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Related Experiment Video

Updated: Jul 11, 2025

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Dissecting the human leptomeninges at single-cell resolution.

Nicola A Kearns1, Artemis Iatrou1,2, Daniel J Flood1

  • 1Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, 60612, USA.

Nature Communications
|November 4, 2023
PubMed
Summary
This summary is machine-generated.

This study maps human leptomeningeal cells, revealing unique subtypes and their roles in Alzheimer's Disease (AD) immunity and fibrosis. It identifies border-associated macrophages (BAMs) expressing AD risk genes, offering new insights into brain border defense.

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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.