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1
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Quan Q, Ma X, Feng J, Li W, Li X. Ginsenoside Rg1 improves autophagy dysfunction to ameliorate Alzheimer's disease via targeting FGR proto-oncogene. Neuropeptides 2025; 111:102514. [PMID: 40073763 DOI: 10.1016/j.npep.2025.102514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/28/2025] [Accepted: 03/02/2025] [Indexed: 03/14/2025]
Abstract
Alzheimer's disease (AD) is a neurodegeneration driven by beta-amyloid (Aβ) deposits in the brain involving autophagy dysfunction. Ginsenoside Rg1, a pharmacologically active compound found in ginseng, has possible therapeutic effects for AD. This study discovered that FGR proto-oncogene (FGR) was a therapeutic target of Rg1 in AD and it was possibly involved in autophagy. C57BL/6 J mice were injected with 5 μL (1 μg/mL) Aβ1-42 in the right lateral ventricle to establish an AD model. AD mouse hippocampus had high FGR expression. Intragastrically administered Rg1 (40 mg/kg) decreased FGR protein levels in AD mice's hippocampus and improved memory function in AD mice. Both sides of the mice hippocampal fissure were administered with 2 μL lentiviral particles (1 × 107 TU) containing FGR overexpression plasmids. FGR overexpression rendered Rg1 ineffectual in restoring memory function and reducing hippocampal neuron damage. We injected 2 μL lentiviral particles (1 × 107 TU) containing short hairpin RNA plasmids targeting FGR to the mice hippocampal fissures. FGR knockdown improved spatial memory function of AD mice, reduced hippocampal neuron apoptosis, and prevented Aβ accumulation. HT22 cells were transfected with small interfering RNA targeting FGR. FGR knockdown increased the viability of Aβ1-42 treated HT22 cells. BACE1 and LC3II/I protein levels were decreased and p62 and SIRT1 were increased in AD mice and cells with FGR knockdown. LC3 was down-regulated after inhibiting FGR expression in Aβ1-42 treated hippocampal neurons. In conclusion, Rg1 exerts anti-AD functions by targeting FGR and downregulating its expression.
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Affiliation(s)
- Qiankun Quan
- Department of Geriatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xinxin Ma
- Department of Psychology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - JianJun Feng
- Department of Geriatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wanni Li
- Department of Geriatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xi Li
- Department of Geriatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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2
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Bhatia V, Chandel A, Minhas Y, Kushawaha SK. "Advances in biomarker discovery and diagnostics for alzheimer's disease". Neurol Sci 2025:10.1007/s10072-025-08023-y. [PMID: 39893357 DOI: 10.1007/s10072-025-08023-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 01/20/2025] [Indexed: 02/04/2025]
Abstract
BACKGROUND Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by intracellular neurofibrillary tangles with tau protein and extracellular β-amyloid plaques. Early and accurate diagnosis is crucial for effective treatment and management. OBJECTIVE The purpose of this review is to investigate new technologies that improve diagnostic accuracy while looking at the current diagnostic criteria for AD, such as clinical evaluations, cognitive testing, and biomarker-based techniques. METHODS A thorough review of the literature was done in order to assess both conventional and contemporary diagnostic methods. Multimodal strategies integrating clinical, imaging, and biochemical evaluations were emphasised. The promise of current developments in biomarker discovery was also examined, including mass spectrometry and artificial intelligence. RESULTS Current diagnostic approaches include cerebrospinal fluid (CSF) biomarkers, imaging tools (MRI, PET), cognitive tests, and new blood-based markers. Integrating these technologies into multimodal diagnostic procedures enhances diagnostic accuracy and distinguishes dementia from other conditions. New technologies that hold promise for improving biomarker identification and diagnostic reliability include mass spectrometry and artificial intelligence. CONCLUSION Advancements in AD diagnostics underscore the need for accessible, minimally invasive, and cost-effective techniques to facilitate early detection and intervention. The integration of novel technologies with traditional methods may significantly enhance the accuracy and feasibility of AD diagnosis.
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Affiliation(s)
- Vandana Bhatia
- Department of Pharmacology, Laureate Institute of Pharmacy Kathog, Kangra, 177101, India.
| | - Anjali Chandel
- Department of Pharmacology, Laureate Institute of Pharmacy Kathog, Kangra, 177101, India
| | - Yavnika Minhas
- Department of Pharmacology, Laureate Institute of Pharmacy Kathog, Kangra, 177101, India
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3
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Jáuregui GV, Parpura V. Neuron-Astrocyte Interactions in Aging and Alzheimer's Disease: Dysregulation of Amyloid Precursor Protein. AGEING & LONGEVITY 2025; 6:117-128. [PMID: 40098995 PMCID: PMC11911455 DOI: 10.47855/jal9020-2025-2-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Amyloid precursor protein (APP) is central to Alzheimer's disease (AD) by its role in Aβ build-up and in neuronal and astrocytic malfunction. The major risk factor for late-onset AD is aging, which increases APP processing in both neurons and astrocytes, and consequently increases Aβ production. This focused review covers the subjects of how aging and AD affect APP dynamics within the both cell types and how astrocytes dysfunction can enhance neuroinflammation and neuronal dysfunction and injury. We discuss the interplay between neurons and astrocytes in aging and AD brains, where bi-directional cellular interactions accelerate neurodegeneration.
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Affiliation(s)
- Gretsen Velezmoro Jáuregui
- International Translational Neuroscience Research Institute, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P.R. China
| | - Vladimir Parpura
- International Translational Neuroscience Research Institute, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P.R. China
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4
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Martá-Ariza M, Leitner DF, Kanshin E, Suazo J, Giusti Pedrosa A, Thierry M, Lee EB, Devinsky O, Drummond E, Fortea J, Lleó A, Ueberheide B, Wisniewski T. Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer's disease, and late-onset Alzheimer's disease. Acta Neuropathol 2025; 149:9. [PMID: 39825890 PMCID: PMC11742868 DOI: 10.1007/s00401-025-02844-z] [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: 11/08/2024] [Revised: 01/02/2025] [Accepted: 01/04/2025] [Indexed: 01/20/2025]
Abstract
Down syndrome (DS) is strongly associated with Alzheimer's disease (AD) due to APP overexpression, exhibiting Amyloid-β (Aβ) and Tau pathology similar to early-onset (EOAD) and late-onset AD (LOAD). We evaluated the Aβ plaque proteome of DS, EOAD, and LOAD using unbiased localized proteomics on post-mortem paraffin-embedded tissues from four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 ± 4.07 y/o), LOAD (82.1 ± 6.37 y/o), and controls (66.4 ± 13.04). We identified differentially abundant proteins when comparing Aβ plaques and neighboring non-plaque tissue (FDR < 5%, fold-change > 1.5) in DS (n = 132), EOAD (n = 192), and LOAD (n = 128), with 43 plaque-associated proteins shared across all groups. Positive correlations were observed between plaque-associated proteins in DS and EOAD (R2 = .77), DS and LOAD (R2 = .73), and EOAD and LOAD (R2 = .67). Top gene ontology biological processes (GOBP) included lysosomal transport (p = 1.29 × 10-5) for DS, immune system regulation (p = 4.33 × 10-5) for EOAD, and lysosome organization (p = 0.029) for LOAD. Protein networks revealed a plaque-associated protein signature involving APP metabolism, immune response, and lysosomal functions. In DS, EOAD, and LOAD non-plaque vs. control tissue, we identified 263, 269, and 301 differentially abundant proteins, with 65 altered proteins shared across all cohorts. Non-plaque proteins in DS showed modest correlations with EOAD (R2 = .59) and LOAD (R2 = .33) compared to the correlation between EOAD and LOAD (R2 = .79). Top GOBP term for all groups was chromatin remodeling (p < 0.001), with additional terms for DS including extracellular matrix, and protein-DNA complexes and gene expression regulation for EOAD and LOAD. Our study reveals key functional characteristics of the amyloid plaque proteome in DS, compared to EOAD and LOAD, highlighting shared pathways in endo/lysosomal functions and immune responses. The non-plaque proteome revealed distinct alterations in ECM and chromatin structure, underscoring unique differences between DS and AD subtypes. Our findings enhance our understanding of AD pathogenesis and identify potential biomarkers and therapeutic targets.
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Affiliation(s)
- Mitchell Martá-Ariza
- Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Dominique F Leitner
- Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Comprehensive Epilepsy Center, Department of Neurology, NYU Langone Health and Grossman School of Medicine, New York, NY, USA
| | - Evgeny Kanshin
- Proteomics Laboratory, Division of Advanced Research Technologies, NYU Grossman School of Medicine, New York, NY, USA
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
| | - Jianina Suazo
- Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, USA
| | | | - Manon Thierry
- Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, USA
| | - Edward B Lee
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Orrin Devinsky
- Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Comprehensive Epilepsy Center, Department of Neurology, NYU Langone Health and Grossman School of Medicine, New York, NY, USA
| | - Eleanor Drummond
- Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Brain and Mind Centre and School of Medical Sciences, University of Sydney, Camperdown, NSW, Australia
| | - Juan Fortea
- Memory Unit, Department of Neurology, Institut de Recerca Sant Pau, Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Barcelona Down Medical Center, Fundació Catalana de Síndrome de Down, Barcelona, Spain
| | - Alberto Lleó
- Memory Unit, Department of Neurology, Institut de Recerca Sant Pau, Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Beatrix Ueberheide
- Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA
- Proteomics Laboratory, Division of Advanced Research Technologies, NYU Grossman School of Medicine, New York, NY, USA
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
| | - Thomas Wisniewski
- Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA.
- Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, USA.
- Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA.
- Department of Psychiatry, NYU Grossman School of Medicine, New York, NY, USA.
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5
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Aisen P, Bateman RJ, Crowther D, Cummings J, Dwyer J, Iwatsubo T, Kosco‐Vilbois M, McDade E, Mohs R, Scheltens P, Sperling R, Selkoe D. The case for regulatory approval of amyloid-lowering immunotherapies in Alzheimer's disease based on clearcut biomarker evidence. Alzheimers Dement 2025; 21:e14342. [PMID: 39535341 PMCID: PMC11772734 DOI: 10.1002/alz.14342] [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: 06/18/2024] [Revised: 09/23/2024] [Accepted: 09/27/2024] [Indexed: 11/16/2024]
Abstract
Decades of research have provided evidence that Alzheimer's disease (AD) is caused in part by cerebral accumulation of amyloid beta-protein (Aβ). In 2023, the US Food and Drug Administration gave full regulatory approval to a disease-modifying Aβ antibody for early AD. Secondary prevention trials with Aβ antibodies are underway. We summarize peer-reviewed evidence for targeting Aβ and argue that regulators should consider approving new agents working by similar mechanisms (Aβ antibodies and vaccines) based on robust amyloid lowering and reasonable safety. The urgent need to provide treatments to millions of mildly symptomatic patients suggests that AD should join other diseases for which standard approval is based on significant changes in mechanistically meaningful biomarkers coupled with safety. Robust amyloid lowering in secondary prevention trials of people who have amyloid plaques but are asymptomatic could also provide evidence of a change in the pathophysiological progression of AD as a basis for regulatory approval. HIGHLIGHTS: Thirteen key findings support amyloid beta as a cause of Alzheimer's disease (AD). Three immunotherapies lower amyloid and slow decline, allowing regulatory approval. New such agents could be considered for approval due to amyloid lowering and safety. Urgency suggests AD may join diseases with approval due to a key biomarker + safety.
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Affiliation(s)
- Paul Aisen
- USC Alzheimer's Therapeutic Research InstituteSan DiegoCaliforniaUSA
| | - Randall J. Bateman
- Department of NeurologyWashington University School of MedicineSt. LouisMissouriUSA
| | - Damian Crowther
- TRIMTECH Therapeutics Ltd and Medical and More LtdBostonMassachusettsUSA
| | - Jeff Cummings
- School of Integrated Health SciencesUniversity of Nevada Las VegasLas VegasNevadaUSA
| | - John Dwyer
- Global Alzheimer's Platform Foundation WashingtonWashingtonDistrict of ColumbiaUSA
| | | | | | - Eric McDade
- Department of NeurologyWashington University School of MedicineSt. LouisMissouriUSA
| | - Richard Mohs
- Global Alzheimer's Platform Foundation WashingtonWashingtonDistrict of ColumbiaUSA
| | - Philip Scheltens
- Medical Center and EQT Life SciencesAmsterdam UniversityAmsterdamThe Netherlands
| | - Reisa Sperling
- Dpartment of NeurologyBrigham and Women's Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Dennis Selkoe
- Dpartment of NeurologyBrigham and Women's Hospital and Harvard Medical SchoolBostonMassachusettsUSA
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6
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Engelhardt E, Resende EDPF, Gomes KB. Physiopathological mechanisms underlying Alzheimer's disease: a narrative review. Dement Neuropsychol 2024; 18:e2024VR01. [PMID: 39697643 PMCID: PMC11654088 DOI: 10.1590/1980-5764-dn-2024-vr01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 08/21/2024] [Indexed: 12/20/2024] Open
Abstract
The neuropathological signature of Alzheimer's disease (AD) comprises mainly amyloid plaques, and neurofibrillary tangles, resulting in synaptic and neuronal loss. These pathological structures stem from amyloid dysfunctional metabolism according to the amyloid cascade hypothesis, leading to the formation of plaques, and apparently inducing the initiation of the abnormal tau pathway, with phosphorylation and aggregation of these proteins, ultimately causing the formation of tangles. In this narrative review, the existing hypothesis related to the pathophysiology of AD were compiled, and biological pathways were highlighted in order to identify the molecules that could represent biological markers of the disease, necessary to establish early diagnosis, as well as the selection of patients for therapeutical interventional strategies.
