Amyloid β, Tau, and α-Synuclein aggregates in the pathogenesis, prognosis, and therapeutics for neurodegenerative diseases

Progress in Neurobiology, Journal Year: 2022, Volume and Issue: 214, P. 102270 - 102270

Published: April 18, 2022

Aggregation of specific proteins are histopathological hallmarks several neurodegenerative diseases, such as, Amyloid β (Aβ) plaques and tau neurofibrillary tangles in Alzheimer's disease (AD); morphologically different inclusions ratiometric 3 repeat (3 R) 4 (4 isoforms progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's (PiD); α-Synuclein (α-Syn) containing Lewy bodies (LBs) dystrophic neurites (LNs) Parkinson's (PD) dementia with (DLB). However, mixed brain protein pathologies have been frequently observed many these diseases normal aging brains, among which Aβ/tau tau/α-Syn crosstalks received increased attention. Interestingly, studies also shown synergistic interplay Aβ, tau, α-Syn suggesting a triumvirate. In this review, we summarize the emerging evidence aggregation pathophysiology, their overlap spectrum including AD, PSP, PiD, CBD, PD DLB. We discuss prognostic advancements made biomarker imaging techniques triumvirate proteinopathies. Finally, combined therapeutic modality involving biomarkers for future combinatorial immunotherapeutic targeting more than one aggregates. hope that multitarget approach will or additive effects to manage two might uncover promising strategy personalized combination therapies. Managing by optimizing diagnostic criteria correct immunotherapies be key factor success treatment.

Language: Английский

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Extracellular protein components of amyloid plaques and their roles in Alzheimer’s disease pathology

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: Aug. 28, 2021

Abstract Alzheimer’s disease (AD) is pathologically defined by the presence of fibrillar amyloid β (Aβ) peptide in extracellular senile plaques and tau filaments intracellular neurofibrillary tangles. Extensive research has focused on understanding assembly mechanisms neurotoxic effects Aβ during last decades but still we only have a brief associated biological processes. This review highlights many other constituents that, beside Aβ, are accumulated plaques, with focus proteins. All living organisms rely delicate network protein functionality. Deposition significant amounts certain proteins insoluble inclusions will unquestionably lead to disturbances network, which may contribute AD copathology. paper provide comprehensive overview that been shown interact discussion their potential roles pathology. Methods can expand knowledge about how incorporated described. Top-down methods analyze post-mortem tissue bottom-up approaches molecular insights organization plaque-like particles compared. Finally, analysis Aβ-interacting partners enriched functional structural key words presented.

Language: Английский

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Exploring the Pathogenesis of Alzheimer Disease in Basal Forebrain Cholinergic Neurons: Converging Insights From Alternative Hypotheses

Frontiers in Neuroscience, Journal Year: 2019, Volume and Issue: 13

Published: May 7, 2019

Alzheimer disease (AD) represents an oncoming epidemic that without effective treatment promises to exact extraordinary financial and emotional burdens (Apostolova, 2016). Studies of pathogenesis are essential for defining critical molecular cellular events discovering therapies prevent or mitigate their effects. Through studies neuropathology, genetic cellular, biology recent decades have provided many important insights. Several hypotheses been suggested. Documentation in the 1980s selective loss cholinergic neurons basal forebrain, followed by clinical improvement those treated with inhibitors acetylycholinesterase, supported "cholinergic hypothesis age-related cognitive dysfunction" (Bartus et al., 1982). A second hypothesis, prompted discovery central nervous system (CNS) neurotrophic factors, including nerve growth factor (NGF), "deficient hypothesis" (Chen 2018). The most persuasive amyloid cascade first proposed more than 25 years ago (Selkoe Hardy, 2016), is a wealth observations. Genetic were exceptionally important, pointing increased dose gene precursor protein (APP) Down syndrome (DS) familial AD (FAD) due duplication APP mutations genes Presenilin 1 2 (

Language: Английский

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Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer’s Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(12), P. 6355 - 6355

Published: June 14, 2021

A large body of clinical and nonclinical evidence supports the role neurotoxic soluble beta amyloid (amyloid, Aβ) oligomers as upstream pathogenic drivers Alzheimer’s disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species Aβ provide compelling inhibition oligomer toxicity represents an effective approach to slow or stop progression: (1) only target show efficacy patients; (2) clearance plaque does not correlate with improvements; (3) predominantly monomers failed effects; (4) positive trials, is greater carriers ε4 allele apolipoprotein E (APOE4), who are known higher brain concentrations oligomers. These also inhibiting neurotoxicity leads a reduction tau pathology, suggesting sequence events where drives increase formation deposition. The biomarker data include four antibodies engage (aducanumab, lecanemab, gantenerumab, donanemab) ALZ-801, oral agent fully blocks at dose.

