Cholesterol homeostasis coordination by astrocytes to regulate Alzheimer’s pathology

Brain cholesterol homeostasis is regulated by astrocytes, but the mechanisms disrupted in Alzheimer’s disease (AD) are unclear. 

By integrating human transcriptomics with mouse models, the researchers demonstrate that the astrocyte-enriched adipocyte enhancer-binding protein 1 (AEBP1) drives Alzheimer’s pathology.

The authors show that AEBP1 levels upregulated in AD and rise with age and disease progression. Astrocyte-specific AEBP1 knockdown ameliorates, while overexpression worsens, amyloid-β (Aβ) pathology in AD mice model.

AEBP1 sequesters the transcription factor NPAS3 in the cytoplasm, repressing LIPA expression, leading to lipid droplet accumulation, excess cholesteryl ester storage.

This disrupts lysosomal cholesterol catabolism and Aβ clearance, identifying the AEBP1-NPAS3- LIPA axis as a potential therapeutic target.

https://www.cell.com/cell-reports/fulltext/S2211-1247(26)00271-8

https://sciencemission.com/Astrocytic-AEBP1-NPAS3-LIPA-pathway