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Affiliation(s)
- Eliasz Engelhardt
- Universidade Federal do Rio de Janeiro, Instituto de Neurologia Deolindo Couto, Rio de Janeiro RJ, Brazil
| | - Elisa de Paula França Resende
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Belo Horizonte MG, Brazil
- Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte MG, Brazil
| | - Karina Braga Gomes
- Universidade Federal de Minas Gerais, Faculdade de Farmácia, Belo Horizonte MG, Brazil
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7
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Saxena SK, Ansari S, Maurya VK, Kumar S, Sharma D, Malhotra HS, Tiwari S, Srivastava C, Paweska JT, Abdel-Moneim AS, Nityanand S. Neprilysin-Mediated Amyloid Beta Clearance and Its Therapeutic Implications in Neurodegenerative Disorders. ACS Pharmacol Transl Sci 2024; 7:3645-3657. [PMID: 39698259 PMCID: PMC11651204 DOI: 10.1021/acsptsci.4c00400] [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: 07/08/2024] [Revised: 09/04/2024] [Accepted: 09/09/2024] [Indexed: 12/20/2024]
Abstract
Neprilysin (NEP) is a neutral endopeptidase, important for the degradation of amyloid beta (Aβ) peptides and other neuropeptides, including enkephalins, substance P, and bradykinin, in the brain, that influences various physiological processes such as blood pressure homeostasis, pain perception, and neuroinflammation. NEP breaks down Aβ peptides into smaller fragments, preventing the development of detrimental aggregates such as Aβ plaques. NEP clears Aβ plaques predominantly by enzymatic breakdown in the extracellular space. However, NEP activity may be regulated by a variety of factors, including its expression and activity levels as well as interactions with other proteins or substances present in the brain. The Aβ de novo synthesis results from the amyloidogenic and nonamyloidogenic processing of the amyloid precursor protein (APP). In addition to Aβ synthesis, enzymatic degradation and various clearance pathways also contribute to the degradation of the monomeric form of Aβ peptides in the brain. Higher production, dysfunction of degradation enzymes, defective clearance mechanisms, intracellular accumulation of phosphorylated tau proteins, and extracellular deposition of Aβ are hallmarks of neurodegenerative diseases. Strategies for promoting NEP levels or activity, such as pharmaceutical interventions or gene therapy procedures, are being studied as possible therapies for neurodegenerative diseases including Alzheimer's disease. Therefore, in this perspective, we discuss the recent developments in NEP-mediated amyloidogenic and plausible mechanisms of nonamyloidogenic clearance of Aβ. We further highlight the current therapeutic interventions such as pharmaceutical agents, gene therapy, monoclonal antibodies, and stem-cell-based therapies targeting NEP for the management of neurodegenerative disorders.
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Affiliation(s)
- Shailendra K. Saxena
- Centre
for Advanced Research (CFAR), Faculty of Medicine, King George’s Medical University (KGMU), Lucknow 226003, India
- The
World Society for Virology (WSV), Northampton, Massachusetts 01060, United States
| | - Saniya Ansari
- Centre
for Advanced Research (CFAR), Faculty of Medicine, King George’s Medical University (KGMU), Lucknow 226003, India
- The
World Society for Virology (WSV), Northampton, Massachusetts 01060, United States
| | - Vimal K. Maurya
- Centre
for Advanced Research (CFAR), Faculty of Medicine, King George’s Medical University (KGMU), Lucknow 226003, India
- The
World Society for Virology (WSV), Northampton, Massachusetts 01060, United States
| | - Swatantra Kumar
- Centre
for Advanced Research (CFAR), Faculty of Medicine, King George’s Medical University (KGMU), Lucknow 226003, India
- The
World Society for Virology (WSV), Northampton, Massachusetts 01060, United States
| | - Deepak Sharma
- Centre
for Advanced Research (CFAR), Faculty of Medicine, King George’s Medical University (KGMU), Lucknow 226003, India
| | - Hardeep S. Malhotra
- Department
of Neurology, King George’s Medical
University, Lucknow 226003, India
| | - Sneham Tiwari
- F.
M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard
Medical School, Boston, Massachusetts 02115, United States
| | - Chhitij Srivastava
- Department
of Neurosurgery, King George’s Medical
University, Lucknow 226003, India
| | - Janusz T. Paweska
- The
World Society for Virology (WSV), Northampton, Massachusetts 01060, United States
- Centre for
Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases of the National Health
Laboratory Service, Private Bag X4, Sandringham, Johannesburg 2131, South Africa
| | - Ahmed S. Abdel-Moneim
- Department
of Microbiology, College of Medicine, Taif
University, Al-Taif 21944 Saudi Arabia
| | - Soniya Nityanand
- Centre
for Advanced Research (CFAR), Faculty of Medicine, King George’s Medical University (KGMU), Lucknow 226003, India
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8
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Shirokov A, Zlatogosrkaya D, Adushkina V, Vodovozova E, Kardashevskaya K, Sultanov R, Kasyanov S, Blokhina I, Terskov A, Tzoy M, Evsyukova A, Dubrovsky A, Tuzhilkin M, Elezarova I, Dmitrenko A, Manzhaeva M, Krupnova V, Semiachkina-Glushkovskaia A, Ilyukov E, Myagkov D, Tuktarov D, Popov S, Inozemzev T, Navolokin N, Fedosov I, Semyachkina-Glushkovskaya O. Plasmalogens Improve Lymphatic Clearance of Amyloid Beta from Mouse Brain and Cognitive Functions. Int J Mol Sci 2024; 25:12552. [PMID: 39684263 DOI: 10.3390/ijms252312552] [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: 09/12/2024] [Revised: 11/16/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024] Open
Abstract
Amyloid beta (Aβ) is a neuronal metabolic product that plays an important role in maintaining brain homeostasis. Normally, intensive brain Aβ formation is accompanied by its effective lymphatic removal. However, the excessive accumulation of brain Aβ is observed with age and during the development of Alzheimer's disease (AD) leading to cognitive impairment and memory deficits. There is emerging evidence that plasmalogens (Pls), as one of the key brain lipids, may be beneficial for AD and cognitive aging. Here, we studied the effects of Pls on cognitive functions and the lymphatic clearance of Aβ from the brain of AD mice and mice of different ages. The results showed that Pls effectively reduce brain Aβ levels and facilitate learning in aged but not old mice. In AD mice, Pls improve the lymphatic clearance of Aβ that is accompanied by an increase in general motor activity and an improvement of the emotional status and learning ability. Thus, these findings suggest that Pls could be a promising candidate for the alternative or concomitant therapy of AD and age-related brain diseases to enhance the lymphatic clearance of Aβ from the brain and cognitive functions.
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Affiliation(s)
- Alexander Shirokov
- Institute of Biochemistry and Physiology of Plants and Microorganisms, Russian Academy of Sciences, Prospekt Entuziastov 13, 410049 Saratov, Russia
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia
| | - Daria Zlatogosrkaya
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia
| | - Viktoria Adushkina
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia
| | - Elena Vodovozova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, 117997 Moscow, Russia
| | - Kristina Kardashevskaya
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, 117997 Moscow, Russia
| | - Ruslan Sultanov
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevskogo Str. 17, 690041 Vladivostok, Russia
| | - Sergey Kasyanov
- A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, Palchevskogo Str. 17, 690041 Vladivostok, Russia
| | - Inna Blokhina
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia
| | - Andrey Terskov
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia
| | - Maria Tzoy
- Physics Department, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia
| | - Arina Evsyukova
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia
| | - Alexander Dubrovsky
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, 117997 Moscow, Russia
| | - Matvey Tuzhilkin
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia
| | - Inna Elezarova
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia
| | - Alexander Dmitrenko
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia
| | - Maria Manzhaeva
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia
| | - Valeria Krupnova
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia
| | | | - Egor Ilyukov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, 117997 Moscow, Russia
| | - Dmitry Myagkov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, 117997 Moscow, Russia
| | - Dmitry Tuktarov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, 117997 Moscow, Russia
| | - Sergey Popov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, 117997 Moscow, Russia
| | - Tymophey Inozemzev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, 117997 Moscow, Russia
| | - Nikita Navolokin
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia
- Department of Pathological Anatomy, Saratov Medical State University, Bolshaya Kazachaya Str. 112, 410012 Saratov, Russia
| | - Ivan Fedosov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, 117997 Moscow, Russia
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9
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Studart-Neto A, Barbosa BJAP, Coutinho AM, de Souza LC, Schilling LP, da Silva MNM, Castilhos RM, Bertolucci PHF, Borelli WV, Gomes HR, Fernandes GBP, Barbosa MT, Balthazar MLF, Frota NAF, Forlenza OV, Smid J, Brucki SMD, Caramelli P, Nitrini R, Engelhardt E, Resende EDPF. Guidelines for the use and interpretation of Alzheimer's disease biomarkers in clinical practice in Brazil: recommendations from the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology. Dement Neuropsychol 2024; 18:e2024C001. [PMID: 39534442 PMCID: PMC11556292 DOI: 10.1590/1980-5764-dn-2024-c001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 08/16/2024] [Indexed: 11/16/2024] Open
Abstract
In recent years, the diagnostic accuracy of Alzheimer's disease has been enhanced by the development of different types of biomarkers that indicate the presence of neuropathological processes. In addition to improving patient selection for clinical trials, biomarkers can assess the effects of new treatments on pathological processes. However, there is concern about the indiscriminate and poorly supported use of biomarkers, especially in asymptomatic individuals or those with subjective cognitive decline. Difficulties interpreting these tests, high costs, and unequal access make this scenario even more challenging in healthcare. This article presents the recommendations from the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology (Departamento Científico de Neurologia Cognitiva e Envelhecimento da Academia Brasileira de Neurologia) regarding the rational use and interpretation of Alzheimer's disease biomarkers in clinical practice. The clinical diagnosis of cognitive-behavioral syndrome is recommended as the initial step to guide the request for biomarkers.
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Affiliation(s)
- Adalberto Studart-Neto
- Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Departamento de Neurologia, Grupo de Neurologia Cognitiva e do Comportamento, São Paulo SP, Brazil
| | - Breno José Alencar Pires Barbosa
- Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil
- Universidade Federal de Pernambuco, Hospital das Clínicas, Recife, Centro de Ciências Médicas, Recife PE, Brazil
- Universidade Federal de Pernambuco, Empresa Brasileira de Serviços Hospitalares, Hospital das Clínicas, Departamento de Neurologia, Recife PE, Brazil
| | - Artur Martins Coutinho
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Instituto de Radiologia, Centro de Medicina Nuclear, Laboratório de Investigação Médica (LIM 43), São Paulo SP, Brazil
- Hospital Sírio-Libanês, Medicina Nuclear e Serviço de PET-CT, São Paulo SP, Brazil
| | - Leonardo Cruz de Souza
- Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Unidade de Neurologia Cognitiva e do Comportamento, Belo Horizonte MG, Brazil
| | - Lucas Porcello Schilling
- Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil
- Pontifícia Universidade do Rio Grande do Sul, Escola de Medicina, Serviço de Neurologia, Porto Alegre RS, Brazil
| | - Mari Nilva Maia da Silva
- Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil
- Hospital Nina Rodrigues, Serviço de Neuropsiquiatria, São Luís MA, Brazil
| | - Raphael Machado Castilhos
- Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil
- Hospital de Clínicas de Porto Alegre, Serviço de Neurologia, Centro de Neurologia Cognitiva e Comportamental, Porto Alegre RS, Brazil
| | - Paulo Henrique Ferreira Bertolucci
- Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil
- Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Neurologia e Neurocirurgia, São Paulo SP, Brazil
| | - Wyllians Vendramini Borelli
- Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil
- Universidade Federal do Rio Grande do Sul, Instituto de Ciências Básicas da Saúde, Departamento de Ciências Morfológicas, Porto Alegre RS, Brazil
| | - Hélio Rodrigues Gomes
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Laboratório de Líquido Cefalorraquidiano, São Paulo SP, Brazil
- Universidade de São Paulo, Faculdade de Medicina, Laboratório de Investigação Médica (LIM 15), São Paulo SP, Brazil
- Departamento Científico de Líquido Cefalorraquiano, Academia Brasileira de Neurologia, São Paulo SP, Brazil
| | | | - Maira Tonidandel Barbosa
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Unidade de Neurologia Cognitiva e do Comportamento, Belo Horizonte MG, Brazil
| | - Marcio Luiz Figueredo Balthazar
- Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil
- Universidade Estadual de Campinas, Faculdade de Ciências Médicas, Departamento de Neurologia, Campinas SP, Brazil
| | - Norberto Anízio Ferreira Frota
- Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil
- Hospital Geral de Fortaleza, Serviço de Neurologia, Fortaleza CE, Brazil
- Universidade de Fortaleza, Fortaleza, CE, Brazil
| | - Orestes Vicente Forlenza
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Instituto de Psiquiatria, Laboratório de Neurociências, São Paulo SP, Brazil
| | - Jerusa Smid
- Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Departamento de Neurologia, Grupo de Neurologia Cognitiva e do Comportamento, São Paulo SP, Brazil
| | - Sonia Maria Dozzi Brucki
- Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Departamento de Neurologia, Grupo de Neurologia Cognitiva e do Comportamento, São Paulo SP, Brazil
| | - Paulo Caramelli
- Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Unidade de Neurologia Cognitiva e do Comportamento, Belo Horizonte MG, Brazil
| | - Ricardo Nitrini
- Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Departamento de Neurologia, Grupo de Neurologia Cognitiva e do Comportamento, São Paulo SP, Brazil
| | - Eliasz Engelhardt
- Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil
- Universidade Federal do Rio de Janeiro, Instituto de Neurologia Deolindo Couto, Rio de Janeiro RJ, Brazil
- Universidade Federal do Rio de Janeiro, Instituto de Psiquiatria, Rio de Janeiro RJ, Brazil
| | - Elisa de Paula França Resende
- Academia Brasileira de Neurologia, Departamento Científico de Neurologia Cognitiva e do Envelhecimento, São Paulo SP, Brazil
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Unidade de Neurologia Cognitiva e do Comportamento, Belo Horizonte MG, Brazil
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10
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Sharma P, Sharma S, Yadav Y, Shukla P, Sagar R. Current pharmacophore based approaches for the development of new anti-Alzheimer's agents. Bioorg Med Chem 2024; 113:117926. [PMID: 39306973 DOI: 10.1016/j.bmc.2024.117926] [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: 07/24/2024] [Revised: 09/06/2024] [Accepted: 09/10/2024] [Indexed: 10/13/2024]
Abstract
Amyloid beta peptide (Aβ) and hyperphosphorylated neuronal tau proteins accumulate in neurofibrillary tangles in Alzheimer's disease (AD), a chronic neurodegenerative illness. Chronic inflammation in the brain, which promotes disease progression, is another feature of the Alzheimer's disease pathogenesis. Approximately 60-70 % of dementia cases are caused by AD. The development of effective therapies for the treatment of AD is urgently needed given the severity of the condition and its rapidly rising prevalence. Cholinesterase inhibitors, beta-amyloid (A-beta), tau inhibitors, and many other medications are currently used as preventive medicine for AD. These medications can temporarily suppress dementia symptoms but cannot halt or reverse the disease's progression. Many international pharmaceutical companies have tried numerous times to develop an amyloid clearing medication based on the amyloid hypothesis, but without success. Therefore, the amyloid theory may not be entirely plausible. This review mainly covers the recent and important reported pharmacophores as the starting point to discuss already known targets like tau, butyrylcholinesterase, amyloid beta, and acetylcholinesterase and covers the literature between years 2019-2024.
