Multi-modal choroid plexus pathology in aging and Alzheimer's disease

Area of Science:

• Neuroscience
• Pathology
• Aging Research

Background:

• Brain barriers, cerebrospinal fluid (CSF) dynamics, and peripheral factors are linked to Alzheimer's disease (AD).
• The choroid plexus (ChP) is a critical blood-brain interface producing CSF and forming the blood-CSF barrier.
• ChP pathology development across the lifespan and its contribution to AD remain undercharacterized.

Purpose of the Study:

• To systematically characterize choroid plexus (ChP) pathology across the lifespan and in Alzheimer's disease (AD).
• To integrate multi-modal data for a comprehensive understanding of ChP dysfunction.

Main Methods:

• Multi-modal atlas integrating single-nucleus transcriptomics from 49 individuals.
• AI-assisted quantitative histopathology on >500 postmortem samples (ages 16-105).
• Spatial transcriptomics and functional studies in 5xFAD mouse models.

Main Results:

• Identified fibrosis, calcification, and macrophage abnormalities as hallmarks of ChP aging.
• Observed AD pathology exacerbates ChP aging, expanding a pro-inflammatory fibroblast-macrophage signaling niche.
• Demonstrated macrophage dysfunction impairs epithelial barrier maintenance and repair in 5xFAD mice.

Conclusions:

• Established a foundational resource for studying ChP dysfunction in aging and AD.
• Proposed the macrophage-fibroblast-epithelial barrier axis as a key driver of ChP pathology.
• Highlighted the ChP's role in neurodegenerative disease pathogenesis.