Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2020, Volume and Issue: 15(1)

Published: July 16, 2020

Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There currently no effective treatment for AD, which may be attributed part to lack of a clear underlying mechanism. Studies within last few decades provide growing evidence central role amyloid β (Aβ) and tau, as well glial contributions various molecular cellular pathways AD pathogenesis. Herein, we review recent progress with respect Aβ- tau-associated mechanisms, discuss dysfunction emphasis on neuronal receptors that mediate Aβ-induced toxicity. We also other critical factors affect pathogenesis, including genetics, aging, variables related environment, lifestyle habits, describe potential apolipoprotein E (APOE), viral bacterial infection, sleep, microbiota. Although have gained much towards understanding aspects this devastating disorder, greater commitment research mechanism, diagnostics will needed future research.

Language: Английский

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Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(4), P. 2545 - 2647

Published: Feb. 5, 2021

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural dynamic characterization all species along pathways from monomers to fibrils challenging by experimental computational means because they involve intrinsically disordered proteins most diseases. Yet understanding how amyloid become toxic challenge developing treatment for these Here we review what computer, vitro, vivo, pharmacological experiments tell us about accumulation deposition oligomers (Aβ, tau), α-synuclein, IAPP, superoxide dismutase 1 proteins, which have been mainstream concept underlying Alzheimer's disease (AD), Parkinson's (PD), type II diabetes (T2D), amyotrophic lateral sclerosis (ALS) research, respectively, years.

Language: Английский

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Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation

Frontiers in Neurology, Journal Year: 2021, Volume and Issue: 11

Published: Jan. 7, 2021

Post-translational modifications (PTMs) on tau have long been recognized as affecting protein function and contributing to neurodegeneration. The explosion of information potential observed PTMs provides an opportunity better understand these in the context homeostasis, which becomes perturbed with aging disease. Prevailing views regard a that undergoes abnormal phosphorylation prior its accumulation into toxic aggregates implicated Alzheimer's disease (AD) other tauopathies. However, may, fact, represent part normal but interrupted catabolism protein. In addition phosphorylation, another forms post-translational modification including (but not limited to), acetylation, ubiquitination, glycation, glycosylation, SUMOylation, methylation, oxidation, nitration. A holistic appreciation how regulate during health are potentially hijacked remains elusive. Recent studies reinforced idea play critical role localization, protein-protein interactions, maintenance levels, modifying aggregate structure. These also provide tantalizing clues possibility neurons actively choose is post-translationally modified, competitive combinatorial ways, achieve broad, cellular programs commensurate distinctive environmental conditions found development, aging, stress, Here, we review describe what currently known about their functional impacts. addition, classify from perspectives electrostatics, stability, all contribute homeostasis. Finally, assess impact solubility aggregation. Tau occupies undoubtedly important position biology neurodegenerative diseases. This aims integrated perspective actively, purposefully, dynamically remodel function, clearance, doing so, hope enable more comprehensive understanding will positively future studies.

Language: Английский

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The Microbiota–Gut–Brain Axis and Alzheimer’s Disease: Neuroinflammation Is to Blame?

Nutrients, Journal Year: 2020, Volume and Issue: 13(1), P. 37 - 37

Published: Dec. 24, 2020

For years, it has been reported that Alzheimer’s disease (AD) is the most common cause of dementia. Various external and internal factors may contribute to early onset AD. This review highlights a contribution disturbances in microbiota–gut–brain (MGB) axis development Alteration gut microbiota composition determined by increase permeability barrier immune cell activation, leading impairment blood–brain function promotes neuroinflammation, neuronal loss, neural injury, ultimately Numerous studies have shown plays crucial role brain changes behavior individuals formation bacterial amyloids. Lipopolysaccharides amyloids synthesized can trigger cells residing activate response neuroinflammation. Growing experimental clinical data indicate prominent dysbiosis microbiota–host interactions Modulation with antibiotics or probiotic supplementation create new preventive therapeutic options Accumulating evidences affirm research on MGB involvement AD necessary for treatment targets therapies

Language: Английский

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Four-repeat tauopathies

Progress in Neurobiology, Journal Year: 2019, Volume and Issue: 180, P. 101644 - 101644

Published: June 22, 2019

Language: Английский

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Cellular and pathological heterogeneity of primary tauopathies

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

Published: Aug. 23, 2021

Abstract Microtubule-associated protein tau is abnormally aggregated in neuronal and glial cells a range of neurodegenerative diseases that are collectively referred to as tauopathies. Multiple studies have suggested pathological species may act seed promotes aggregation endogenous naïve contributes propagation pathology. While they share common feature, tauopathies distinct from one another with respect predominant isoforms accumulate the selective vulnerability brain regions cell types inclusions. For instance, primary present pathology, while it mostly Alzheimer’s disease (AD). Also, morphologies inclusions can greatly vary even within same type, suggesting mechanisms or conformers each tauopathy. Neuropathological heterogeneity across challenges our understanding pathophysiology behind seeding aggregation, well efforts develop effective therapeutic strategies for AD other In this review, we describe diverse neuropathological features discuss what has been learned experimental mouse models, advanced transcriptomics, cryo-electron microscopy (cryo-EM) on biology underlying type-specific

Language: Английский

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Tau-targeting therapies for Alzheimer disease: current status and future directions

Nature Reviews Neurology, Journal Year: 2023, Volume and Issue: 19(12), P. 715 - 736

Published: Oct. 24, 2023

Language: Английский

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Tau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(17), P. 9207 - 9207

Published: Aug. 26, 2021

Tau protein plays a critical role in the assembly, stabilization, and modulation of microtubules, which are important for normal function neurons brain. In diseased conditions, several pathological modifications tau manifest. These changes lead to aggregation formation paired helical filaments (PHF) neurofibrillary tangles (NFT), common hallmarks Alzheimer’s disease other tauopathies. The accumulation PHFs NFTs results impairment physiological functions, apoptosis, neuronal loss, is reflected as cognitive impairment, late stages disease, leads death. causes this transformation haven’t been fully understood yet. both interacts with proteins maintain their proper or can participate modifications. Interaction partners associated molecular pathways either initiate drive pathology act neuroprotective, by reducing inflammation. review, we focus on multifunctional its known interacting active regulations different processes roles these

Language: Английский

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Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

Chemical Society Reviews, Journal Year: 2021, Volume and Issue: 51(2), P. 513 - 565

Published: Dec. 10, 2021

We discuss novel approaches for embracing and reproducing complexity of Tau pathology required developing disease-relevant diagnostics effective therapies.

Language: Английский

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Targeted Dephosphorylation of Tau by Phosphorylation Targeting Chimeras (PhosTACs) as a Therapeutic Modality

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(7), P. 4045 - 4055

Published: Feb. 8, 2023

Microtubule-associated protein tau is essential for microtubule assembly and stabilization. Hyperphosphorylation of the microtubule-associated plays an important pathological role in development Alzheimer's disease other tauopathies. In vivo studies using kinase inhibitors suggest that reducing phosphorylation levels has therapeutic potential; however, such approaches showed limited benefits. We sought to further develop our targeting chimera (PhosTAC) technology specifically induce dephosphorylation. Herein, we use small molecule-based PhosTACs recruit PP2A, a native phosphatase. induced formation stable ternary complex, leading rapid, efficient, sustained dephosphorylation, which also correlated with enhanced downregulation protein. Mass spectrometry data validated downregulated multiple sites tau. believe PhosTAC possesses several advantages over current strategies modulate represents new avenue disease-modifying therapies

Language: Английский

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