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Affiliation(s)
- Prachi Sharma
- Department of Chemistry, Birla Institute of Technology and Sciences, Pilani, Rajasthan 333031, India
| | - Sunil Sharma
- Glycochemistry Laboratory, School of Physical Sciences, Jawaharlal Nehru University, New Delhi 110067, India
| | - Yogesh Yadav
- Glycochemistry Laboratory, School of Physical Sciences, Jawaharlal Nehru University, New Delhi 110067, India
| | - Paritosh Shukla
- Department of Chemistry, Birla Institute of Technology and Sciences, Pilani, Rajasthan 333031, India.
| | - Ram Sagar
- Glycochemistry Laboratory, School of Physical Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
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11
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Costa ACS. On the Therapeutic Use of Monoclonal Antibodies Against Amyloid Plaques in Older Adults with Down Syndrome: A Narrative Review and Perspective. Brain Sci 2024; 14:1084. [PMID: 39595846 PMCID: PMC11591668 DOI: 10.3390/brainsci14111084] [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: 10/08/2024] [Revised: 10/27/2024] [Accepted: 10/28/2024] [Indexed: 11/28/2024] Open
Abstract
Down syndrome (DS) is a genetic disorder caused by an extra copy of chromosome 21 (trisomy 21 or T21) and is associated with an increased risk of early-onset Alzheimer's disease (AD), also known as DS-associated AD (DSAD). Individuals with DS typically develop amyloid neuropathology in their late-thirties to early-forties and the mean age of onset of clinical dementia is approximately 55 years. Recent advances in AD clinical research have focused on monoclonal antibodies (mAbs) targeting amyloid-β (Aβ) plaques as a potential therapeutic approach. Therefore, there has been guarded enthusiasm about using anti-amyloid mAbs in the prevention/treatment of DSAD. This narrative review and perspective explores the current understanding of amyloid pathology in AD and DSAD, the rationale for using anti-amyloid mAbs in the treatment of DSAD, and the challenges and opportunities for research toward the application of this therapeutic strategy to older adults with DS.
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Affiliation(s)
- Alberto C S Costa
- Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106-6090, USA
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12
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Paterno G, Moore BD, Bell BM, Gorion KMM, Ran Y, Prokop S, Golde TE, Giasson BI. Novel Monoclonal Antibody Specific toward Amyloid-β Binds to a Unique Epitope within the N-Terminal Region. Antibodies (Basel) 2024; 13:68. [PMID: 39189239 PMCID: PMC11348109 DOI: 10.3390/antib13030068] [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: 07/03/2024] [Revised: 08/04/2024] [Accepted: 08/06/2024] [Indexed: 08/28/2024] Open
Abstract
Amyloid-β (Aβ) deposition throughout the neuroaxis is a classical hallmark of several neurodegenerative diseases, most notably Alzheimer's disease (AD). Aβ peptides of varied length and diverse structural conformations are deposited within the parenchyma and vasculature in the brains of individuals with AD. Neuropathologically, Aβ pathology can be assessed using antibodies to label and characterize their features, which in turn leads to a more extensive understanding of the pathological process. In the present study, we generated a novel monoclonal antibody, which we found to be specific for the N-terminal region of Aβ. This antibody reacted to amyloid precursor protein expressed in cultured cells and labels Aβ plaques and cerebral amyloid angiopathy in brain tissue from a mouse model of amyloidosis as well as post-mortem brain tissue from patients diagnosed with AD. This highly specific novel antibody will serve as a unique tool for future studies investigating Aβ deposition in novel mouse models and cross-sectional studies using post-mortem human tissue.
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Affiliation(s)
- Giavanna Paterno
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (G.P.); (B.M.B.); (K.-M.M.G.)
- Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA;
| | - Brenda D. Moore
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA; (B.D.M.); (Y.R.); (T.E.G.)
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Brach M. Bell
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (G.P.); (B.M.B.); (K.-M.M.G.)
- Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA;
| | - Kimberly-Marie M. Gorion
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (G.P.); (B.M.B.); (K.-M.M.G.)
- Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA;
| | - Yong Ran
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA; (B.D.M.); (Y.R.); (T.E.G.)
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Stefan Prokop
- Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA;
- McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
- Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Todd E. Golde
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA; (B.D.M.); (Y.R.); (T.E.G.)
- Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Benoit I. Giasson
- Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (G.P.); (B.M.B.); (K.-M.M.G.)
- Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL 32610, USA;
- McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
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13
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Saraceno C, Cervellati C, Trentini A, Crescenti D, Longobardi A, Geviti A, Bonfiglio NS, Bellini S, Nicsanu R, Fostinelli S, Mola G, Riccetti R, Moretti DV, Zanetti O, Binetti G, Zuliani G, Ghidoni R. Serum Beta-Secretase 1 Activity Is a Potential Marker for the Differential Diagnosis between Alzheimer's Disease and Frontotemporal Dementia: A Pilot Study. Int J Mol Sci 2024; 25:8354. [PMID: 39125924 PMCID: PMC11313328 DOI: 10.3390/ijms25158354] [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: 07/05/2024] [Revised: 07/23/2024] [Accepted: 07/28/2024] [Indexed: 08/12/2024] Open
Abstract
Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two major neurodegenerative diseases causing dementia. Due to similar clinical phenotypes, differential diagnosis is challenging without specific biomarkers. Beta-site Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is a β-secretase pivotal in AD pathogenesis. In AD and mild cognitive impairment subjects, BACE1 activity is increased in brain/cerebrospinal fluid, and plasma levels appear to reflect those in the brain. In this study, we aim to evaluate serum BACE1 activity in FTD, since, to date, there is no evidence about its role. The serum of 30 FTD patients and 30 controls was analyzed to evaluate (i) BACE1 activity, using a fluorescent assay, and (ii) Glial Fibrillary Acid Protein (GFAP) and Neurofilament Light chain (NfL) levels, using a Simoa kit. As expected, a significant increase in GFAP and NfL levels was observed in FTD patients compared to controls. Serum BACE1 activity was not altered in FTD patients. A significant increase in serum BACE1 activity was shown in AD vs. FTD and controls. Our results support the hypothesis that serum BACE1 activity is a potential biomarker for the differential diagnosis between AD and FTD.
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Affiliation(s)
- Claudia Saraceno
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (C.S.); (D.C.); (A.L.); (S.B.); (R.N.)
| | - Carlo Cervellati
- Department of Translational Medicine and for Romagna, University of Ferrara, 44121 Ferrara, Italy; (C.C.); (G.M.); (G.Z.)
| | - Alessandro Trentini
- Department of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, Italy; (A.T.); (R.R.)
| | - Daniela Crescenti
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (C.S.); (D.C.); (A.L.); (S.B.); (R.N.)
| | - Antonio Longobardi
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (C.S.); (D.C.); (A.L.); (S.B.); (R.N.)
| | - Andrea Geviti
- Service of Statistics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (A.G.); (N.S.B.)
| | - Natale Salvatore Bonfiglio
- Service of Statistics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (A.G.); (N.S.B.)
| | - Sonia Bellini
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (C.S.); (D.C.); (A.L.); (S.B.); (R.N.)
| | - Roland Nicsanu
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (C.S.); (D.C.); (A.L.); (S.B.); (R.N.)
| | - Silvia Fostinelli
- MAC–Memory Clinic and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (S.F.); (G.B.)
| | - Gianmarco Mola
- Department of Translational Medicine and for Romagna, University of Ferrara, 44121 Ferrara, Italy; (C.C.); (G.M.); (G.Z.)
| | - Raffaella Riccetti
- Department of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, Italy; (A.T.); (R.R.)
| | - Davide Vito Moretti
- Alzheimer’s Rehabilitation Operative Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy;
| | - Orazio Zanetti
- Alzheimer’s Research Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy;
| | - Giuliano Binetti
- MAC–Memory Clinic and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (S.F.); (G.B.)
| | - Giovanni Zuliani
- Department of Translational Medicine and for Romagna, University of Ferrara, 44121 Ferrara, Italy; (C.C.); (G.M.); (G.Z.)
| | - Roberta Ghidoni
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (C.S.); (D.C.); (A.L.); (S.B.); (R.N.)
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14
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Azargoonjahromi A. The duality of amyloid-β: its role in normal and Alzheimer's disease states. Mol Brain 2024; 17:44. [PMID: 39020435 PMCID: PMC11256416 DOI: 10.1186/s13041-024-01118-1] [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: 04/29/2024] [Accepted: 07/14/2024] [Indexed: 07/19/2024] Open
Abstract
Alzheimer's disease (AD) is a degenerative neurological condition that gradually impairs cognitive abilities, disrupts memory retention, and impedes daily functioning by impacting the cells of the brain. A key characteristic of AD is the accumulation of amyloid-beta (Aβ) plaques, which play pivotal roles in disease progression. These plaques initiate a cascade of events including neuroinflammation, synaptic dysfunction, tau pathology, oxidative stress, impaired protein clearance, mitochondrial dysfunction, and disrupted calcium homeostasis. Aβ accumulation is also closely associated with other hallmark features of AD, underscoring its significance. Aβ is generated through cleavage of the amyloid precursor protein (APP) and plays a dual role depending on its processing pathway. The non-amyloidogenic pathway reduces Aβ production and has neuroprotective and anti-inflammatory effects, whereas the amyloidogenic pathway leads to the production of Aβ peptides, including Aβ40 and Aβ42, which contribute to neurodegeneration and toxic effects in AD. Understanding the multifaceted role of Aβ, particularly in AD, is crucial for developing effective therapeutic strategies that target Aβ metabolism, aggregation, and clearance with the aim of mitigating the detrimental consequences of the disease. This review aims to explore the mechanisms and functions of Aβ under normal and abnormal conditions, particularly in AD, by examining both its beneficial and detrimental effects.
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15
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Martá-Ariza M, Leitner DF, Kanshin E, Suazo J, Pedrosa AG, Thierry M, Lee EB, Devinsky O, Drummond E, Fortea J, Lleó A, Ueberheide B, Wisniewski T. Comparison of the Amyloid Plaque Proteome in Down Syndrome, Early-Onset Alzheimer's Disease and Late-Onset Alzheimer's Disease. RESEARCH SQUARE 2024:rs.3.rs-4469045. [PMID: 39070643 PMCID: PMC11275979 DOI: 10.21203/rs.3.rs-4469045/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Background Down syndrome (DS) is strongly associated with Alzheimer's disease (AD), attributable to APP overexpression. DS exhibits Amyloid-β (Aβ) and Tau pathology similar to early-onset AD (EOAD) and late-onset AD (LOAD). The study aimed to evaluate the Aβ plaque proteome of DS, EOAD and LOAD. Methods Using unbiased localized proteomics, we analyzed amyloid plaques and adjacent plaque-devoid tissue ('non-plaque') from post-mortem paraffin-embedded tissues in four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 ± 4.07 y/o), LOAD (82.1 ± 6.37 y/o) and controls (66.4 ± 13.04). We assessed functional associations using Gene Ontology (GO) enrichment and protein interaction networks. Results We identified differentially abundant Aβ plaque proteins vs. non-plaques (FDR < 5%, fold-change > 1.5) in DS (n = 132), EOAD (n = 192) and in LOAD (n = 128); there were 43 plaque-associated proteins shared between all groups. Positive correlations (p < 0.0001) were observed between plaque-associated proteins in DS and EOAD (R2 = 0.77), DS and LOAD (R2 = 0.73), and EOAD vs. LOAD (R2 = 0.67). Top Biological process (BP) GO terms (p < 0.0001) included lysosomal transport for DS, immune system regulation for EOAD, and lysosome organization for LOAD. Protein networks revealed a plaque enriched signature across all cohorts involving APP metabolism, immune response, and lysosomal functions. In DS, EOAD and LOAD non-plaque vs. control tissue, we identified 263, 269, and 301 differentially abundant proteins, including 65 altered non-plaque proteins across all cohorts. Differentially abundant non-plaque proteins in DS showed a significant (p < 0.0001) but weaker positive correlation with EOAD (R2 = 0.59) and LOAD (R2 = 0.33) compared to the stronger correlation between EOAD and LOAD (R2 = 0.79). The top BP GO term for all groups was chromatin remodeling (DS p = 0.0013, EOAD p = 5.79×10- 9, and LOAD p = 1.69×10- 10). Additional GO terms for DS included extracellular matrix (p = 0.0068), while EOAD and LOAD were associated with protein-DNA complexes and gene expression regulation (p < 0.0001). Conclusions We found strong similarities among the Aβ plaque proteomes in individuals with DS, EOAD and LOAD, and a robust association between the plaque proteomes and lysosomal and immune-related pathways. Further, non-plaque proteomes highlighted altered pathways related to chromatin structure and extracellular matrix (ECM), the latter particularly associated with DS. We identified novel Aβ plaque proteins, which may serve as biomarkers or therapeutic targets.
