC7005081 DOI: 10.3389/fimmu.2020.00049] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 01/09/2020] [Indexed: 12/13/2022] Open
Abstract
Impaired synaptic integrity and function due to accumulation of amyloid β-protein (Aβ42) oligomers is thought to be a major contributor to cognitive decline in Alzheimer's disease (AD). However, the exact role of Aβ42 oligomers in synaptotoxicity and the ability of peripheral innate immune cells to rescue synapses remain poorly understood due to the metastable nature of oligomers. Here, we utilized photo-induced cross-linking to stabilize pure oligomers and study their effects vs. fibrils on synapses and protection by Aβ-phagocytic macrophages. We found that cortical neurons were more susceptible to Aβ42 oligomers than fibrils, triggering additional neuritic arborization retraction, functional alterations (hyperactivity and spike waveform), and loss of VGluT1- and PSD95-excitatory synapses. Co-culturing neurons with bone marrow-derived macrophages protected synapses against Aβ42 fibrils; moreover, immune activation with glatiramer acetate (GA) conferred further protection against oligomers. Mechanisms involved increased Aβ42 removal by macrophages, amplified by GA stimulation: fibrils were largely cleared through intracellular CD36/EEA1+-early endosomal proteolysis, while oligomers were primarily removed via extracellular/MMP-9 enzymatic degradation. In vivo studies in GA-immunized or CD115+-monocyte-grafted APPSWE/PS1ΔE9-transgenic mice followed by pre- and postsynaptic analyses of entorhinal cortex and hippocampal substructures corroborated our in vitro findings of macrophage-mediated synaptic preservation. Together, our data demonstrate that activated macrophages effectively clear Aβ42 oligomers and rescue VGluT1/PSD95 synapses, providing rationale for harnessing macrophages to treat AD.
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Affiliation(s)
- Songlin Li
- Institute of Neuroscience and Chemistry, Wenzhou University, Wenzhou, China
- Institute of Life Sciences, Wenzhou University, Wenzhou, China
- Department of Neurosurgery, Cedars-Sinai Medical Center, Maxine-Dunitz Neurosurgical Institute, Los Angeles, CA, United States
| | - Eric Y. Hayden
- Department of Neurology, David Geffen School of Medicine at UCLA, Mary S. Easton Center for Alzheimer's Disease Research at UCLA, Brain Research Institute, Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, United States
| | - Veronica J. Garcia
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Dieu-Trang Fuchs
- Department of Neurosurgery, Cedars-Sinai Medical Center, Maxine-Dunitz Neurosurgical Institute, Los Angeles, CA, United States
| | - Julia Sheyn
- Department of Neurosurgery, Cedars-Sinai Medical Center, Maxine-Dunitz Neurosurgical Institute, Los Angeles, CA, United States
| | - David A. Daley
- Department of Neurosurgery, Cedars-Sinai Medical Center, Maxine-Dunitz Neurosurgical Institute, Los Angeles, CA, United States
| | - Altan Rentsendorj
- Department of Neurosurgery, Cedars-Sinai Medical Center, Maxine-Dunitz Neurosurgical Institute, Los Angeles, CA, United States
| | - Tania Torbati
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
| | - Keith L. Black
- Department of Neurosurgery, Cedars-Sinai Medical Center, Maxine-Dunitz Neurosurgical Institute, Los Angeles, CA, United States
| | - Ueli Rutishauser
- Department of Neurosurgery, Cedars-Sinai Medical Center, Maxine-Dunitz Neurosurgical Institute, Los Angeles, CA, United States
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - David B. Teplow
- Department of Neurology, David Geffen School of Medicine at UCLA, Mary S. Easton Center for Alzheimer's Disease Research at UCLA, Brain Research Institute, Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, United States
| | - Yosef Koronyo
- Department of Neurosurgery, Cedars-Sinai Medical Center, Maxine-Dunitz Neurosurgical Institute, Los Angeles, CA, United States
| | - Maya Koronyo-Hamaoui
- Department of Neurosurgery, Cedars-Sinai Medical Center, Maxine-Dunitz Neurosurgical Institute, Los Angeles, CA, United States
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
