How do APOE ε4-driven differences in lipid droplet accumulation and cholesterol metabolism in single microglial subpopulations alter their phagocytic and degradative capacity for amyloid-beta clearance, and does targeting microglial lipid metabolism restore amyloid clearance in APOE ε4 mouse models?
APOE ε4 promotes excessive cholesterol esterification and neutral lipid droplet accumulation in a discrete lipid-associated microglia (LAM) substate in the AD brain. Lipid droplet overloading impairs lysosomal membrane integrity, reduces cathepsin B/D activity, and halves the phagocytic capacity for fibrillar amyloid-beta in APOE ε4/ε4 microglia compared to ε3/ε3 controls. Liver X receptor (LXR) agonist treatment to promote cholesterol efflux should restore lysosomal function and amyloid clearance specifically in APOE ε4 LAM.
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Evidence Matrix — sortable by strength/year, click Abstract to expand
APOE deficiency inhibits amyloid-facilitated (A) tau pathology (T) and neurodegeneration (N), halting progress…MEDIUM▼
APOE deficiency inhibits amyloid-facilitated (A) tau pathology (T) and neurodegeneration (N), halting progressive ATN pathology in a preclinical model.
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