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Affiliation(s)
| | | | | | | | | | | | - Edward B Lee
- University of Pennsylvania Perelman School of Medicine
| | | | | | - Juan Fortea
- Universitat Autònoma de Barcelona: Universitat Autonoma de Barcelona
| | - Alberto Lleó
- Universitat Autònoma de Barcelona: Universitat Autonoma de Barcelona
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16
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Castillo-Ordoñez WO, Cajas-Salazar N, Velasco-Reyes MA. Genetic and epigenetic targets of natural dietary compounds as anti-Alzheimer's agents. Neural Regen Res 2024; 19:846-854. [PMID: 37843220 PMCID: PMC10664119 DOI: 10.4103/1673-5374.382232] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/15/2023] [Accepted: 07/18/2023] [Indexed: 10/17/2023] Open
Abstract
Alzheimer's disease is a progressive neurodegenerative disorder and the most common cause of dementia that principally affects older adults. Pathogenic factors, such as oxidative stress, an increase in acetylcholinesterase activity, mitochondrial dysfunction, genotoxicity, and neuroinflammation are present in this syndrome, which leads to neurodegeneration. Neurodegenerative pathologies such as Alzheimer's disease are considered late-onset diseases caused by the complex combination of genetic, epigenetic, and environmental factors. There are two main types of Alzheimer's disease, known as familial Alzheimer's disease (onset < 65 years) and late-onset or sporadic Alzheimer's disease (onset ≥ 65 years). Patients with familial Alzheimer's disease inherit the disease due to rare mutations on the amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2) genes in an autosomal-dominantly fashion with closely 100% penetrance. In contrast, a different picture seems to emerge for sporadic Alzheimer's disease, which exhibits numerous non-Mendelian anomalies suggesting an epigenetic component in its etiology. Importantly, the fundamental pathophysiological mechanisms driving Alzheimer's disease are interfaced with epigenetic dysregulation. However, the dynamic nature of epigenetics seems to open up new avenues and hope in regenerative neurogenesis to improve brain repair in Alzheimer's disease or following injury or stroke in humans. In recent years, there has been an increase in interest in using natural products for the treatment of neurodegenerative illnesses such as Alzheimer's disease. Through epigenetic mechanisms, such as DNA methylation, non-coding RNAs, histone modification, and chromatin conformation regulation, natural compounds appear to exert neuroprotective effects. While we do not purport to cover every in this work, we do attempt to illustrate how various phytochemical compounds regulate the epigenetic effects of a few Alzheimer's disease-related genes.
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Affiliation(s)
- Willian Orlando Castillo-Ordoñez
- Facultad de Ciencias Naturales-Exactas y de la Educación, Departamento de Biología. Universidad del Cauca, Popayán-Cauca, Colombia
- Departamento de Estudios Psicológicos, Universidad Icesi, Cali, Colombia
| | - Nohelia Cajas-Salazar
- Facultad de Ciencias Naturales-Exactas y de la Educación, Departamento de Biología. Universidad del Cauca, Popayán-Cauca, Colombia
| | - Mayra Alejandra Velasco-Reyes
- Facultad de Ciencias Naturales-Exactas y de la Educación, Departamento de Biología. Universidad del Cauca, Popayán-Cauca, Colombia
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17
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Selkoe DJ. The advent of Alzheimer treatments will change the trajectory of human aging. NATURE AGING 2024; 4:453-463. [PMID: 38641654 DOI: 10.1038/s43587-024-00611-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 03/08/2024] [Indexed: 04/21/2024]
Abstract
Slowing neurodegenerative disorders of late life has lagged behind progress on other chronic diseases. But advances in two areas, biochemical pathology and human genetics, have now identified early pathogenic events, enabling molecular hypotheses and disease-modifying treatments. A salient example is the discovery that antibodies to amyloid ß-protein, long debated as a causative factor in Alzheimer's disease (AD), clear amyloid plaques, decrease levels of abnormal tau proteins and slow cognitive decline. Approval of amyloid antibodies as the first disease-modifying treatments means a gradually rising fraction of the world's estimated 60 million people with symptomatic disease may decline less or even stabilize. Society is entering an era in which the unchecked devastation of AD is no longer inevitable. This Perspective considers the impact of slowing AD and other neurodegenerative disorders on the trajectory of aging, allowing people to survive into late life with less functional decline. The implications of this moment for medicine and society are profound.
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Affiliation(s)
- Dennis J Selkoe
- Ann Romney Center for Neurologic Diseases Brigham and Women's Hospital Harvard Medical School, Boston, MA, USA.
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18
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Kot K, Kot Y, Kurbanov R, Andriiash H, Tigunova O, Blume Y, Shulga S. The effect of human PBMCs immobilization on their Аβ42 aggregates-dependent proinflammatory state on a cellular model of Alzheimer's disease. Front Neurosci 2024; 18:1325287. [PMID: 38406587 PMCID: PMC10884286 DOI: 10.3389/fnins.2024.1325287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 01/26/2024] [Indexed: 02/27/2024] Open
Abstract
The leading pathological mechanisms of Alzheimer's disease are amyloidosis and inflammation. The presented work was aimed to study the effect of human peripheral blood mononuclear cells (hPBMcs) cells-matrix adhesion on their pro-inflammatory state in vitro. Although direct interaction of Аβ42 to PBMC is not a cellular model of Alzheimer's disease, PBMCs may serve as test cells to detect Аβ42-dependent molecular effects in monitoring disease progression. Peripheral blood mononuclear cells (PBMCs) are used to assess changes in cytokines released in response to diseases or Alzheimer's disease-specific cytotoxic molecules such as Aβ42. The effect of recombinant amyloid β-peptide rАβ42 on the concentration of endogenous amyloid β-peptide Aβ40 and pro-inflammatory cytokines TNFα and IL-1β in human peripheral blood mononuclear cells that were cultured in suspension and immobilized in alginate microcarriers for 24 h were investigated. The localization and accumulation of Aβ40 and rAβ42 peptides in cells, as well as quantitative determination of the concentration of Aβ40 peptide, TNFα and IL-1β cytokines, was performed by intravital fluorescence imaging. The results were qualitatively similar for both cell models. It was determined that the content of TNFα and Aβ40 in the absence of rAβ42 in the incubation medium did not change for 24 h after incubation, and the content of IL-1β was lower compared to the cells that were not incubated. Incubation of cells in vitro with exogenous rAβ42 led to an increase in the intracellular content of TNFα and Aβ40, and no accumulation of IL-1β in cells was observed. The accumulation of Aβ40 in the cytoplasm was accompanied by the aggregation of rAβ42 on the outer surface of the cell plasma membrane. It was shown that the basic levels of indicators and the intensity of the response of immobilized cells to an exogenous stimulus were significantly greater than those of cells in suspension. To explore whether non-neuronal cells effects in alginate microcarriers were cell-matrix adhesion mediated, we tested the effect of blocking β1 integrins on proamyloidogenic and proinflammation cellular state. Immobilization within alginate hydrogels after incubation with the β1 integrins blocking antibodies showed a remarkable inhibition of TNFα and Aβ40 accumulation in rAβ42-treated cells. It can be concluded that activation of signal transduction and synthesizing activity of a portion of mononuclear cells of human peripheral blood is possible (can significantly increase) in the presence of cell-matrix adhesion.
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Affiliation(s)
- Kateryna Kot
- Biochemistry Department, V. N. Karazin Kharkiv National University of Ministry of Education and Science of Ukraine, Kharkiv, Ukraine
| | - Yurii Kot
- Biochemistry Department, V. N. Karazin Kharkiv National University of Ministry of Education and Science of Ukraine, Kharkiv, Ukraine
| | - Rustam Kurbanov
- Biochemistry Department, V. N. Karazin Kharkiv National University of Ministry of Education and Science of Ukraine, Kharkiv, Ukraine
| | - Hanna Andriiash
- Department of Genomics and Molecular Biotechnology, Institute of Food Biotechnology and Genomics National Academy of Science of Ukraine, Kyiv, Ukraine
| | - Olena Tigunova
- Department of Genomics and Molecular Biotechnology, Institute of Food Biotechnology and Genomics National Academy of Science of Ukraine, Kyiv, Ukraine
| | - Yaroslav Blume
- Department of Genomics and Molecular Biotechnology, Institute of Food Biotechnology and Genomics National Academy of Science of Ukraine, Kyiv, Ukraine
| | - Sergiy Shulga
- Department of Genomics and Molecular Biotechnology, Institute of Food Biotechnology and Genomics National Academy of Science of Ukraine, Kyiv, Ukraine
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19
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Cournut A, Moustiez P, Coffinier Y, Enjalbal C, Bich C. Innovative SALDI mass spectrometry analysis for Alzheimer's disease synthetic peptides detection. Talanta 2024; 268:125357. [PMID: 37951181 DOI: 10.1016/j.talanta.2023.125357] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 10/12/2023] [Accepted: 10/26/2023] [Indexed: 11/13/2023]
Abstract
Alzheimer's disease (AD) is nowadays the prominent cause of senile dementia. This pathology is characterized by aggregation of neurofibrillary tangles in cells and by the accumulation of amyloid plaques in the brain. Noteworthy, a phosphorylated protein (tau protein) and a peptide presenting two overlapping sequences of 40 or 42 residues named β-amyloid peptides 1-40 (Aβ 1-40) and 1-42 (Aβ 1-42), respectively, were related to such deleterious phenomena. Singularly, the neurotoxicity was primarily attributed to the amyloid peptide Aβ 1-42 form due to its capacity to fold into beta-sheets rendering it insoluble thus causing subsequent aggregation and accumulation in vivo. Regarding AD diagnosis relying on mass spectrometry, Aβ 1-42 and/or Aβ 1-40 were considered as relevant biomarkers being measured in cerebrospinal fluids (CSF), blood and urine. Under that context, we aimed at implementing an innovative method to evidence the depletion of circulating Aβ 1-42 amyloid peptide compared to the shorter Aβ 1-40 form indicating a pathologic state. We investigated Surface-Assisted Laser Desorption/Ionization Mass Spectrometry (SALDI-MS) in order to monitor the Aβ 1-42/Aβ 1-40 ratio without any prior sample treatment or enrichment. Taking into account that β-amyloid peptide and 1-42 can aggregate into beta-sheets depending on the experimental conditions, specific attention was devoted to sample integrity monitoring performed by circular dichroism experiments during SALDI-MS method development.
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Affiliation(s)
- Aline Cournut
- Univ Montpellier, IBMM, CNRS, ENSCM, Montpellier, France
| | - Paul Moustiez
- Univ Lille, IEMN, UMR CNRS 8520, Villeneuve d'Ascq, France
| | | | | | - Claudia Bich
- Univ Montpellier, IBMM, CNRS, ENSCM, Montpellier, France.
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20
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Davra V, Benzeroual KE. Flavonoids and fibrate modulate apoE4-induced processing of amyloid precursor protein in neuroblastoma cells. Front Neurosci 2023; 17:1245895. [PMID: 38204816 PMCID: PMC10777729 DOI: 10.3389/fnins.2023.1245895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 11/28/2023] [Indexed: 01/12/2024] Open
Abstract
Introduction Apolipoprotein (apo) E4, being a major genetic risk factor for Alzheimer's disease (AD), is actively involved in the proteolytic processing of amyloid precursor protein (APP) to amyloid β (Aβ) peptide, the principle constituent of amyloid plaques in Alzheimer Disease (AD) patients. ApoE4 is believed to affect APP processing through intracellular cholesterol homeostasis, whereas lowering the cholesterol level by pharmacological agents has been suggested to reduce Aβ production. This study has investigated the effects of hypolipidemic agents fenofibrate, and the flavonoids-naringenin and diosmetin-on apoE4-induced APP processing in rat neuroblastoma cells stably transfected with human wild-type APP 695 (B103-hAPP695wt). Results B103-hAPP695wt cells were pretreated with different doses of flavonoids and fenofibrate for 1 h prior to apoE4 exposure for 24 h. ApoE4-induced production of intra- and extracellular Aβ peptides has been reduced with fenofibrate, naringenin, and diosmetin treatments. Pretreatment with diosmetin has significantly reduced apoE4-induced full-length APP (fl- APP) expression, whereas naringenin and fenofibrate had no effect on it. In addition, the increase in the apoE4-induced secretion of sAPPtotal and sAPPα has been dose-dependently reduced with drug pretreatment. On the other hand, the decrease in the expression of both APP-carboxy terminal fragments (CTF)-α and -β (generated by the α- or β-secretase cleavage of APP) by apoE4 was dose-dependently increased in cells pretreated with fenofibrate and naringenin but not diosmetin. Conclusion Thus, we suggest that fenofibrate, naringenin, and diosmetin treatments can reduce apoE4- induced Aβ production by distinct mechanisms that may prove useful in developing drugs for AD patients.
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Affiliation(s)
| | - Kenza E. Benzeroual
- Department of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, United States
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21
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Self WK, Holtzman DM. Emerging diagnostics and therapeutics for Alzheimer disease. Nat Med 2023; 29:2187-2199. [PMID: 37667136 DOI: 10.1038/s41591-023-02505-2] [Citation(s) in RCA: 128] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 07/18/2023] [Indexed: 09/06/2023]
Abstract
Alzheimer disease (AD) is the most common contributor to dementia in the world, but strategies that slow or prevent its clinical progression have largely remained elusive, until recently. This Review highlights the latest advances in biomarker technologies and therapeutic development to improve AD diagnosis and treatment. We review recent results that enable pathological staging of AD with neuroimaging and fluid-based biomarkers, with a particular emphasis on the role of amyloid, tau and neuroinflammation in disease pathogenesis. We discuss the lessons learned from randomized controlled trials, including some supporting the proposal that certain anti-amyloid antibodies slow cognitive decline during the mildly symptomatic phase of AD. In addition, we highlight evidence for newly identified therapeutic targets that may be able to modify AD pathogenesis and progression. Collectively, these recent discoveries-and the research directions that they open-have the potential to move AD clinical care toward disease-modifying treatment strategies with maximal benefits for patients.
