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Based on molecular structures: Amyloid-β generation, clearance, toxicity and therapeutic strategies.

ABSTRACT: Amyloid-β (Aβ) has long been considered as one of the most important pathogenic factors in Alzheimer's disease (AD), but the specific pathogenic mechanism of Aβ is still not completely understood. In recent years, the development of structural biology technology has led to new understandings about Aβ molecular structures, Aβ generation and clearance from the brain and peripheral tissues, and its pathological toxicity. The purpose of the review is to discuss Aβ metabolism and toxicity, and the therapeutic strategy of AD based on the latest progress in molecular structures of Aβ. The Aβ structure at the atomic level has been analyzed, which provides a new and refined perspective to comprehend the role of Aβ in AD and to formulate therapeutic strategies of AD.

SUBMITTER: Yang H

PROVIDER: S-EPMC9470852 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Based on molecular structures: Amyloid-β generation, clearance, toxicity and therapeutic strategies.

Yang Hai H Li Jinping J Li Xiaoxiong X Ma Linqiu L Hou Mingliang M Zhou Huadong H Zhou Rui R

Frontiers in molecular neuroscience 20220831

Amyloid-β (Aβ) has long been considered as one of the most important pathogenic factors in Alzheimer's disease (AD), but the specific pathogenic mechanism of Aβ is still not completely understood. In recent years, the development of structural biology technology has led to new understandings about Aβ molecular structures, Aβ generation and clearance from the brain and peripheral tissues, and its pathological toxicity. The purpose of the review is to discuss Aβ metabolism and toxicity, and the th ...[more]

PMID: 36117918

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Project description:BackgroundMicroglia are the endogenous immune cells of the brain and act as sensors of pathology to maintain brain homeostasis and eliminate potential threats. In Alzheimer's disease (AD), toxic amyloid beta (Aβ) accumulates in the brain and forms stiff plaques. In late-onset AD accounting for 95% of all cases, this is thought to be due to reduced clearance of Aβ. Human genome-wide association studies and animal models suggest that reduced clearance results from aberrant function of microglia. While the impact of neurochemical pathways on microglia had been broadly studied, mechanical receptors regulating microglial functions remain largely unexplored.MethodsHere we showed that a mechanotransduction ion channel, PIEZO1, is expressed and functional in human and mouse microglia. We used a small molecule agonist, Yoda1, to study how activation of PIEZO1 affects AD-related functions in human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGL) under controlled laboratory experiments. Cell survival, metabolism, phagocytosis and lysosomal activity were assessed using real-time functional assays. To evaluate the effect of activation of PIEZO1 in vivo, 5-month-old 5xFAD male mice were infused daily with Yoda1 for two weeks through intracranial cannulas. Microglial Iba1 expression and Aβ pathology were quantified with immunohistochemistry and confocal microscopy. Published human and mouse AD datasets were used for in-depth analysis of PIEZO1 gene expression and related pathways in microglial subpopulations.ResultsWe show that PIEZO1 orchestrates Aβ clearance by enhancing microglial survival, phagocytosis, and lysosomal activity. Aβ inhibited PIEZO1-mediated calcium transients, whereas activation of PIEZO1 with a selective agonist, Yoda1, improved microglial phagocytosis resulting in Aβ clearance both in human and mouse models of AD. Moreover, PIEZO1 expression was associated with a unique microglial transcriptional phenotype in AD as indicated by assessment of cellular metabolism, and human and mouse single-cell datasets.ConclusionThese results indicate that the compromised function of microglia in AD could be improved by controlled activation of PIEZO1 channels resulting in alleviated Aβ burden. Pharmacological regulation of these mechanoreceptors in microglia could represent a novel therapeutic paradigm for AD.

Dataset Information

Based on molecular structures: Amyloid-β generation, clearance, toxicity and therapeutic strategies.

Publications

Based on molecular structures: Amyloid-β generation, clearance, toxicity and therapeutic strategies.

Similar Datasets

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