Astrocytic AEBP1-NPAS3-LIPA pathway coordinates cholesterol homeostasis to regulate Alzheimer's pathology - PubMed
5 hours ago
- #Alzheimer's disease
- #astrocytes
- #cholesterol homeostasis
- Astrocytes play a key role in brain cholesterol homeostasis, with disruptions linked to Alzheimer's disease (AD).
- AEBP1, an astrocyte-enriched factor, is upregulated in AD and correlates with disease progression in both human tissue and 5×FAD mice.
- Modulating AEBP1 levels in astrocytes affects amyloid-β (Aβ) pathology: knockdown improves, while overexpression worsens, Aβ accumulation.
- AEBP1 overexpression in astrocytes represses LIPA, leading to lipid droplet accumulation, cholesteryl ester storage, and lysosomal Aβ retention.
- Restoring LIPA reverses the negative effects of AEBP1 overexpression on lipid metabolism and Aβ retention.
- Transcriptomic and metabolomic analyses show that AEBP1 knockdown or LIPA overexpression in 5×FAD mice remodels cholesterol/lipid pathways, reduces Aβ burden, and improves cognition.
- Mechanistically, AEBP1 sequesters NPAS3 in the cytoplasm, reducing its binding to the Lipa promoter, thereby linking lysosomal cholesterol catabolism to AD pathology.