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Affiliation(s)
- Wade K Self
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - David M Holtzman
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
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22
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Scheres SHW, Ryskeldi-Falcon B, Goedert M. Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids. Nature 2023; 621:701-710. [PMID: 37758888 DOI: 10.1038/s41586-023-06437-2] [Citation(s) in RCA: 80] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 07/14/2023] [Indexed: 09/29/2023]
Abstract
Abnormal assembly of tau, α-synuclein, TDP-43 and amyloid-β proteins into amyloid filaments defines most human neurodegenerative diseases. Genetics provides a direct link between filament formation and the causes of disease. Developments in cryo-electron microscopy (cryo-EM) have made it possible to determine the atomic structures of amyloids from postmortem human brains. Here we review the structures of brain-derived amyloid filaments that have been determined so far and discuss their impact on research into neurodegeneration. Whereas a given protein can adopt many different filament structures, specific amyloid folds define distinct diseases. Amyloid structures thus provide a description of neuropathology at the atomic level and a basis for studying disease. Future research should focus on model systems that replicate the structures observed in disease to better understand the molecular mechanisms of disease and develop improved diagnostics and therapies.
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Affiliation(s)
- Sjors H W Scheres
- Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
| | | | - Michel Goedert
- Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
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23
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Hou X, Zhang X, Zou H, Guan M, Fu C, Wang W, Zhang ZR, Geng Y, Chen Y. Differential and substrate-specific inhibition of γ-secretase by the C-terminal region of ApoE2, ApoE3, and ApoE4. Neuron 2023; 111:1898-1913.e5. [PMID: 37040764 DOI: 10.1016/j.neuron.2023.03.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 01/16/2023] [Accepted: 03/17/2023] [Indexed: 04/13/2023]
Abstract
Aberrant low γ-secretase activity is associated with most of the presenilin mutations that underlie familial Alzheimer's disease (fAD). However, the role of γ-secretase in the more prevalent sporadic AD (sAD) remains unaddressed. Here, we report that human apolipoprotein E (ApoE), the most important genetic risk factor of sAD, interacts with γ-secretase and inhibits it with substrate specificity in cell-autonomous manners through its conserved C-terminal region (CT). This ApoE CT-mediated inhibitory activity is differentially compromised in different ApoE isoforms, resulting in an ApoE2 > ApoE3 > ApoE4 potency rank order inversely correlating to their associated AD risk. Interestingly, in an AD mouse model, neuronal ApoE CT migrates to amyloid plaques in the subiculum from other regions and alleviates the plaque burden. Together, our data reveal a hidden role of ApoE as a γ-secretase inhibitor with substrate specificity and suggest that this precision γ-inhibition by ApoE may protect against the risk of sAD.
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Affiliation(s)
- Xianglong Hou
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd., B13, Pudongxinqu, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xuexin Zhang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd., B13, Pudongxinqu, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Huan Zou
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd., B13, Pudongxinqu, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Mingfeng Guan
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd., B13, Pudongxinqu, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chaoying Fu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd., B13, Pudongxinqu, Shanghai 201210, China
| | - Wenyuan Wang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd., B13, Pudongxinqu, Shanghai 201210, China
| | - Zai-Rong Zhang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd., B13, Pudongxinqu, Shanghai 201210, China
| | - Yang Geng
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd., B13, Pudongxinqu, Shanghai 201210, China.
| | - Yelin Chen
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd., B13, Pudongxinqu, Shanghai 201210, China.
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24
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Chaves-Coira I, García-Magro N, Zegarra-Valdivia J, Torres-Alemán I, Núñez Á. Cognitive Deficits in Aging Related to Changes in Basal Forebrain Neuronal Activity. Cells 2023; 12:1477. [PMID: 37296598 PMCID: PMC10252596 DOI: 10.3390/cells12111477] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/22/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
Aging is a physiological process accompanied by a decline in cognitive performance. The cholinergic neurons of the basal forebrain provide projections to the cortex that are directly engaged in many cognitive processes in mammals. In addition, basal forebrain neurons contribute to the generation of different rhythms in the EEG along the sleep/wakefulness cycle. The aim of this review is to provide an overview of recent advances grouped around the changes in basal forebrain activity during healthy aging. Elucidating the underlying mechanisms of brain function and their decline is especially relevant in today's society as an increasingly aged population faces higher risks of developing neurodegenerative diseases such as Alzheimer's disease. The profound age-related cognitive deficits and neurodegenerative diseases associated with basal forebrain dysfunction highlight the importance of investigating the aging of this brain region.
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Affiliation(s)
- Irene Chaves-Coira
- Department of Anatomy, Histology and Neurosciences, Universidad Autónoma de Madrid, 28029 Madrid, Spain;
| | - Nuria García-Magro
- Facultad de Ciencias de la Salud, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223 Madrid, Spain;
| | - Jonathan Zegarra-Valdivia
- Achucarro Basque Center for Neuroscience, 48940 Leioa, Spain; (J.Z.-V.); (I.T.-A.)
- Facultad de Ciencias de la Salud, Universidad Señor de Sipán, Chiclayo 02001, Peru
| | - Ignacio Torres-Alemán
- Achucarro Basque Center for Neuroscience, 48940 Leioa, Spain; (J.Z.-V.); (I.T.-A.)
- Ikerbasque Science Foundation, 48009 Bilbao, Spain
| | - Ángel Núñez
- Department of Anatomy, Histology and Neurosciences, Universidad Autónoma de Madrid, 28029 Madrid, Spain;
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25
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Rey F, Berardo C, Maghraby E, Mauri A, Messa L, Esposito L, Casili G, Ottolenghi S, Bonaventura E, Cuzzocrea S, Zuccotti G, Tonduti D, Esposito E, Paterniti I, Cereda C, Carelli S. Redox Imbalance in Neurological Disorders in Adults and Children. Antioxidants (Basel) 2023; 12:antiox12040965. [PMID: 37107340 PMCID: PMC10135575 DOI: 10.3390/antiox12040965] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/03/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Oxygen is a central molecule for numerous metabolic and cytophysiological processes, and, indeed, its imbalance can lead to numerous pathological consequences. In the human body, the brain is an aerobic organ and for this reason, it is very sensitive to oxygen equilibrium. The consequences of oxygen imbalance are especially devastating when occurring in this organ. Indeed, oxygen imbalance can lead to hypoxia, hyperoxia, protein misfolding, mitochondria dysfunction, alterations in heme metabolism and neuroinflammation. Consequently, these dysfunctions can cause numerous neurological alterations, both in the pediatric life and in the adult ages. These disorders share numerous common pathways, most of which are consequent to redox imbalance. In this review, we will focus on the dysfunctions present in neurodegenerative disorders (specifically Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis) and pediatric neurological disorders (X-adrenoleukodystrophies, spinal muscular atrophy, mucopolysaccharidoses and Pelizaeus-Merzbacher Disease), highlighting their underlining dysfunction in redox and identifying potential therapeutic strategies.
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Affiliation(s)
- Federica Rey
- Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Sciences, University of Milano, 20157 Milano, Italy
- Center of Functional Genomics and Rare diseases, Department of Pediatrics, Buzzi Children's Hospital, 20154 Milano, Italy
| | - Clarissa Berardo
- Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Sciences, University of Milano, 20157 Milano, Italy
- Center of Functional Genomics and Rare diseases, Department of Pediatrics, Buzzi Children's Hospital, 20154 Milano, Italy
| | - Erika Maghraby
- Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Sciences, University of Milano, 20157 Milano, Italy
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100 Pavia, Italy
| | - Alessia Mauri
- Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Sciences, University of Milano, 20157 Milano, Italy
- Center of Functional Genomics and Rare diseases, Department of Pediatrics, Buzzi Children's Hospital, 20154 Milano, Italy
| | - Letizia Messa
- Center of Functional Genomics and Rare diseases, Department of Pediatrics, Buzzi Children's Hospital, 20154 Milano, Italy
- Department of Electronics, Information and Bioengineering (DEIB), Politecnico di Milano, 20133 Milano, Italy
| | - Letizia Esposito
- Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Sciences, University of Milano, 20157 Milano, Italy
- Center of Functional Genomics and Rare diseases, Department of Pediatrics, Buzzi Children's Hospital, 20154 Milano, Italy
| | - Giovanna Casili
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Sara Ottolenghi
- Department of Medicine and Surgery, University of Milano Bicocca, 20126 Milano, Italy
| | - Eleonora Bonaventura
- Child Neurology Unit, Buzzi Children's Hospital, 20154 Milano, Italy
- Center for Diagnosis and Treatment of Leukodystrophies and Genetic Leukoencephalopathies (COALA), Buzzi Children's Hospital, 20154 Milano, Italy
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Gianvincenzo Zuccotti
- Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Sciences, University of Milano, 20157 Milano, Italy
- Department of Pediatrics, Buzzi Children's Hospital, 20154 Milano, Italy
| | - Davide Tonduti
- Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Sciences, University of Milano, 20157 Milano, Italy
- Child Neurology Unit, Buzzi Children's Hospital, 20154 Milano, Italy
- Center for Diagnosis and Treatment of Leukodystrophies and Genetic Leukoencephalopathies (COALA), Buzzi Children's Hospital, 20154 Milano, Italy
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Irene Paterniti
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Cristina Cereda
- Center of Functional Genomics and Rare diseases, Department of Pediatrics, Buzzi Children's Hospital, 20154 Milano, Italy
| | - Stephana Carelli
- Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Sciences, University of Milano, 20157 Milano, Italy
- Center of Functional Genomics and Rare diseases, Department of Pediatrics, Buzzi Children's Hospital, 20154 Milano, Italy
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26
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Yoon JH, Hwang J, Son SU, Choi J, You SW, Park H, Cha SY, Maeng S. How Can Insulin Resistance Cause Alzheimer's Disease? Int J Mol Sci 2023; 24:3506. [PMID: 36834911 PMCID: PMC9966425 DOI: 10.3390/ijms24043506] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/17/2023] [Accepted: 01/27/2023] [Indexed: 02/12/2023] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder associated with cognitive decline. Despite worldwide efforts to find a cure, no proper treatment has been developed yet, and the only effective countermeasure is to prevent the disease progression by early diagnosis. The reason why new drug candidates fail to show therapeutic effects in clinical studies may be due to misunderstanding the cause of AD. Regarding the cause of AD, the most widely known is the amyloid cascade hypothesis, in which the deposition of amyloid beta and hyperphosphorylated tau is the cause. However, many new hypotheses were suggested. Among them, based on preclinical and clinical evidence supporting a connection between AD and diabetes, insulin resistance has been pointed out as an important factor in the development of AD. Therefore, by reviewing the pathophysiological background of brain metabolic insufficiency and insulin insufficiency leading to AD pathology, we will discuss how can insulin resistance cause AD.
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Affiliation(s)
- Ji Hye Yoon
- Age-Tech Service Convergence Major, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
| | - JooHyun Hwang
- Age-Tech Service Convergence Major, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
| | - Sung Un Son
- Department of Comprehensive Health Science, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
| | - Junhyuk Choi
- Age-Tech Service Convergence Major, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
| | - Seung-Won You
- Department of Comprehensive Health Science, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
| | - Hyunwoo Park
- Department of Comprehensive Health Science, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
- Health Park Co., Ltd., Seoul 02447, Republic of Korea
| | - Seung-Yun Cha
- Department of Comprehensive Health Science, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
| | - Sungho Maeng
- Age-Tech Service Convergence Major, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
- Department of Comprehensive Health Science, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
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27
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Kobro-Flatmoen A, Hormann TM, Gouras G. Intracellular Amyloid-β in the Normal Rat Brain and Human Subjects and Its relevance for Alzheimer's Disease. J Alzheimers Dis 2023; 95:719-733. [PMID: 37574734 PMCID: PMC10578257 DOI: 10.3233/jad-230349] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2023] [Indexed: 08/15/2023]
Abstract
BACKGROUND Amyloid-β (Aβ) is a normal product of neuronal activity, including that of the aggregation-prone Aβ42 variant that is thought to cause Alzheimer's disease (AD). Much knowledge about AD comes from studies of transgenic rodents expressing mutated human amyloid-β protein precursor (AβPP) to increase Aβ production or the Aβ42/40 ratio. Yet, little is known about the normal expression of Aβ42 in rodent brains. OBJECTIVE To characterize the brain-wide expression of Aβ42 throughout the life span of outbred Wistar rats, and to relate these findings to brains of human subjects without neurological disease. METHODS Aβ42 immunolabeling of 12 Wistar rat brains (3-18 months of age) and brain sections from six human subjects aged 20-88 years. RESULTS In healthy Wistar rats, we find intracellular Aβ42 (iAβ42) in neurons throughout the brain at all ages, but levels vary greatly between brain regions. The highest levels are in neurons of entorhinal cortex layer II, alongside hippocampal neurons at the CA1/subiculum border. Concerning entorhinal cortex layer II, we find similarly high levels of iAβ42 in the human subjects. CONCLUSION Expression of iAβ42 in healthy Wistar rats predominates in the same structures where iAβ accumulates and Aβ plaques initially form in the much used, Wistar based McGill-R-Thy1-APP rat model for AD. The difference between wild-type Wistar rats and these AD model rats, with respect to Aβ42, is therefore quantitative rather that qualitative. This, taken together with our human results, indicate that the McGill rat model in fact models the underlying wild-type neuronal population-specific vulnerability to Aβ42 accumulation.
