Published November 11, 2024 | Version v1
Journal article Open

APOE from astrocytes restores Alzheimer's Aβ-pathology and DAM-like responses in APOE deficient microglia

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Description

The major genetic risk factor for Alzheimer’s disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by APOE expressed in microglia or astrocytes is debated. We express here the human APOE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques. We find that both APOE4 and the protective APOE2 from astrocytes increase fibrillar plaque deposition, but differentially affect soluble Aβ aggregates. Microglia and astrocytes show specific alterations in function of APOE genotype expressed in astrocytes. Our experiments indicate a central role of the astrocytes in APOE mediated amyloid plaque pathology and in the induction of associated microglia responses.

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Funding

Ministerio de Ciencia, Innovación y Universidades
MCIN/AEI/10.13039/501100011033 (PID2021-125443OB-100 also by FEDER, UE and RYC2020-029494-I by FSE invierte en tu futuro)
Alzheimer's Association
AARG-21-850389
Basque Government
PIBA-2020-1-0030