Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics.
Acta Neuropathol
; 147(1): 78, 2024 05 02.
Article
em En
| MEDLINE
| ID: mdl-38695952
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 p16INK4A (up to twofold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater ß-amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for ß-amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased ß-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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Senescência Celular
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Doença de Alzheimer
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Transcriptoma
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Reino Unido