Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline
Publication year
2018Source
Nature, 562, 7728, (2018), pp. 578-582ISSN
Publication type
Article / Letter to editor
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Organization
Cell Biology (UMC)
Journal title
Nature
Volume
vol. 562
Issue
iss. 7728
Page start
p. 578
Page end
p. 582
Subject
Radboudumc 19: Nanomedicine RIMLS: Radboud Institute for Molecular Life Sciences; Cell Biology - Radboud University Medical CenterAbstract
Cellular senescence, which is characterized by an irreversible cell-cycle arrest(1) accompanied by a distinctive secretory phenotype(2), can be induced through various intracellular and extracellular factors. Senescent cells that express the cell cycle inhibitory protein p16(INK4A) have been found to actively drive naturally occurring age-related tissue deterioration(3,4) and contribute to several diseases associated with ageing, including atherosclerosis(5) and osteoarthritis(6). Various markers of senescence have been observed in patients with neurodegenerative diseases(7-9); however, a role for senescent cells in the aetiology of these pathologies is unknown. Here we show a causal link between the accumulation of senescent cells and cognition-associated neuronal loss. We found that the MAPT(P301S)PS19 mouse model of tau-dependent neurodegenerative disease(10) accumulates p16(INK4A)-positive senescent astrocytes and microglia. Clearance of these cells as they arise using INK-ATTAC transgenic mice prevents gliosis, hyperphosphorylation of both soluble and insoluble tau leading to neurofibrillary tangle deposition, and degeneration of cortical and hippocampal neurons, thus preserving cognitive function. Pharmacological intervention with a first-generation senolytic modulates tau aggregation. Collectively, these results show that senescent cells have a role in the initiation and progression of tau-mediated disease, and suggest that targeting senescent cells may provide a therapeutic avenue for the treatment of these pathologies.
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- Academic publications [245262]
- Faculty of Medical Sciences [93207]
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