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Affiliation(s)
- Asgeir Kobro-Flatmoen
- Kavli Institute for Systems Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway
- K.G. Jebsen Centre for Alzheimer’s Disease, NTNU, Trondheim, Norway
| | - Thea Meier Hormann
- Kavli Institute for Systems Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway
| | - Gunnar Gouras
- Department of Experimental Medical Science, Experimental Dementia Research Unit, Lund University, Lund, Sweden
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28
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Sun Y, Islam S, Gao Y, Nakamura T, Zou K, Michikawa M. Apolipoprotein E4 inhibits γ-secretase activity via binding to the γ-secretase complex. J Neurochem 2022; 164:858-874. [PMID: 36582176 DOI: 10.1111/jnc.15750] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 11/07/2022] [Accepted: 12/16/2022] [Indexed: 12/31/2022]
Abstract
The mechanisms of amyloid accumulation in familial Alzheimer's disease (FAD) and sporadic AD (SAD) are controversial. In FAD, mutations in presenilin (PSEN) impair γ-secretase activity and lead to abnormal amyloid β-protein (Aβ) production, thereby increasing the Aβ42/40 ratio. SAD is postulated to be caused by decreased Aβ clearance of apolipoprotein E4 (APOE4), the strongest risk factor for SAD. However, whether intracellular APOE4 affects Aβ production is unclear. Using APOE3 and APOE4 knock-in (KI) mouse brain and primary cultured fibroblasts from these mice, in this study, we demonstrated that APOE3 and APOE4 bind to the γ-secretase complex and isoform-dependently regulate its activity and Aβ production. We found that Aβ40 levels and γ-secretase activity were higher in APOE knockout mouse brain than in wild-type mouse brain. APOE4-KI fibroblasts had significant lower Aβ levels and γ-secretase activity but higher Aβ42/40 ratio compared with APOE3-KI cells, indicating that APOE4-KI reduces Aβ production by inhibiting γ-secretase activity. Interestingly, the levels of γ-secretase complex bound to APOE4 are higher than those bound to APOE3, and the levels of γ-secretase complex in the brain and fibroblasts of APOE4-KI mice were higher than those of APOE3-KI mice. Taken together, our findings demonstrate that intracellular APOE4 inhibits Aβ production, more preferentially inhibits Aβ40 production, and thereby induces an increase in the Aβ42/40 ratio via binding to the γ-secretase complex. These results suggest a novel mechanism in which intracellular APOE4 contributes to the pathogenesis of SAD by inhibiting γ-secretase activity.
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Affiliation(s)
- Yang Sun
- Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Sadequl Islam
- Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Yuan Gao
- Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Tomohisa Nakamura
- Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Kun Zou
- Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Makoto Michikawa
- Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
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29
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Vergilio J, Lockhart C, Klimov DK. De Novo Transmembrane Aggregation of Aβ10-40 Peptides in an Anionic Lipid Bilayer. J Chem Inf Model 2022; 62:6228-6241. [PMID: 36455155 DOI: 10.1021/acs.jcim.2c01192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Using the all-atom model and 10 μs serial replica-exchange molecular dynamics (SREMD), we investigated the binding of Alzheimer's Aβ10-40 peptides to the anionic dimyristoylphosphatidylcholine/dimyristoylphosphatidylglycerol (DMPC/DMPG) lipid bilayer. Our objective was to probe de novo transmembrane Aβ10-40 aggregation and to test the utility of SREMD. Our results are threefold. First, upon binding, Aβ10-40 adopts a helical structure in the C-terminus and deeply inserts into the bilayer. Binding is primarily controlled by electrostatic interactions of the peptides with water, ions, and lipids, particularly, anionic DMPG. Second, Aβ-bilayer interactions reorganize lipids in the proximity of the bound peptides, causing an influx of DMPG lipids into the Aβ binding footprint. Third and most important, computed free energy landscapes reveal that Aβ10-40 peptides partition into monomeric and dimeric species. The dimers result from transmembrane aggregation of the peptides and induce a striking lipid density void throughout both leaflets in the bilayer. There are multiple factors stabilizing transmembrane dimers, including van der Waals and steric interactions, electrostatic interactions, and hydrogen bonding, hydration, and entropic gains originating from dimer conformations and lipid disorder. We argue that helix dipole-dipole interactions underestimated in the all-atom force field must be a contributing factor to stabilizing antiparallel transmembrane dimers. We propose that transmembrane aggregates serve as mechanistic links between the populations of extra- and intracellular Aβ peptides. From the computational perspective, SREMD is found to be a viable alternative to traditional replica-exchange simulations.
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Affiliation(s)
- James Vergilio
- School of Systems Biology, George Mason University, Manassas, Virginia 20110, United States
| | - Christopher Lockhart
- School of Systems Biology, George Mason University, Manassas, Virginia 20110, United States
| | - Dmitri K Klimov
- School of Systems Biology, George Mason University, Manassas, Virginia 20110, United States
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30
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Huntingtin and Other Neurodegeneration-Associated Proteins in the Development of Intracellular Pathologies: Potential Target Search for Therapeutic Intervention. Int J Mol Sci 2022; 23:ijms232415533. [PMID: 36555175 PMCID: PMC9779313 DOI: 10.3390/ijms232415533] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/02/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022] Open
Abstract
Neurodegenerative diseases are currently incurable. Numerous experimental data accumulated over the past fifty years have brought us closer to understanding the molecular and cell mechanisms responsible for their development. However, these data are not enough for a complete understanding of the genesis of these diseases, nor to suggest treatment methods. It turns out that many cellular pathologies developing during neurodegeneration coincide from disease to disease. These observations give hope to finding a common intracellular target(s) and to offering a universal method of treatment. In this review, we attempt to analyze data on similar cellular disorders among neurodegenerative diseases in general, and polyglutamine neurodegenerative diseases in particular, focusing on the interaction of various proteins involved in the development of neurodegenerative diseases with various cellular organelles. The main purposes of this review are: (1) to outline the spectrum of common intracellular pathologies and to answer the question of whether it is possible to find potential universal target(s) for therapeutic intervention; (2) to identify specific intracellular pathologies and to speculate about a possible general approach for their treatment.
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31
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González-Naranjo P, Pérez C, González-Sánchez M, Gironda-Martínez A, Ulzurrun E, Bartolomé F, Rubio-Fernández M, Martin-Requero A, Campillo NE, Páez JA. Multitarget drugs as potential therapeutic agents for alzheimer's disease. A new family of 5-substituted indazole derivatives as cholinergic and BACE1 inhibitors. J Enzyme Inhib Med Chem 2022; 37:2348-2356. [PMID: 36050834 PMCID: PMC9477487 DOI: 10.1080/14756366.2022.2117315] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Multitarget drugs are a promising therapeutic approach against Alzheimer’s disease. In this work, a new family of 5-substituted indazole derivatives with a multitarget profile including cholinesterase and BACE1 inhibition is described. Thus, the synthesis and evaluation of a new class of 5-substituted indazoles has been performed. Pharmacological evaluation includes in vitro inhibitory assays on AChE/BuChE and BACE1 enzymes. Also, the corresponding competition studies on BuChE were carried out. Additionally, antioxidant properties have been calculated from ORAC assays. Furthermore, studies of anti-inflammatory properties on Raw 264.7 cells and neuroprotective effects in human neuroblastoma SH-SY5Y cells have been performed. The results of pharmacological tests have shown that some of these 5-substituted indazole derivatives 1–4 and 6 behave as AChE/BuChE and BACE1 inhibitors, simultaneously. In addition, some indazole derivatives showed anti-inflammatory (3, 6) and neuroprotective (1–4 and 6) effects against Aβ-induced cell death in human neuroblastoma SH-SY5Y cells with antioxidant properties.
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Affiliation(s)
| | | | | | | | - Eugenia Ulzurrun
- Centro de Investigaciones Biológicas Margarita Salas (CSIC), Madrid, Spain.,Centro Nacional de Biotecnología (CSIC), Madrid, Spain
| | - Fernando Bartolomé
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.,Instituto de Investigación Hospital Doce de Octubre, Madrid, Spain
| | - Marcos Rubio-Fernández
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Angeles Martin-Requero
- Centro de Investigaciones Biológicas Margarita Salas (CSIC), Madrid, Spain.,Instituto de Investigación Hospital Doce de Octubre, Madrid, Spain
| | - Nuria E Campillo
- Centro de Investigaciones Biológicas Margarita Salas (CSIC), Madrid, Spain.,Instituto de Ciencias Matemáticas (CSIC), Madrid, Spain
| | - Juan A Páez
- Instituto de Química Médica (CSIC), Madrid, Spain
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32
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Hajjo R, Sabbah DA, Abusara OH, Al Bawab AQ. A Review of the Recent Advances in Alzheimer's Disease Research and the Utilization of Network Biology Approaches for Prioritizing Diagnostics and Therapeutics. Diagnostics (Basel) 2022; 12:diagnostics12122975. [PMID: 36552984 PMCID: PMC9777434 DOI: 10.3390/diagnostics12122975] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 11/16/2022] [Accepted: 11/18/2022] [Indexed: 11/29/2022] Open
Abstract
Alzheimer's disease (AD) is a polygenic multifactorial neurodegenerative disease that, after decades of research and development, is still without a cure. There are some symptomatic treatments to manage the psychological symptoms but none of these drugs can halt disease progression. Additionally, over the last few years, many anti-AD drugs failed in late stages of clinical trials and many hypotheses surfaced to explain these failures, including the lack of clear understanding of disease pathways and processes. Recently, different epigenetic factors have been implicated in AD pathogenesis; thus, they could serve as promising AD diagnostic biomarkers. Additionally, network biology approaches have been suggested as effective tools to study AD on the systems level and discover multi-target-directed ligands as novel treatments for AD. Herein, we provide a comprehensive review on Alzheimer's disease pathophysiology to provide a better understanding of disease pathogenesis hypotheses and decipher the role of genetic and epigenetic factors in disease development and progression. We also provide an overview of disease biomarkers and drug targets and suggest network biology approaches as new tools for identifying novel biomarkers and drugs. We also posit that the application of machine learning and artificial intelligence to mining Alzheimer's disease multi-omics data will facilitate drug and biomarker discovery efforts and lead to effective individualized anti-Alzheimer treatments.
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Affiliation(s)
- Rima Hajjo
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
- Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carlina at Chapel Hill, Chapel Hill, NC 27599, USA
- National Center for Epidemics and Communicable Disease Control, Amman 11118, Jordan
- Correspondence:
| | - Dima A. Sabbah
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
| | - Osama H. Abusara
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
| | - Abdel Qader Al Bawab
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
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33
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Vojtechova I, Machacek T, Kristofikova Z, Stuchlik A, Petrasek T. Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity. PLoS Pathog 2022; 18:e1010929. [PMCID: PMC9671327 DOI: 10.1371/journal.ppat.1010929] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
The amyloid cascade hypothesis, focusing on pathological proteins aggregation, has so far failed to uncover the root cause of Alzheimer’s disease (AD), or to provide an effective therapy. This traditional paradigm essentially explains a mechanism involved in the development of sporadic AD rather than its cause. The failure of an overwhelming majority of clinical studies (99.6%) demonstrates that a breakthrough in therapy would be difficult if not impossible without understanding the etiology of AD. It becomes more and more apparent that the AD pathology might originate from brain infection. In this review, we discuss a potential role of bacteria, viruses, fungi, and eukaryotic parasites as triggers of AD pathology. We show evidence from the current literature that amyloid beta, traditionally viewed as pathological, actually acts as an antimicrobial peptide, protecting the brain against pathogens. However, in case of a prolonged or excessive activation of a senescent immune system, amyloid beta accumulation and aggregation becomes damaging and supports runaway neurodegenerative processes in AD. This is paralleled by the recent study by Alam and colleagues (2022) who showed that alpha-synuclein, the protein accumulating in synucleinopathies, also plays a critical physiological role in immune reactions and inflammation, showing an unforeseen link between the 2 unrelated classes of neurodegenerative disorders. The multiplication of the amyloid precursor protein gene, recently described by Lee and collegues (2018), and possible reactivation of human endogenous retroviruses by pathogens fits well into the same picture. We discuss these new findings from the viewpoint of the infection hypothesis of AD and offer suggestions for future research. More than a century after its discovery, Alzheimer’s disease (AD) remains incurable and mysterious. The dominant hypothesis of amyloid cascade has succeeded in explaining the key pathological mechanism, but not its trigger. Amyloid beta has been traditionally considered a pathological peptide, and its physiological functions remain poorly known. These knowledge gaps have contributed to repeated failures of clinical studies. The emerging infectious hypothesis of AD considers central nervous system (CNS) infection the primary trigger of sporadic AD. A closely connected hypothesis claims that amyloid beta is an antimicrobial peptide. In this review, we discuss the available evidence for the involvement of infections in AD, coming from epidemiological studies, post mortem analyses of brain tissue, and experiments in vitro and in vivo. We argue there is no unique “Alzheimer’s germ,” instead, AD is a general reaction of the CNS to chronic infections, in the milieu of an aged immune system. The pathology may become self-sustained even without continuous presence of microbes in the brain. Importantly, the infectious hypothesis leads to testable predictions. Targeting amyloid beta should be ineffective, unless the triggering pathogen and inflammatory response are addressed as well. Meticulous control of selected infections might be the best near-term strategy for AD prevention.
