Abstract

Astrocytes regulate brain cholesterol homeostasis, but the astrocyte-specific mechanisms disrupted in Alzheimer’s disease (AD) are poorly understood. By integrating human bulk transcriptomes with single-nucleus RNA sequencing (RNA-seq), we identified adipocyte enhancer-binding protein 1 ( AEBP1 ) as an astrocyte-enriched factor upregulated in AD. In postmortem human tissue and 5×FAD mice, astrocytic AEBP1 levels rise with age and disease progression. Astrocyte-specific AEBP1 knockdown ameliorates, while overexpression worsens, amyloid-β (Aβ) pathology in 5×FAD mice, confirming causality in vivo . In cultured astrocytes, AEBP1 overexpression represses lysosomal acid lipase (LIPA), leading to lipid droplet accumulation, excess cholesteryl ester storage, and lysosomal Aβ retention. LIPA restoration reverses these effects. Hippocampal transcriptomics and metabolomics from AEBP1-knockdown or LIPA-overexpressing 5×FAD mice show converged cholesterol/lipid pathway remodeling, reduced Aβ burden, and cognitive improvement. Mechanistically, AEBP1 sequesters NPAS3 in the cytoplasm, reducing its binding to the Lipa promoter. Thus, the astrocytic AEBP1-NPAS3-LIPA axis links lysosomal cholesterol catabolism to AD pathology.