Co-aggregation with Apolipoprotein E modulates the function of Amyloid-ß in Alzheimer's disease.
Nat Commun
; 15(1): 4695, 2024 Jun 01.
Article
en En
| MEDLINE
| ID: mdl-38824138
ABSTRACT
Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-ß (Aß) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aß in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aß co-aggregates account for ~50% of the mass of diffusible Aß aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aß tune disease-related functions of Aß aggregates throughout the course of aggregation. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aß. Selectively removing non-lipidated apoE4-Aß co-aggregates enhances clearance of toxic Aß by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Apolipoproteínas E
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Péptidos beta-Amiloides
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Apolipoproteína E4
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Enfermedad de Alzheimer
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Año:
2024
Tipo del documento:
Article