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Affiliation(s)
- Iveta Vojtechova
- National Institute of Mental Health, Klecany, Czech Republic
- Laboratory of Neurophysiology of Memory, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
- * E-mail: , (IV); , (TP)
| | - Tomas Machacek
- Department of Parasitology, Faculty of Science, Charles University, Prague, Czech Republic
| | | | - Ales Stuchlik
- National Institute of Mental Health, Klecany, Czech Republic
- Laboratory of Neurophysiology of Memory, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Tomas Petrasek
- National Institute of Mental Health, Klecany, Czech Republic
- Laboratory of Neurophysiology of Memory, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
- * E-mail: , (IV); , (TP)
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34
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Kanagasingam S, von Ruhland C, Welbury R, Chukkapalli SS, Singhrao SK. Porphyromonas gingivalis Conditioned Medium Induces Amyloidogenic Processing of the Amyloid-β Protein Precursor upon in vitro Infection of SH-SY5Y Cells. J Alzheimers Dis Rep 2022; 6:577-587. [PMID: 36275415 PMCID: PMC9535609 DOI: 10.3233/adr-220029] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 08/23/2022] [Indexed: 12/27/2022] Open
Abstract
Background: Cleavage of the amyloid-β protein precursor (AβPP) mediated by host secretase enzymes, releases several fragments including amyloid-β (Aβ40 and Aβ42). Objective: To determine if Porphyromonas gingivalis conditioned medium cleaved AβPP to release Aβ40 and Aβ42. Methods: The SH-SY5Y cell line was challenged, in vitro, with P. gingivalis (Pg381) conditioned medium in the presence/absence of cytokines. The cells and their supernatants were assessed for AβPP cleavage fragments by immunoblotting and transmission electron microscopy. Results: Western blotting of the cell lysates with the anti-AβPP C-terminal antibody demonstrated variable molecular weight bands corresponding to full length and fragmented AβPP in lanes treated with the following factors: Tryptic soy broth (TSB), Pg381, IL-6, Pg381 + IL-1β, and Pg381 + TNF-α. The low molecular weight bands corresponding to the C99 dimerized fragment were observed in the Pg381 and interlukin-6 (IL-6) treated groups and were significantly more intense in the presence of Pg381 with either IL-6 or TNF-α. Bands corresponding to the dimerized C83 fragment were observed with cells treated with TNF-α alone and with Pg381 combined with IL-1β or IL-6 or TNF-α. The anti-Aβ antibody detected statistically significant Aβ40 and Aβ42, levels when these two Aβ species were pooled across test samples and compared to the untreated group. Electron microscopic examination of the supernatants demonstrated insoluble Aβ40 and Aβ42. Conclusion: These observations strongly imply that AβPP is an infection responsive protein cleaved via the amyloidogenic pathway on exposure to conditioned medium and in the presence of pro-inflammatory mediators.
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Affiliation(s)
- Shalini Kanagasingam
- Brain and Behavior Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK
| | - Christopher von Ruhland
- Electron and Light Microscopy Facility, College of Biomedical and Life Sciences, Cardiff University, Wales, UK
| | - Richard Welbury
- Brain and Behavior Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK
| | | | - Sim K. Singhrao
- Brain and Behavior Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK
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35
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Kim J, Wulschner LEG, Oh WC, Ko J. Trans
‐synaptic mechanisms orchestrated by mammalian synaptic cell adhesion molecules. Bioessays 2022; 44:e2200134. [DOI: 10.1002/bies.202200134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/18/2022] [Accepted: 08/31/2022] [Indexed: 11/11/2022]
Affiliation(s)
- Jinhu Kim
- Department of Brain Sciences Daegu Gyeongbuk Institute of Science and Technology (DGIST) Daegu Korea
- Center for Synapse Diversity and Specificity DGIST Daegu Korea
| | | | - Won Chan Oh
- Department of Pharmacology University of Colorado School of Medicine Aurora Colorado USA
| | - Jaewon Ko
- Department of Brain Sciences Daegu Gyeongbuk Institute of Science and Technology (DGIST) Daegu Korea
- Center for Synapse Diversity and Specificity DGIST Daegu Korea
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36
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McKendell AK, Houser MCQ, Mitchell SPC, Wolfe MS, Berezovska O, Maesako M. In-Depth Characterization of Endo-Lysosomal Aβ in Intact Neurons. BIOSENSORS 2022; 12:663. [PMID: 36005059 PMCID: PMC9406119 DOI: 10.3390/bios12080663] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/17/2022] [Accepted: 08/18/2022] [Indexed: 12/21/2022]
Abstract
Amyloid-beta (Aβ) peptides are produced within neurons. Some peptides are released into the brain parenchyma, while others are retained inside the neurons. However, the detection of intracellular Aβ remains a challenge since antibodies against Aβ capture Aβ and its precursor proteins (i.e., APP and C99). To overcome this drawback, we recently developed 1) the C99 720-670 biosensor for recording γ-secretase activity and 2) a unique multiplexed immunostaining platform that enables the selective detection of intracellular Aβ with subcellular resolution. Using these new assays, we showed that C99 is predominantly processed by γ-secretase in late endosomes and lysosomes, and intracellular Aβ is enriched in the same subcellular loci in intact neurons. However, the detailed properties of Aβ in the acidic compartments remain unclear. Here, we report using fluorescent lifetime imaging microscopy (FLIM) that intracellular Aβ includes both long Aβ intermediates bound to γ-secretase and short peptides dissociated from the protease complex. Surprisingly, our results also suggest that the dissociated Aβ is bound to the glycoproteins on the inner membrane of lysosomes. Furthermore, we show striking cell-to-cell heterogeneity in intracellular Aβ levels in primary neurons and APP transgenic mouse brains. These findings provide a basis for the further investigation of the role(s) of intracellular Aβ and its relevance to Alzheimer's disease (AD).
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Affiliation(s)
- Alec K. McKendell
- Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, 114, 16th street, Charlestown, MA 02129, USA
| | - Mei C. Q. Houser
- Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, 114, 16th street, Charlestown, MA 02129, USA
| | - Shane P. C. Mitchell
- Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, 114, 16th street, Charlestown, MA 02129, USA
| | - Michael S. Wolfe
- Department of Medicinal Chemistry, University of Kansas, 1567 Irving Hill Rd, Lawrence, Kansas City, KS 66045, USA
| | - Oksana Berezovska
- Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, 114, 16th street, Charlestown, MA 02129, USA
| | - Masato Maesako
- Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, 114, 16th street, Charlestown, MA 02129, USA
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37
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Trinh PNH, Baltos JA, Hellyer SD, May LT, Gregory KJ. Adenosine receptor signalling in Alzheimer’s disease. Purinergic Signal 2022; 18:359-381. [PMID: 35870032 PMCID: PMC9391555 DOI: 10.1007/s11302-022-09883-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 07/02/2022] [Indexed: 12/11/2022] Open
Abstract
Alzheimer’s disease (AD) is the most common dementia in the elderly and its increasing prevalence presents treatment challenges. Despite a better understanding of the disease, the current mainstay of treatment cannot modify pathogenesis or effectively address the associated cognitive and memory deficits. Emerging evidence suggests adenosine G protein-coupled receptors (GPCRs) are promising therapeutic targets for Alzheimer’s disease. The adenosine A1 and A2A receptors are expressed in the human brain and have a proposed involvement in the pathogenesis of dementia. Targeting these receptors preclinically can mitigate pathogenic β-amyloid and tau neurotoxicity whilst improving cognition and memory. In this review, we provide an accessible summary of the literature on Alzheimer’s disease and the therapeutic potential of A1 and A2A receptors. Although there are no available medicines targeting these receptors approved for treating dementia, we provide insights into some novel strategies, including allosterism and the targeting of oligomers, which may increase drug discovery success and enhance the therapeutic response.
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Affiliation(s)
- Phuc N. H. Trinh
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052 Australia
- Department of Pharmacology, Monash University, Parkville, VIC 3052 Australia
| | - Jo-Anne Baltos
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052 Australia
- Department of Pharmacology, Monash University, Parkville, VIC 3052 Australia
| | - Shane D. Hellyer
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052 Australia
| | - Lauren T. May
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052 Australia
- Department of Pharmacology, Monash University, Parkville, VIC 3052 Australia
| | - Karen J. Gregory
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052 Australia
- Department of Pharmacology, Monash University, Parkville, VIC 3052 Australia
- ARC Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Parkville, 3052 Australia
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Haass C, Selkoe D. If amyloid drives Alzheimer disease, why have anti-amyloid therapies not yet slowed cognitive decline? PLoS Biol 2022; 20:e3001694. [PMID: 35862308 PMCID: PMC9302755 DOI: 10.1371/journal.pbio.3001694] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Strong genetic evidence supports an imbalance between production and clearance of amyloid β-protein (Aβ) in people with Alzheimer disease (AD). Microglia that are potentially involved in alternative mechanisms are actually integral to the amyloid cascade. Fluid biomarkers and brain imaging place accumulation of Aβ at the beginning of molecular and clinical changes in the disease. So why have clinical trials of anti-amyloid therapies not provided clear-cut benefits to patients with AD? Can anti-amyloid therapies robustly decrease Aβ in the human brain, and if so, could this lowering be too little, too late? These central questions in research on AD are being urgently addressed. Evidence suggests that an imbalance between production and clearance of amyloid-beta is an early, invariant feature of Alzheimer disease that drives its neuronal and glial pathology and precedes cognitive symptoms. So why are we still unable to slow cognitive decline with anti-amyloid therapies?
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Affiliation(s)
- Christian Haass
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
- Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
- * E-mail: (CH); (DS)
| | - Dennis Selkoe
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail: (CH); (DS)
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39
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Distefano A, Caruso G, Oliveri V, Bellia F, Sbardella D, Zingale GA, Caraci F, Grasso G. Neuroprotective Effect of Carnosine Is Mediated by Insulin-Degrading Enzyme. ACS Chem Neurosci 2022; 13:1588-1593. [PMID: 35471926 PMCID: PMC9121383 DOI: 10.1021/acschemneuro.2c00201] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
![]()
l-Carnosine
is an endogenous dipeptide that has high potential
for therapeutic purposes, being an antioxidant with metal chelating,
anti-aggregating, anti-inflammatory, and neuroprotective properties.
Despite its potential therapeutic values, the biomolecular mechanisms
involved in neuroprotection are not fully understood. Here, we demonstrate,
at chemical and biochemical levels, that insulin-degrading enzyme
plays a pivotal role in carnosine neuroprotection.
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Affiliation(s)
- Alessia Distefano
- Department of Chemical Sciences, University of Catania, Viale Andrea Doria 6, Catania 95125, Italy
| | - Giuseppe Caruso
- Department of Drug and Health Sciences, University of Catania, Viale Andrea Doria 6, Catania 95125, Italy
- Oasi Research Institute-IRCCS, Via Conte Ruggero 73, Troina 94018, Italy
| | - Valentina Oliveri
- Department of Chemical Sciences, University of Catania, Viale Andrea Doria 6, Catania 95125, Italy
| | - Francesco Bellia
- Institute of Crystallography, CNR, Via Paolo Gaifami 18, Catania 95126, Italy
| | | | - Gabriele Antonio Zingale
- Department of Chemical Sciences, University of Catania, Viale Andrea Doria 6, Catania 95125, Italy
| | - Filippo Caraci
- Department of Drug and Health Sciences, University of Catania, Viale Andrea Doria 6, Catania 95125, Italy
- Oasi Research Institute-IRCCS, Via Conte Ruggero 73, Troina 94018, Italy
| | - Giuseppe Grasso
- Department of Chemical Sciences, University of Catania, Viale Andrea Doria 6, Catania 95125, Italy
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40
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Doroszkiewicz J, Groblewska M, Mroczko B. Molecular Biomarkers and Their Implications for the Early Diagnosis of Selected Neurodegenerative Diseases. Int J Mol Sci 2022; 23:ijms23094610. [PMID: 35563001 PMCID: PMC9100918 DOI: 10.3390/ijms23094610] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/15/2022] [Accepted: 04/20/2022] [Indexed: 02/07/2023] Open
Abstract
The degeneration and dysfunction of neurons are key features of neurodegenerative diseases (NDs). Currently, one of the main challenges facing researchers and clinicians is the ability to obtain reliable diagnostic tools that will allow for the diagnosis of NDs as early as possible and the detection of neuronal dysfunction, preferably in the presymptomatic stage. Additionally, better tools for assessing disease progression in this group of disorders are also being sought. The ideal biomarker must have high sensitivity and specificity, be easy to measure, give reproducible results, and reflect the disease progression. Molecular biomarkers include miRNAs and extracellular microvesicles known as exosomes. They may be measured in two extracellular fluids of the highest importance in NDs, i.e., cerebrospinal fluid (CSF) and blood. The aim of the current review is to summarize the pathophysiology of the four most frequent NDs—i.e., Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)—as well as current progress in the research into miRNAs as biomarkers in these major neurodegenerative diseases. In addition, we discuss the possibility of using miRNA-based therapies in the treatment of neurodegenerative diseases, and present the limitations of this type of therapy.
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Affiliation(s)
- Julia Doroszkiewicz
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland;
- Correspondence: ; Tel.: +48-85-686-51-68
| | - Magdalena Groblewska
- Department of Biochemical Diagnostics, University Hospital in Białystok, 15-269 Bialystok, Poland;
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland;
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
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41
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Golde TE. Alzheimer’s disease – the journey of a healthy brain into organ failure. Mol Neurodegener 2022; 17:18. [PMID: 35248124 PMCID: PMC8898417 DOI: 10.1186/s13024-022-00523-1] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 02/17/2022] [Indexed: 12/19/2022] Open
Abstract
As the most common dementia, Alzheimer’s disease (AD) exacts an immense personal, societal, and economic toll. AD was first described at the neuropathological level in the early 1900s. Today, we have mechanistic insight into select aspects of AD pathogenesis and have the ability to clinically detect and diagnose AD and underlying AD pathologies in living patients. These insights demonstrate that AD is a complex, insidious, degenerative proteinopathy triggered by Aβ aggregate formation. Over time Aβ pathology drives neurofibrillary tangle (NFT) pathology, dysfunction of virtually all cell types in the brain, and ultimately, overt neurodegeneration. Yet, large gaps in our knowledge of AD pathophysiology and huge unmet medical need remain. Though we largely conceptualize AD as a disease of aging, heritable and non-heritable factors impact brain physiology, either continuously or at specific time points during the lifespan, and thereby alter risk for devolvement of AD. Herein, I describe the lifelong journey of a healthy brain from birth to death with AD, while acknowledging the many knowledge gaps that remain regarding our understanding of AD pathogenesis. To ensure the current lexicon surrounding AD changes from inevitable, incurable, and poorly manageable to a lexicon of preventable, curable, and manageable we must address these knowledge gaps, develop therapies that have a bigger impact on clinical symptoms or progression of disease and use these interventions at the appropriate stage of disease.
