Towards a unitary hypothesis of Alzheimer’s disease pathogenesis

33 p.-6 fig.-1 tab.

Detalles Bibliográficos
Autores: Area-Gomez, Estela, Schon, Eric A.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/355423
Acceso en línea:http://hdl.handle.net/10261/355423
Access Level:acceso abierto
Palabra clave:Amyloid
C99
Cholesterol
Endoplasmic reticulum
MAM
Mitochondria
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spelling Towards a unitary hypothesis of Alzheimer’s disease pathogenesisArea-Gomez, EstelaSchon, Eric A.AmyloidC99CholesterolEndoplasmic reticulumMAMMitochondria33 p.-6 fig.-1 tab.The “amyloid cascade” hypothesis of Alzheimer’s disease (AD) pathogenesis invokes the accumulation in the brain of plaques (containing the amyloid- protein precursor [A PP] cleavage product amyloid- [A ]) and tangles (containing hyperphosphorylated tau) as drivers of pathogenesis. However, the poor track record of clinical trials based on this hypothesis suggests that the accumulation of these peptides is not the only cause of AD. Here, an alternative hypothesis is proposed in which the A PP cleavage product C99, not A , is the main culprit, via its role as a regulator of cholesterol metabolism. C99,which is a cholesterol sensor, promotes the formation of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM), a cholesterol-rich lipid raft-like subdomain of the ER that communicates, both physically and biochemically, with mitochondria. We propose that in early-onset AD (EOAD), MAM-localized C99 is elevated above normal levels, resulting in increased transport of cholesterol from the plasma membrane to membranes of intracellular organelles, such as ER/endosomes,thereby upregulating MAM function and driving pathology. By the same token, late-onset AD (LOAD) is triggered by any genetic variant that increases the accumulation of intracellular cholesterol that, in turn, boosts the levels of C99 and again upregulates MAM function. Thus, the functional cause of AD is upregulated MAM function that, in turn, causes the hallmark disease phenotypes, including the plaques and tangles. Accordingly, the MAM hypothesis invokes two key interrelated elements, C99 and cholesterol, that converge at the MAM to drive AD pathogenesis. From this perspective, AD is, at bottom,a lipid disorder.This work was supported by grants from the U.S. National Institutes of Health (to EAG [1R01AG056387] and EAS [1R01NS117538]) and the J. Willard and Alice S. Marriott Foundation (to EAS).Peer reviewedIOS PressNational Institutes of Health (US)J. Willard Marriott FoundationArea-Gomez, Estela [0000-0002-0962-1570]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/355423reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.3233/JAD-231318Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3554232026-05-22T06:33:51Z
dc.title.none.fl_str_mv Towards a unitary hypothesis of Alzheimer’s disease pathogenesis
title Towards a unitary hypothesis of Alzheimer’s disease pathogenesis
spellingShingle Towards a unitary hypothesis of Alzheimer’s disease pathogenesis
Area-Gomez, Estela
Amyloid
C99
Cholesterol
Endoplasmic reticulum
MAM
Mitochondria
title_short Towards a unitary hypothesis of Alzheimer’s disease pathogenesis
title_full Towards a unitary hypothesis of Alzheimer’s disease pathogenesis
title_fullStr Towards a unitary hypothesis of Alzheimer’s disease pathogenesis
title_full_unstemmed Towards a unitary hypothesis of Alzheimer’s disease pathogenesis
title_sort Towards a unitary hypothesis of Alzheimer’s disease pathogenesis
dc.creator.none.fl_str_mv Area-Gomez, Estela
Schon, Eric A.
author Area-Gomez, Estela
author_facet Area-Gomez, Estela
Schon, Eric A.
author_role author
author2 Schon, Eric A.
author2_role author
dc.contributor.none.fl_str_mv National Institutes of Health (US)
J. Willard Marriott Foundation
Area-Gomez, Estela [0000-0002-0962-1570]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Amyloid
C99
Cholesterol
Endoplasmic reticulum
MAM
Mitochondria
topic Amyloid
C99
Cholesterol
Endoplasmic reticulum
MAM
Mitochondria
description 33 p.-6 fig.-1 tab.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/355423
url http://hdl.handle.net/10261/355423
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.3233/JAD-231318
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv IOS Press
publisher.none.fl_str_mv IOS Press
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812429

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