Dissecting the human leptomeninges at single-cell resolution

Nicola A. Kearns, Artemis Iatrou, Daniel J. Flood, Sashini Tissera, Zachary M. Mullaney, Jishu Xu, Chris Gaiteri, David A. Bennett and Yanling Wang ()
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Nicola A. Kearns: Rush University Medical Center
Artemis Iatrou: Rush University Medical Center
Daniel J. Flood: Rush University Medical Center
Sashini Tissera: Rush University Medical Center
Zachary M. Mullaney: Rush University Medical Center
Jishu Xu: Rush University Medical Center
Chris Gaiteri: Rush University Medical Center
David A. Bennett: Rush University Medical Center
Yanling Wang: Rush University Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Emerging evidence shows that the meninges conduct essential immune surveillance and immune defense at the brain border, and the dysfunction of meningeal immunity contributes to aging and neurodegeneration. However, no study exists on the molecular properties of cell types within human leptomeninges. Here, we provide single nuclei profiling of dissected postmortem leptomeninges from aged individuals. We detect diverse cell types, including unique meningeal endothelial, mural, and fibroblast subtypes. For immune cells, we show that most T cells express CD8 and bear characteristics of tissue-resident memory T cells. We also identify distinct subtypes of border-associated macrophages (BAMs) that display differential gene expressions from microglia and express risk genes for Alzheimer’s Disease (AD), as nominated by genome-wide association studies (GWAS). We discover cell-type-specific differentially expressed genes in individuals with Alzheimer’s dementia, particularly in fibroblasts and BAMs. Indeed, when cultured, leptomeningeal cells display the signature of ex vivo AD fibroblasts upon amyloid-β treatment. We further explore ligand-receptor interactions within the leptomeningeal niche and computationally infer intercellular communications in AD. Thus, our study establishes a molecular map of human leptomeningeal cell types, providing significant insight into the border immune and fibrotic responses in AD.

Date: 2023
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DOI: 10.1038/s41467-023-42825-y

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