Neurovascular dysfunction in GRN-associated frontotemporal dementia identified by single-nucleus RNA sequencing of human cerebral cortex

Nat Neurosci. 2022 Aug;25(8):1034-1048. doi: 10.1038/s41593-022-01124-3. Epub 2022 Jul 25.

Abstract

Frontotemporal dementia (FTD) is the second most prevalent form of early-onset dementia, affecting predominantly frontal and temporal cerebral lobes. Heterozygous mutations in the progranulin gene (GRN) cause autosomal-dominant FTD (FTD-GRN), associated with TDP-43 inclusions, neuronal loss, axonal degeneration and gliosis, but FTD-GRN pathogenesis is largely unresolved. Here we report single-nucleus RNA sequencing of microglia, astrocytes and the neurovasculature from frontal, temporal and occipital cortical tissue from control and FTD-GRN brains. We show that fibroblast and mesenchymal cell numbers were enriched in FTD-GRN, and we identified disease-associated subtypes of astrocytes and endothelial cells. Expression of gene modules associated with blood-brain barrier (BBB) dysfunction was significantly enriched in FTD-GRN endothelial cells. The vasculature supportive function and capillary coverage by pericytes was reduced in FTD-GRN tissue, with increased and hypertrophic vascularization and an enrichment of perivascular T cells. Our results indicate a perturbed BBB and suggest that the neurovascular unit is severely affected in FTD-GRN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood-Brain Barrier / physiopathology
  • Endothelial Cells / pathology
  • Frontotemporal Dementia* / genetics
  • Frontotemporal Dementia* / pathology
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Mutation
  • Progranulins* / genetics
  • Sequence Analysis, RNA
  • Temporal Lobe / pathology

Substances

  • GRN protein, human
  • Intercellular Signaling Peptides and Proteins
  • Progranulins