Language: Английский

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PPARγ/PGC1α signaling as a potential therapeutic target for mitochondrial biogenesis in neurodegenerative disorders

Pharmacology & Therapeutics, Journal Year: 2020, Volume and Issue: 219, P. 107705 - 107705

Published: Oct. 9, 2020

Language: Английский

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Melatonin regulates Aβ production/clearance balance and Aβ neurotoxicity: A potential therapeutic molecule for Alzheimer’s disease

Biomedicine & Pharmacotherapy, Journal Year: 2020, Volume and Issue: 132, P. 110887 - 110887

Published: Nov. 2, 2020

Alzheimer's disease (AD) is an age-related neurodegenerative with multiple predisposing factors and complicated pathogenesis. Aβ peptide one of the most important pathogenic in etiology AD. Accumulating evidence indicates that imbalance production clearance brain AD patients leads to deposition neurotoxic oligomer formation. Melatonin shows a potent neuroprotective effect can prevent or slow down progression AD, supporting view melatonin potential therapeutic molecule for modulates regulatory network secretase expression affects function secretase, thereby inhibiting amyloidogenic APP processing production. Additionally, ameliorates Aβ-induced neurotoxicity probably promotes through glymphatic-lymphatic drainage, BBB transportation degradation pathways. In this review, we summarize discuss role against Aβ-dependent We explore cellular molecular mechanisms on assembly, clearance, circadian cycle disruption. clinical trials treatment patients, showing has promising improving sleep quality cognitive function. This review aims stimulate further research as agent

Language: Английский

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Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

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Neuronal cell death mechanisms in Alzheimer’s disease: An insight

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 15

Published: Aug. 25, 2022

Regulated cell death (RCD) is an ordered and tightly orchestrated set of changes/signaling events in both gene expression protein activity responsible for normal development as well maintenance tissue homeostasis. Aberrant activation this pathway results by various mechanisms including apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-dependent death. Such pathological changes neurons alone or combination have been observed the pathogenesis neurodegenerative diseases Alzheimer’s disease (AD). Pathological hallmarks AD focus primarily on accumulation two main markers: amyloid β peptides abnormally phosphorylated tau proteins. These aggregates result formation A-β plaques neuro-fibrillary tangles (NFTs) induce neuroinflammation neurodegeneration over years to decades leading a multitude cognitive behavioral deficits. Autopsy findings reveal massive neuronal manifested form cortical volume shrinkage, reduction sizes gyri up 50% increase sulci. Multiple forms recorded from different studies conducted so far. However, understanding mechanism/s patients remains mystery trigger that aberrant RCD unknown because limited availability dying neurons. This review attempts elucidate process death, how it gets unregulated response intra extracellular stressors, their interplay role Disease human experimental models AD. Further we plan explore correlation amyloid-beta Tau with loss seen

Language: Английский

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Role of Aducanumab in the Treatment of Alzheimer’s Disease: Challenges and Opportunities

Clinical Interventions in Aging, Journal Year: 2022, Volume and Issue: Volume 17, P. 797 - 810

Published: May 1, 2022

Abstract: Aducanumab is a monoclonal antibody selective for amyloid β (Aβ) aggregates. In June 2021, aducanumab became the first drug underlying pathophysiology of Alzheimer's disease (AD) approved by US Food and Drug Administration (FDA), under accelerated approval pathway. The decision was based on ability to remove Aβ plaques, without any evidence that clearance correlated with less cognitive or functional decline. This has generated considerable debate in scientific community, especially because results from two Phase 3 trials, EMERGE ENGAGE, were divergent and, even after post hoc analysis, data insufficient prove efficacy. Moreover, some researchers think this will be an obstacle progress also demonstrated concerns about cost its safety profile. European Medicines Agency's rejection December 2021 just brought more controversy over FDA's decision. Now, Biogen designing required confirmatory study, named ENVISION, which should complete 2026. Despite controversy, showed affect downstream tau pathology, could open doors combination therapy approach AD (anti-tau anti-amyloid drug). review summarizes clinical development until regulatory agencies' decisions, available trials AD. Keywords: anti-Aβ antibody, ARIA, Agency, Administration, protein

Language: Английский

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Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(10), P. 5404 - 5404

Published: May 12, 2022

Alzheimer's disease (AD) constitutes the most prominent form of dementia among elderly individuals worldwide. Disease modeling using murine transgenic mice was first initiated thanks to discovery heritable mutations in amyloid precursor protein (APP) and presenilins (PS) genes. However, due repeated failure translational applications from animal models human patients, along with recent advances genetic susceptibility our current understanding on biology, these have evolved over time an attempt better reproduce complexity this devastating improve their applicability. In review, we provide a comprehensive overview about major pathological elements AD (plaques, tauopathy, synaptic damage, neuronal death, neuroinflammation glial dysfunction), discussing knowledge that available mouse provided mechanisms underlying disease. Moreover, highlight pros cons models, revolution offered by concomitant use omics technologies may lead more rapid improvement present battery.

Language: Английский

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