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Scientific article
Open access
English

Characterisation of premature cell senescence in Alzheimer’s disease using single nuclear transcriptomics

Published inActa neuropathologica, vol. 147, no. 1, 78
Publication date2024-05-02
First online date2024-05-02
Abstract

Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls (NDC) and donors with Alzheimer’s disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (> 200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (> fourfold) and p16 INK4A (up to twofold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater β-amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for β-amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased β-amyloid leading to premature senescence in microglia. We replicated these observations with independent AD snRNA-seq datasets. Our results describe a burden of senescent glia with AD that is sufficiently high to contribute to disease progression. These findings support the hypothesis that microglia are a primary target for senolytic treatments in AD.

eng
Keywords
  • Aging
  • Alzheimer’s disease
  • Astrocyte
  • Cell stress
  • Glia
  • Image mass cytometry
  • Microglia
  • Neuron
  • Oligodendroglia
  • Senescence
  • Senolytics
  • Single cell transcriptomics
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism
  • Brain / metabolism
  • Brain / pathology
  • Cellular Senescence / genetics
  • Cellular Senescence / physiology
  • Female
  • Humans
  • Male
  • Microglia / metabolism
  • Microglia / pathology
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Transcriptome
Citation (ISO format)
FANCY, Nurun N. et al. Characterisation of premature cell senescence in Alzheimer’s disease using single nuclear transcriptomics. In: Acta neuropathologica, 2024, vol. 147, n° 1, p. 78. doi: 10.1007/s00401-024-02727-9
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Article (Published version)
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Identifiers
ISSN of the journal0001-6322
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