Towards a unitary hypothesis of Alzheimer’s disease pathogenesis
33 p.-6 fig.-1 tab.
| Autores: | , |
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| 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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oai:digital.csic.es:10261/355423 |
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España |
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Towards a unitary hypothesis of Alzheimer’s disease pathogenesis Area-Gomez, Estela Schon, Eric A. Amyloid C99 Cholesterol Endoplasmic reticulum MAM Mitochondria 33 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 reviewed IOS Press http://hdl.handle.net/10261/355423 |
| 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 |
| author |
Area-Gomez, Estela |
| author_facet |
Area-Gomez, Estela Schon, Eric A. |
| author_role |
author |
| author2 |
Schon, Eric A. |
| author2_role |
author |
| topic |
Amyloid C99 Cholesterol Endoplasmic reticulum MAM Mitochondria |
| topic_facet |
Amyloid C99 Cholesterol Endoplasmic reticulum MAM Mitochondria |
| description |
33 p.-6 fig.-1 tab. |
| publishDate |
2024 |
| format |
article |
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publishedVersion |
| url |
http://hdl.handle.net/10261/355423 |
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openAccess |
| publisher |
IOS Press |
| institution |
Consejo Superior de Investigaciones Científicas (CSIC) |
| collection |
DIGITAL.CSIC. Repositorio Institucional del CSIC |
| reponame_str |
DIGITAL.CSIC. Repositorio Institucional del CSIC |
| instname_str |
Consejo Superior de Investigaciones Científicas (CSIC) |
| _version_ |
1878442106418102272 |
| publishDateSort |
2024 |
| author_browse |
Area-Gomez, Estela Schon, Eric A. |
| publisherStr |
IOS Press |
| score |
6,9303427 |