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42
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Duan Y, Lv J, Zhang Z, Chen Z, Wu H, Chen J, Chen Z, Yang J, Wang D, Liu Y, Chen F, Tian Y, Cao X. Exogenous Aβ 1-42 monomers improve synaptic and cognitive function in Alzheimer's disease model mice. Neuropharmacology 2022; 209:109002. [PMID: 35196539 DOI: 10.1016/j.neuropharm.2022.109002] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/28/2022] [Accepted: 02/15/2022] [Indexed: 01/16/2023]
Abstract
Growing evidence has suggested the poor correlation between brain amyloid plaque and Alzheimer's disease (AD). Presenilin1 (PS1) and presenilin2 (PS2) conditional double knockout (cDKO) mice exhibited the reduced 42-amino acid amyloid-β peptide (Aβ1-42) level and AD-like symptoms, indicating a different pathological mechanism from the amyloid cascade hypothesis for AD. Here we found that exogenous synthetic Aβ1-42 monomers could improve the impaired memory not only in cDKO mice without Aβ1-42 deposition but also in the APP/PS1/Tau triple transgenic 3 × Tg-AD mice with Aβ1-42 deposition, which were mediated by α7-nAChR. Our findings demonstrate for the first time that reduced soluble Aβ1-42 level is the main cause of cognitive dysfunction in cDKO mice, and support the opinions that low soluble Aβ1-42 level due to Aβ1-42 deposition may also cause cognitive deficits in 3 × Tg-AD mice. Therefore, "loss-of-function" of Aβ1-42 should be avoided when designing therapies aimed at reducing Aβ1-42 burden in AD.
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Affiliation(s)
- Yanhong Duan
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, 3663 N. Zhongshan Rd., Shanghai, 200062, China
| | - Junyan Lv
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, 3663 N. Zhongshan Rd., Shanghai, 200062, China
| | - Zhonghui Zhang
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 3663 N. Zhongshan Rd., Shanghai, 200062, China
| | - Zhenzhen Chen
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, 3663 N. Zhongshan Rd., Shanghai, 200062, China
| | - Hao Wu
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, 3663 N. Zhongshan Rd., Shanghai, 200062, China
| | - Jinnan Chen
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, 3663 N. Zhongshan Rd., Shanghai, 200062, China
| | - Zhidong Chen
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, 3663 N. Zhongshan Rd., Shanghai, 200062, China
| | - Jiarun Yang
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, 3663 N. Zhongshan Rd., Shanghai, 200062, China
| | - Dasheng Wang
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, 3663 N. Zhongshan Rd., Shanghai, 200062, China
| | - Yamei Liu
- School of Life Sciences, Shanghai University, No. 99 Shangda Rd., Shanghai, 200444, PR China
| | - Fuxue Chen
- School of Life Sciences, Shanghai University, No. 99 Shangda Rd., Shanghai, 200444, PR China
| | - Yang Tian
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 3663 N. Zhongshan Rd., Shanghai, 200062, China
| | - Xiaohua Cao
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, 3663 N. Zhongshan Rd., Shanghai, 200062, China.
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43
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Kawano Y, Tamura K, Egawa M, Tamano H, Takeda A. Isoproterenol, an adrenergic β receptor agonist, induces metallothionein synthesis followed by canceling amyloid β1-42-induced neurodegeneration. Biometals 2022; 35:303-312. [DOI: 10.1007/s10534-022-00365-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 01/14/2022] [Indexed: 11/24/2022]
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44
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The Impact of Medium Chain and Polyunsaturated ω-3-Fatty Acids on Amyloid-β Deposition, Oxidative Stress and Metabolic Dysfunction Associated with Alzheimer's Disease. Antioxidants (Basel) 2021; 10:antiox10121991. [PMID: 34943094 PMCID: PMC8698946 DOI: 10.3390/antiox10121991] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/09/2021] [Accepted: 12/12/2021] [Indexed: 01/22/2023] Open
Abstract
Alzheimer’s disease (AD), the most common cause of dementia in the elderly population, is closely linked to a dysregulated cerebral lipid homeostasis and particular changes in brain fatty acid (FA) composition. The abnormal extracellular accumulation and deposition of the peptide amyloid-β (Aβ) is considered as an early toxic event in AD pathogenesis, which initiates a series of events leading to neuronal dysfunction and death. These include the induction of neuroinflammation and oxidative stress, the disruption of calcium homeostasis and membrane integrity, an impairment of cerebral energy metabolism, as well as synaptic and mitochondrial dysfunction. Dietary medium chain fatty acids (MCFAs) and polyunsaturated ω-3-fatty acids (ω-3-PUFAs) seem to be valuable for disease modification. Both classes of FAs have neuronal health-promoting and cognition-enhancing properties and might be of benefit for patients suffering from mild cognitive impairment (MCI) and AD. This review summarizes the current knowledge about the molecular mechanisms by which MCFAs and ω-3-PUFAs reduce the cerebral Aβ deposition, improve brain energy metabolism, and lessen oxidative stress levels.
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45
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Josephine Boder E, Banerjee IA. Alzheimer's Disease: Current Perspectives and Advances in Physiological Modeling. Bioengineering (Basel) 2021; 8:211. [PMID: 34940364 PMCID: PMC8698996 DOI: 10.3390/bioengineering8120211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/07/2021] [Accepted: 12/10/2021] [Indexed: 12/17/2022] Open
Abstract
Though Alzheimer's disease (AD) is the most common cause of dementia, complete disease-modifying treatments are yet to be fully attained. Until recently, transgenic mice constituted most in vitro model systems of AD used for preclinical drug screening; however, these models have so far failed to adequately replicate the disease's pathophysiology. However, the generation of humanized APOE4 mouse models has led to key discoveries. Recent advances in stem cell differentiation techniques and the development of induced pluripotent stem cells (iPSCs) have facilitated the development of novel in vitro devices. These "microphysiological" systems-in vitro human cell culture systems designed to replicate in vivo physiology-employ varying levels of biomimicry and engineering control. Spheroid-based organoids, 3D cell culture systems, and microfluidic devices or a combination of these have the potential to replicate AD pathophysiology and pathogenesis in vitro and thus serve as both tools for testing therapeutics and models for experimental manipulation.
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Affiliation(s)
| | - Ipsita A. Banerjee
- Department of Chemistry, Fordham University, 441 E. Fordham Road, Bronx, NY 10458, USA;
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46
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Razani E, Pourbagheri-Sigaroodi A, Safaroghli-Azar A, Zoghi A, Shanaki-Bavarsad M, Bashash D. The PI3K/Akt signaling axis in Alzheimer's disease: a valuable target to stimulate or suppress? Cell Stress Chaperones 2021; 26:871-887. [PMID: 34386944 PMCID: PMC8578535 DOI: 10.1007/s12192-021-01231-3] [Citation(s) in RCA: 119] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/23/2021] [Accepted: 08/09/2021] [Indexed: 12/12/2022] Open
Abstract
Among the long list of age-related complications, Alzheimer's disease (AD) has the most dreadful impact on the quality of life due to its devastating effects on memory and cognitive abilities. Although a plausible correlation between the phosphatidylinositol 3-kinase (PI3K) signaling and different processes involved in neurodegeneration has been evidenced, few articles reviewed the task. The current review aims to unravel the mechanisms by which the PI3K pathway plays pro-survival roles in normal conditions, and also to discuss the original data obtained from international research laboratories on this topic. Responses to questions on how alterations of the PI3K/Akt signaling pathway affect Tau phosphorylation and the amyloid cascade are given. In addition, we provide a general overview of the association between oxidative stress, neuroinflammation, alterations of insulin signaling, and altered autophagy with aberrant activation of this axis in the AD brain. The last section provides a special focus on the therapeutic possibility of the PI3K/Akt/mTOR modulators, either categorized as chemicals or herbals, in AD. In conclusion, determining the correct timing for the administration of the drugs seems to be one of the most important factors in the success of these agents. Also, the role of the PI3K/Akt signaling axis in the progression or repression of AD widely depends on the context of the cells; generally speaking, while PI3K/Akt activation in neurons and neural stem cells is favorable, its activation in microglia cells may be harmful.
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Affiliation(s)
- Elham Razani
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ava Safaroghli-Azar
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Anahita Zoghi
- Department of Neurology, School of Medicine, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahsa Shanaki-Bavarsad
- Institute of Neuroscience, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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47
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Alzheimer's disease clinical trial update 2019-2021. J Neurol 2021; 269:1038-1051. [PMID: 34609602 DOI: 10.1007/s00415-021-10790-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 08/31/2021] [Accepted: 09/01/2021] [Indexed: 12/12/2022]
Abstract
The current clinical trial landscape targeting Alzheimer's disease (AD) is reviewed in the context of studies completed from 2019 to 2021. This review focuses on available data for observational and phase II/III clinical trial results, which will have the most impact on the field. ClinicalTrials.gov, the United States (US) comprehensive federal registry, was queried to identify completed trials. There are currently 226 interventional clinical trials and 51 observational studies completed, suspended, terminated, or withdrawn within our selected time frame. This review reveals that the role of biomarkers is expanding and although many lessons have been learned, many challenges remain when targeting disease modification of AD through amyloid and tau. In addition, to halt or slow clinical progression of AD, new clinical and observational trials are focusing on prevention as well as the role of more diverse biological processes known to influence AD pathology.
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48
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Potential Roles of Sestrin2 in Alzheimer's Disease: Antioxidation, Autophagy Promotion, and Beyond. Biomedicines 2021; 9:biomedicines9101308. [PMID: 34680426 PMCID: PMC8533411 DOI: 10.3390/biomedicines9101308] [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: 07/29/2021] [Revised: 09/14/2021] [Accepted: 09/16/2021] [Indexed: 11/17/2022] Open
Abstract
Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease. It presents with progressive memory loss, worsens cognitive functions to the point of disability, and causes heavy socioeconomic burdens to patients, their families, and society as a whole. The underlying pathogenic mechanisms of AD are complex and may involve excitotoxicity, excessive generation of reactive oxygen species (ROS), aberrant cell cycle reentry, impaired mitochondrial function, and DNA damage. Up to now, there is no effective treatment available for AD, and it is therefore urgent to develop an effective therapeutic regimen for this devastating disease. Sestrin2, belonging to the sestrin family, can counteract oxidative stress, reduce activity of the mammalian/mechanistic target of rapamycin (mTOR), and improve cell survival. It may therefore play a crucial role in neurodegenerative diseases like AD. However, only limited studies of sestrin2 and AD have been conducted up to now. In this article, we discuss current experimental evidence to demonstrate the potential roles of sestrin2 in treating neurodegenerative diseases, focusing specifically on AD. Strategies for augmenting sestrin2 expression may strengthen neurons, adapting them to stressful conditions through counteracting oxidative stress, and may also adjust the autophagy process, these two effects together conferring neuronal resistance in cases of AD.
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49
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Bayer TA. N-Truncated Aβ Starting at Position Four-Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer's Disease. Front Aging Neurosci 2021; 13:710579. [PMID: 34489680 PMCID: PMC8417877 DOI: 10.3389/fnagi.2021.710579] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 07/29/2021] [Indexed: 12/21/2022] Open
Abstract
The discussion of whether amyloid plaque Aβ is a valid drug target to fight Alzheimer’s disease (AD) has been a matter of scientific dispute for decades. This question can only be settled by successful clinical trials and the approval of disease-modifying drugs. However, many clinical trials with antibodies against different regions of the amyloid Aβ peptide have been discontinued, as they did not meet the clinical endpoints required. Recently, passive immunization of AD patients with Donanemab, an antibody directed against the N-terminus of pyroglutamate Aβ, showed beneficial effects in a phase II trial, supporting the concept that N-truncated Aβ is a relevant target for AD therapy. There is long-standing evidence that N-truncated Aβ variants are the main variants found in amyloid plaques besides full-length Aβ1–42, t, therefore their role in triggering AD pathology and as targets for drug development are of interest. While the contribution of pyroglutamate Aβ3–42 to AD pathology has been well studied in the past, the potential role of Aβ4–42 has been largely neglected. The present review will therefore focus on Aβ4–42 as a possible drug target based on human and mouse pathology, in vitro and in vivo toxicity, and anti-Aβ4-X therapeutic effects in preclinical models.
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Affiliation(s)
- Thomas A Bayer
- Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center Göttingen (UMG), Georg-August-University, Göttingen, Germany
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50
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Xie Y, Wang Y, Jiang S, Xiang X, Wang J, Ning L. Novel strategies for the fight of Alzheimer's disease targeting amyloid-β protein. J Drug Target 2021; 30:259-268. [PMID: 34435898 DOI: 10.1080/1061186x.2021.1973482] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Alzheimer's disease (AD), which is recognised as a devastating neurodegenerative disease throughout the world and lack of effective treatments, is a growing concern in modern society with a growing population of elderly patients. A growing number of studies reveal that abnormal accumulation and deposition of Aβ is responsible for AD. Inspired by this, strategies for the treatment of AD targeting-Aβ clearance have been discussed for a long period, exploring new drugs which is capable of destroying soluble Aβ oligomers and unsolvable Aβ aggregates. In this paper, results of recent clinical trials on several anti-amyloid-β drugs are presented and several emerging anti-amyloid AD therapies based on recent studies are reviewed. Furthermore, some of the current challenges and novel strategies to prevent AD are addressed. Herein, this review focuses on current pharmacotherapy of AD targeting-Aβ and intends to design a promising therapeutic agent for AD treatment.
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Affiliation(s)
- Yang Xie
- Pharmaceutical Engineering Center, Chongqing Medical and Pharmaceutical College, Chongqing, China
| | - Yan Wang
- Chemistry and Chemical Engineering College, Huangshan University, Huangshan, China
| | - Shangfei Jiang
- Pharmaceutical Engineering Center, Chongqing Medical and Pharmaceutical College, Chongqing, China
| | - Xiaohong Xiang
- Pharmaceutical Engineering Center, Chongqing Medical and Pharmaceutical College, Chongqing, China
| | - Jianhua Wang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, China
| | - Linhong Ning
- Pharmaceutical Engineering Center, Chongqing Medical and Pharmaceutical College, Chongqing, China
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