Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer's disease.

Alzheimer Disease / metabolism Amyloid beta-Peptides / metabolism Humans Apolipoproteins E / metabolism Animals Apolipoprotein E4 / metabolism Protein Isoforms / metabolism Mice Female Protein Aggregates Male Protein Aggregation, Pathological / metabolism Mice, Transgenic Neuroglia / metabolism

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
01 Jun 2024

Historique:

received: 28 02 2024

accepted: 21 05 2024

medline: 2 6 2024

pubmed: 2 6 2024

entrez: 1 6 2024

Statut: epublish

Résumé

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-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% of the mass of diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related functions of Aβ 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 Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.

Identifiants

DOI: 10.1038/s41467-024-49028-z PMID: 38824138

pubmed: 38824138

doi: 10.1038/s41467-024-49028-z

pii: 10.1038/s41467-024-49028-z

doi:

Substances chimiques

Amyloid beta-Peptides 0

Apolipoproteins E 0

Apolipoprotein E4 0

Protein Isoforms 0

Protein Aggregates 0

ApoE protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

4695

Informations de copyright

Références

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