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

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Astrocytes play a crucial role in brain cholesterol homeostasis.
• Mechanisms by which astrocytes contribute to Alzheimer's disease (AD) pathology are not fully understood.

Purpose of the Study:

• To investigate the role of astrocyte-specific factors in AD-related cholesterol dysregulation.
• To identify and characterize the function of adipocyte enhancer-binding protein 1 (AEBP1) in astrocytes during AD progression.

Main Methods:

• Integrated human transcriptomic data with single-nucleus RNA sequencing (RNA-seq).
• Utilized postmortem human tissues and 5×FAD mouse models.
• Performed in vivo and in vitro experiments involving astrocyte-specific AEBP1 knockdown and overexpression.
• Conducted transcriptomic and metabolomic analyses of mouse hippocampi.

Main Results:

• AEBP1 was identified as an astrocyte-enriched factor upregulated in AD, with levels increasing with age and disease progression.
• Astrocyte-specific AEBP1 knockdown ameliorated amyloid-β (Aβ) pathology in 5×FAD mice, while overexpression exacerbated it.
• AEBP1 represses lysosomal acid lipase (LIPA), causing lipid accumulation and impaired Aβ clearance.
• Restoring LIPA or reducing AEBP1 improved cholesterol metabolism, reduced Aβ burden, and enhanced cognition in AD models.
• AEBP1 sequesters NPAS3, inhibiting its binding to the LIPA promoter.

Conclusions:

• The astrocytic AEBP1-NPAS3-LIPA axis is a key regulator of lysosomal cholesterol catabolism in the brain.
• This pathway links astrocyte dysfunction and cholesterol metabolism to Alzheimer's disease pathogenesis.
• Targeting this axis presents a potential therapeutic strategy for AD.