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Amyloid-β in Alzheimer’s disease – front and centre after all?

The amyloid hypothesis, which proposes that accumulation of the peptide amyloid-β at synapses is the key driver of Alzheimer’s disease (AD) pathogenesis, has been the dominant idea in the field of Alzheimer’s research for nearly 30 years. Recently, however, serious doubts about its validity have eme...

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Autores principales: Weglinski, Caroline, Jeans, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9829960/
https://www.ncbi.nlm.nih.gov/pubmed/36687366
http://dx.doi.org/10.1042/NS20220086
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author Weglinski, Caroline
Jeans, Alexander
author_facet Weglinski, Caroline
Jeans, Alexander
author_sort Weglinski, Caroline
collection PubMed
description The amyloid hypothesis, which proposes that accumulation of the peptide amyloid-β at synapses is the key driver of Alzheimer’s disease (AD) pathogenesis, has been the dominant idea in the field of Alzheimer’s research for nearly 30 years. Recently, however, serious doubts about its validity have emerged, largely motivated by disappointing results from anti-amyloid therapeutics in clinical trials. As a result, much of the AD research effort has shifted to understanding the roles of a variety of other entities implicated in pathogenesis, such as microglia, astrocytes, apolipoprotein E and several others. All undoubtedly play an important role, but the nature of this has in many cases remained unclear, partly due to their pleiotropic functions. Here, we propose that all of these AD-related entities share at least one overlapping function, which is the local regulation of amyloid-β levels, and that this may be critical to their role in AD pathogenesis. We also review what is currently known of the actions of amyloid-β at the synapse in health and disease, and consider in particular how it might interact with the key AD-associated protein tau in the disease setting. There is much compelling evidence in support of the amyloid hypothesis; rather than detract from this, the implication of many disparate AD-associated cell types, molecules and processes in the regulation of amyloid-β levels may lend further support.
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spelling pubmed-98299602023-01-19 Amyloid-β in Alzheimer’s disease – front and centre after all? Weglinski, Caroline Jeans, Alexander Neuronal Signal Aging The amyloid hypothesis, which proposes that accumulation of the peptide amyloid-β at synapses is the key driver of Alzheimer’s disease (AD) pathogenesis, has been the dominant idea in the field of Alzheimer’s research for nearly 30 years. Recently, however, serious doubts about its validity have emerged, largely motivated by disappointing results from anti-amyloid therapeutics in clinical trials. As a result, much of the AD research effort has shifted to understanding the roles of a variety of other entities implicated in pathogenesis, such as microglia, astrocytes, apolipoprotein E and several others. All undoubtedly play an important role, but the nature of this has in many cases remained unclear, partly due to their pleiotropic functions. Here, we propose that all of these AD-related entities share at least one overlapping function, which is the local regulation of amyloid-β levels, and that this may be critical to their role in AD pathogenesis. We also review what is currently known of the actions of amyloid-β at the synapse in health and disease, and consider in particular how it might interact with the key AD-associated protein tau in the disease setting. There is much compelling evidence in support of the amyloid hypothesis; rather than detract from this, the implication of many disparate AD-associated cell types, molecules and processes in the regulation of amyloid-β levels may lend further support. Portland Press Ltd. 2023-01-06 /pmc/articles/PMC9829960/ /pubmed/36687366 http://dx.doi.org/10.1042/NS20220086 Text en © 2023 The Author(s). https://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . Open access for this article was enabled by the participation of University of Oxford in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society under a transformative agreement with JISC.
spellingShingle Aging
Weglinski, Caroline
Jeans, Alexander
Amyloid-β in Alzheimer’s disease – front and centre after all?
title Amyloid-β in Alzheimer’s disease – front and centre after all?
title_full Amyloid-β in Alzheimer’s disease – front and centre after all?
title_fullStr Amyloid-β in Alzheimer’s disease – front and centre after all?
title_full_unstemmed Amyloid-β in Alzheimer’s disease – front and centre after all?
title_short Amyloid-β in Alzheimer’s disease – front and centre after all?
title_sort amyloid-β in alzheimer’s disease – front and centre after all?
topic Aging
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9829960/
https://www.ncbi.nlm.nih.gov/pubmed/36687366
http://dx.doi.org/10.1042/NS20220086
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