Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline

By Tyler J. Bussian, Asef Aziz, Charlton F. Meyer, Barbara L. Swenson, J. V. van Deursen, D. Baker. Nature, 2018

1,112 citations recorded by the source corpus.

Cellular senescence, which is characterized by an irreversible cell-cycle arrest1 accompanied by a distinctive secretory phenotype2, can be induced through various intracellular and extracellular factors. Senescent cells that express the cell cycle inhibitory protein p16INK4A have been found to actively drive naturally occurring age-related tissue deterioration3,4 and contribute to several diseases associated with ageing, including atherosclerosis5 and osteoarthritis6. Various markers of senescence have been observed in patients with neurodegenerative diseases7–9; 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 MAPTP301SPS19 mouse model of tau-dependent neurodegenerative disease10 accumulates p16INK4A-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. In a mouse model of tau-dependent neurodegenerative disease, the clearance of senescent glial cells prevents the degeneration of cortical and hippocampal neurons and preserves cognitive function.

Subfields: Immunology, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/d87d9f44b21538d25ac77a65d272a575c57c43e1

How researchers see this paper

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In Immunology

1. T. Wyss‐Coray
2. Chao Gao
3. Shengdi Chen
4. Yuyan Tan
5. Jingwen Jiang

In Neurology

1. T. Wyss‐Coray
2. Chao Gao
3. Shengdi Chen
4. Yuyan Tan
5. Jingwen Jiang

In Physiology

1. T. Wyss‐Coray
2. J. Rutledge
3. H. Oh

Citations in the corpus

• Measuring biological age using omics data (2022, background): “Aged cells may accelerate ageing of other cells through secretion of pro-ageing factors 191,192 , and certain cell types may be more susceptible to pro-ageing factors in their environment 186,189,190 . al.”
• Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023, background): “This finding also suggests that senescent glial cells may provide a therapeutic target.(405)”