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Astrocyte cholesterol is essential for amyloid beta production
Author(s) -
Kulas Joshua A.,
Wang Hao,
Hansen Scott B.,
Ferris Heather A.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.041024
Subject(s) - lipid raft , astrocyte , microbiology and biotechnology , biology , amyloid beta , cholesterol , neuron , hippocampus , lipid metabolism , amyloid precursor protein secretase , amyloid (mycology) , neuroscience , amyloid precursor protein , alzheimer's disease , medicine , endocrinology , biochemistry , peptide , central nervous system , disease , botany
Background Several variants of genes involved in cholesterol metabolism are risk factors for the development of Alzheimer’s disease (AD). We disrupted the master regulator of cellular cholesterol metabolism, SREBP2, and assessed the impacts of this disruption in neuron‐glia primary cell co‐cultures and in the 3xTg mouse model of AD. Method Glial SREBP2 ablation was induced in neuron‐glia cultures by treatment of Aldh1l1‐CRE ERT2 xSREBP2 flox mixed primary cell cultures with 4OH tamoxifen. Amyloid precursor protein (APP) trafficking to lipid raft domains was quantified by dSTORM imaging. SREBP2 was ablated in the brains of 3xTg AD mice by crossing to an SREBP2‐flox and then a GFAP‐CRE. Aged (40 week old) mouse brains were then assessed for Aβ and pTau burden by ELISA. Result Disruption of glial SREBP2 was sufficient to significantly alter localization of APP from α‐secretase rich disordered membrane regions to β‐ and γ‐secretase enriched lipid raft domains (Figure A). In 3xTg‐AD animals, SREBP2 ablation did not alter total levels of APP or Tau, but significantly reduced both Aβ 1‐42 peptide burden and P‐T181 Tau abundance in 40‐week hippocampus (Figure B). Conclusion Disruption of astrocyte‐mediated cholesterol metabolism is sufficient to robustly reduce Aβ and pTau burden in a mouse model of AD, which likely occurs in part through reduced APP localization to lipid rafts.