2. Academic Validation
  3. Astrocytic AEBP1-NPAS3-LIPA pathway coordinates cholesterol homeostasis to regulate Alzheimer's pathology

Astrocytic AEBP1-NPAS3-LIPA pathway coordinates cholesterol homeostasis to regulate Alzheimer's pathology

  • Cell Rep. 2026 Mar 24;45(4):117193. doi: 10.1016/j.celrep.2026.117193.
Jialin Wu 1,  Xiaonan Lu 1,  Jienian Zhang 1,  Shuaihan Wang 1,  Zeyuan Lu 1,  Yutong Han 1,  Ruihan Yang 1,  Yiliang Su 1,  Cheng Tan 1,  Dianqiu Huo 1,  Yong U Liu 2,  Jian Sima 3
Affiliations

Affiliations

  • 1 Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University (CPU), Nanjing, China.
  • 2 Laboratory for Neuroscience in Health and Disease, Guangzhou First People's Hospital School of Medicine, South China University of Technology, Guangzhou, China. Electronic address: [email protected].
  • 3 Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University (CPU), Nanjing, China; Pharmaceutical Research Center for Gender-specific Biology and Medicine (CPU), the Global Alliance for the Development of Pharmaceutical Science (GADPS), China Pharmaceutical University (CPU), Nanjing, China. Electronic address: [email protected].
PMID: 41880326 DOI: 10.1016/j.celrep.2026.117193
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.

Keywords

AEBP1; Alzheimer’s disease; CP: neuroscience; LIPA; astrocyte; lipid metabolism.

Figures
Products