Dissecting the human leptomeninges at single-cell resolution

Area of Science:

• Neuroimmunology
• Cell Biology
• Genomics

Background:

• The meninges, brain's outer layers, are crucial for immune surveillance at the brain border.
• Meningeal immune dysfunction is linked to aging and neurodegenerative diseases like Alzheimer's Disease (AD).
• Molecular characteristics of human leptomeningeal cell types remain largely uncharacterized.

Purpose of the Study:

• To create a molecular atlas of human leptomeningeal cell types using single nuclei profiling.
• To investigate the role of meningeal cells, particularly border-associated macrophages (BAMs), in Alzheimer's Disease (AD).
• To explore intercellular communication within the leptomeningeal niche in the context of AD.

Main Methods:

• Single nuclei RNA sequencing (snRNA-seq) of postmortem human leptomeninges from aged individuals.
• Bioinformatic analysis to identify cell types, subtypes, and differentially expressed genes.
• In vitro culture of leptomeningeal cells and treatment with amyloid-beta to assess cellular responses.

Main Results:

• Identification of diverse meningeal cell types, including unique endothelial, mural, and fibroblast subtypes.
• Characterization of T cells as CD8+ tissue-resident memory cells.
• Discovery of distinct BAM subtypes expressing AD risk genes (from Genome-Wide Association Studies - GWAS) and differing from microglia.
• Identification of cell-type-specific gene expression changes in AD, particularly in fibroblasts and BAMs.
• Demonstration that leptomeningeal cells exhibit AD-like signatures upon amyloid-beta exposure ex vivo.

Conclusions:

• This study provides the first molecular map of human leptomeningeal cells.
• Leptomeningeal cells, especially BAMs and fibroblasts, play a significant role in AD pathogenesis.
• The findings offer critical insights into meningeal immune and fibrotic responses in AD, paving the way for new therapeutic strategies.