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

Author

Listed:
  • Tyler J. Bussian

    (Mayo Clinic)

  • Asef Aziz

    (Mayo Clinic)

  • Charlton F. Meyer

    (Mayo Clinic)

  • Barbara L. Swenson

    (Mayo Clinic)

  • Jan M. van Deursen

    (Mayo Clinic
    Mayo Clinic)

  • Darren J. Baker

    (Mayo Clinic
    Mayo Clinic)

Abstract

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.

Suggested Citation

  • Tyler J. Bussian & Asef Aziz & Charlton F. Meyer & Barbara L. Swenson & Jan M. van Deursen & Darren J. Baker, 2018. "Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline," Nature, Nature, vol. 562(7728), pages 578-582, October.
  • Handle: RePEc:nat:nature:v:562:y:2018:i:7728:d:10.1038_s41586-018-0543-y
    DOI: 10.1038/s41586-018-0543-y
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    Cited by:

    1. Krithi Irmady & Caryn R. Hale & Rizwana Qadri & John Fak & Sitsandziwe Simelane & Thomas Carroll & Serge Przedborski & Robert B. Darnell, 2023. "Blood transcriptomic signatures associated with molecular changes in the brain and clinical outcomes in Parkinson’s disease," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Ines Sturmlechner & Chance C. Sine & Karthik B. Jeganathan & Cheng Zhang & Raul O. Fierro Velasco & Darren J. Baker & Hu Li & Jan M. Deursen, 2022. "Senescent cells limit p53 activity via multiple mechanisms to remain viable," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Madison L. Doolittle & Dominik Saul & Japneet Kaur & Jennifer L. Rowsey & Stephanie J. Vos & Kevin D. Pavelko & Joshua N. Farr & David G. Monroe & Sundeep Khosla, 2023. "Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    4. Xu Zhang & Vesselina M. Pearsall & Chase M. Carver & Elizabeth J. Atkinson & Benjamin D. S. Clarkson & Ethan M. Grund & Michelle Baez-Faria & Kevin D. Pavelko & Jennifer M. Kachergus & Thomas A. White, 2022. "Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Jaskaren Kohli & Chen Ge & Eleni Fitsiou & Miriam Doepner & Simone M. Brandenburg & William J. Faller & Todd W. Ridky & Marco Demaria, 2022. "Targeting anti-apoptotic pathways eliminates senescent melanocytes and leads to nevi regression," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

    More about this item

    Keywords

    Senescent Cells; Microglia; NFT Deposition; Astrocytes; PS1 Mice;
    All these keywords.

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