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Lučiūnaitė A, McManus RM, Jankunec M, Rácz I, Dansokho C, Dalgėdienė I, Schwartz S, Brosseron F, Heneka MT. Soluble Aβ oligomers and protofibrils induce NLRP3 inflammasome activation in microglia. J Neurochem 2020; 155:650-661. [DOI: 10.1111/jnc.14945] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 12/13/2019] [Accepted: 12/13/2019] [Indexed: 12/17/2022]
Affiliation(s)
- Asta Lučiūnaitė
- Institute of Biotechnology, Life Sciences Center Vilnius University Vilnius Lithuania
- Department of Neurodegenerative Disease and Geriatric PsychiatryBonn Germany
- German Center for Neurodegenerative Disease (DZNE) Bonn Germany
| | - Róisín M. McManus
- Department of Neurodegenerative Disease and Geriatric PsychiatryBonn Germany
- German Center for Neurodegenerative Disease (DZNE) Bonn Germany
| | - Marija Jankunec
- Institute of Biochemistry, Life Sciences Center Vilnius University Vilnius Lithuania
| | - Ildikó Rácz
- Department of Neurodegenerative Disease and Geriatric PsychiatryBonn Germany
| | - Cira Dansokho
- Department of Neurodegenerative Disease and Geriatric PsychiatryBonn Germany
- German Center for Neurodegenerative Disease (DZNE) Bonn Germany
| | - Indrė Dalgėdienė
- Institute of Biotechnology, Life Sciences Center Vilnius University Vilnius Lithuania
| | - Stephanie Schwartz
- Department of Neurodegenerative Disease and Geriatric PsychiatryBonn Germany
| | | | - Michael T. Heneka
- Department of Neurodegenerative Disease and Geriatric PsychiatryBonn Germany
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42
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Wirths O, Zampar S. Emerging roles of N- and C-terminally truncated Aβ species in Alzheimer’s disease. Expert Opin Ther Targets 2019; 23:991-1004. [DOI: 10.1080/14728222.2019.1702972] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Oliver Wirths
- Department of Psychiatry and Psychotherapy, Molecular Psychiatry, University Medical Center (UMG), Georg-August-University, Göttingen, Germany
| | - Silvia Zampar
- Department of Psychiatry and Psychotherapy, Molecular Psychiatry, University Medical Center (UMG), Georg-August-University, Göttingen, Germany
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De S, Whiten DR, Ruggeri FS, Hughes C, Rodrigues M, Sideris DI, Taylor CG, Aprile FA, Muyldermans S, Knowles TPJ, Vendruscolo M, Bryant C, Blennow K, Skoog I, Kern S, Zetterberg H, Klenerman D. Soluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer's disease progression. Acta Neuropathol Commun 2019; 7:120. [PMID: 31349874 PMCID: PMC6659275 DOI: 10.1186/s40478-019-0777-4] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 07/18/2019] [Indexed: 01/14/2023] Open
Abstract
Soluble aggregates of amyloid-β (Aβ) have been associated with neuronal and synaptic loss in Alzheimer's disease (AD). However, despite significant recent progress, the mechanisms by which these aggregated species contribute to disease progression are not fully determined. As the analysis of human cerebrospinal fluid (CSF) provides an accessible window into the molecular changes associated with the disease progression, we characterised soluble aggregates present in CSF samples from individuals with AD, mild cognitive impairment (MCI) and healthy controls using a range of sensitive biophysical methods. We used super-resolution imaging and atomic force microscopy to characterise the size and structure of the aggregates present in CSF and correlate this with their ability to permeabilise lipid membranes and induce an inflammatory response. We found that these aggregates are extremely heterogeneous and exist in a range of sizes, varying both structurally and in their mechanisms of toxicity during the disease progression. A higher proportion of small aggregates of Aβ that can cause membrane permeabilization are found in MCI CSF; in established AD, a higher proportion of the aggregates were larger and more prone to elicit a pro-inflammatory response in glial cells, while there was no detectable change in aggregate concentration. These results show that large aggregates, some longer than 100 nm, are present in the CSF of AD patients and suggest that different neurotoxic mechanisms are prevalent at different stages of AD.
