biostudies-literaturePreman PMinisterio de Ciencia e Innovación (MCIN)Alzheimer's Association USAVlaams Instituut voor BiotechnologieBasque government, SpainUK Research and InnovationFonds voor Wetenschappelijk OnderzoekUK Research and Innovation (UKRI)European Research CouncilUK Dementia Research InstituteKU LeuvenMinisterio de Ciencia e InnovaciónThe Queen Elisabeth Medical Foundation for NeurosciencesLeuven Universitair FondsThe Belgian Alzheimer Research Foundation3113-3141https://www.ebi.ac.uk/biostudies/studies/S-EPMC11628604biostudies-literatureUnknown16(12)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 astrocytesEMBO molecular medicineAPOE from astrocytes restores Alzheimer's Aβ-pathology and DAM-like responses in APOE deficient microglia.PMC11628604MR/Y014847/1834682MCIN/AEI/10.13039/501100011033PIBA-2020-1-0030ERC-834682Balusu SDe Strooper BWolfs LShah DPreman PPoovathingal SKlenerman DMancuso RFertan EFiers MArranz AMMoechars DLamote JSerneels LSnellinx AfalseAPOE from astrocytes restores Alzheimer's Aβ-pathology and DAM-like responses in APOE deficient microglia.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 astrocytes2024-01-01T00:00:00Z2024 Dec2026-05-04T06:46:04.845Z2025-04-19T14:37:36.996ZS-EPMC116286043952886110.1038/s44321-024-00162-7