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44
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De S, Wirthensohn DC, Flagmeier P, Hughes C, Aprile FA, Ruggeri FS, Whiten DR, Emin D, Xia Z, Varela JA, Sormanni P, Kundel F, Knowles TPJ, Dobson CM, Bryant C, Vendruscolo M, Klenerman D. Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms. Nat Commun 2019; 10:1541. [PMID: 30948723 PMCID: PMC6449370 DOI: 10.1038/s41467-019-09477-3] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 03/13/2019] [Indexed: 01/20/2023] Open
Abstract
Protein aggregation is a complex process resulting in the formation of heterogeneous mixtures of aggregate populations that are closely linked to neurodegenerative conditions, such as Alzheimer's disease. Here, we find that soluble aggregates formed at different stages of the aggregation process of amyloid beta (Aβ42) induce the disruption of lipid bilayers and an inflammatory response to different extents. Further, by using gradient ultracentrifugation assay, we show that the smaller aggregates are those most potent at inducing membrane permeability and most effectively inhibited by antibodies binding to the C-terminal region of Aβ42. By contrast, we find that the larger soluble aggregates are those most effective at causing an inflammatory response in microglia cells and more effectively inhibited by antibodies targeting the N-terminal region of Aβ42. These findings suggest that different toxic mechanisms driven by different soluble aggregated species of Aβ42 may contribute to the onset and progression of Alzheimer's disease.
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Affiliation(s)
- Suman De
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
| | - David C Wirthensohn
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
| | - Patrick Flagmeier
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
- Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
| | - Craig Hughes
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
- Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, CB3 0ES, UK
| | - Francesco A Aprile
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
- Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
| | - Francesco S Ruggeri
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
- Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
| | - Daniel R Whiten
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
| | - Derya Emin
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
| | - Zengjie Xia
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
| | - Juan A Varela
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
| | - Pietro Sormanni
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
- Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
| | - Franziska Kundel
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
| | - Tuomas P J Knowles
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
- Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
- Cavendish Laboratory, University of Cambridge, J J Thomson Avenue, Cambridge, CB3 1HE, UK
| | - Christopher M Dobson
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
- Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
| | - Clare Bryant
- Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, CB3 0ES, UK
| | - Michele Vendruscolo
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
- Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
| | - David Klenerman
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
- UK Dementia Research Institute, University of Cambridge, Cambridge, CB2 0XY, UK.
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45
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Querol-Vilaseca M, Colom-Cadena M, Pegueroles J, Nuñez-Llaves R, Luque-Cabecerans J, Muñoz-Llahuna L, Andilla J, Belbin O, Spires-Jones TL, Gelpi E, Clarimon J, Loza-Alvarez P, Fortea J, Lleó A. Nanoscale structure of amyloid-β plaques in Alzheimer's disease. Sci Rep 2019; 9:5181. [PMID: 30914681 PMCID: PMC6435662 DOI: 10.1038/s41598-019-41443-3] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 03/08/2019] [Indexed: 12/15/2022] Open
Abstract
Soluble amyloid-β (Aβ) is considered to be a critical component in the pathogenesis of Alzheimer’s disease (AD). Evidence suggests that these non-fibrillar Aβ assemblies are implicated in synaptic dysfunction, neurodegeneration and cell death. However, characterization of these species comes mainly from studies in cellular or animal models, and there is little data in intact human samples due to the lack of adequate optical microscopic resolution to study these small structures. Here, to achieve super-resolution in all three dimensions, we applied Array Tomography (AT) and Stimulated Emission Depletion microscopy (STED), to characterize in postmortem human brain tissue non-fibrillar Aβ structures in amyloid plaques of cases with autosomal dominant and sporadic AD. Ultrathin sections scanned with super-resolution STED microscopy allowed the detection of small Aβ structures of the order of 100 nm. We reconstructed a whole human amyloid plaque and established that plaques are formed by a dense core of higher order Aβ species (~0.022 µm3) and a peripheral halo of smaller Aβ structures (~0.003 µm3). This work highlights the potential of AT-STED for human neuropathological studies.
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Affiliation(s)
- Marta Querol-Vilaseca
- Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Martí Colom-Cadena
- Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Jordi Pegueroles
- Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Raúl Nuñez-Llaves
- Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Joan Luque-Cabecerans
- Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Laia Muñoz-Llahuna
- Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Jordi Andilla
- ICFO-Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology, Castelldefels, Barcelona, Spain
| | - Olivia Belbin
- Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Tara L Spires-Jones
- The University of Edinburgh, UK Dementia Research Institute, Centre for Discovery Brain Sciences, Edinburgh, EH8 9JZ, UK
| | - Ellen Gelpi
- Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS, Barcelona, Spain.,Institute of Neurology, Medical University of Vienna, Vienna, Austria
| | - Jordi Clarimon
- Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Pablo Loza-Alvarez
- ICFO-Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology, Castelldefels, Barcelona, Spain
| | - Juan Fortea
- Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Alberto Lleó
- Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. .,Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
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