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. 2025 Jul 23;113(14):2251-2264.e4.
doi: 10.1016/j.neuron.2025.04.020. Epub 2025 May 16.

p16-expressing microglia and endothelial cells promote tauopathy and neurovascular abnormalities in PS19 mice

Sara I Graves  1 , Charlton F Meyer  1 , Karthik B Jeganathan  1 , Darren J Baker  2
Affiliations

p16-expressing microglia and endothelial cells promote tauopathy and neurovascular abnormalities in PS19 mice

Sara I Graves et al. Neuron. .

Abstract

Cellular senescence is characterized by irreversible cell-cycle exit, a pro-inflammatory secretory phenotype, macromolecular damage, and deregulated metabolism. Senescent cells are highly associated with age-related diseases. We previously demonstrated that targeted elimination of senescent cells prevents neurodegenerative disease in tau (MAPTP301S;PS19) mutant mice. Here, we show that genetic ablation of the senescence mediator p16Ink4a is sufficient to attenuate senescence signatures in PS19 mice. Disease phenotypes-including neuroinflammation, phosphorylated tau, neurodegeneration, and cognitive impairment-were blunted in the absence of p16Ink4a. Additionally, we found that PS19 mouse brains display p16Ink4-dependent neurovascular alterations such as vessel dilation, increased vessel density, deregulated endothelial cell extracellular matrix, and astrocytic endfoot depolarization. Finally, we show that p16Ink4a deletion in endothelial cells and microglia alone attenuates many of the same phenotypes. Altogether, these results indicate that neurodegenerative disease in PS19 mice is driven, at least in part, by p16Ink4a-expressing endothelial cells and microglia.

Keywords: cellular senescence; endothelial cells; microglia; mouse model; neurodegeneration; p16(Ink4a); tauopathy.

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Conflict of interest statement

Declaration of interests D.J.B. has a potential financial interest related to this research. He is a co-inventor on patents held by Mayo Clinic and patent applications licensed to or filed by Unity Biotechnology and is a Unity Biotechnology shareholder. Research in the Baker laboratory has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies.

References

    1. Flatt T. (2012). A New Definition of Aging? Frontiers in Genetics 3. 10.3389/fgene.2012.00148. - DOI - PMC - PubMed
    1. Di Micco R, Krizhanovsky V, Baker D, and d’Adda di Fagagna F (2021). Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nature Reviews Molecular Cell Biology 22, 75–95. 10.1038/s41580-020-00314-w. - DOI - PMC - PubMed
    1. Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D, and Barrett JC (1996). Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci U S A 93, 13742–13747. 10.1073/pnas.93.24.13742. - DOI - PMC - PubMed
    1. Serrano M, Hannon GJ, and Beach D (1993). A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366, 704–707. 10.1038/366704a0. - DOI - PubMed
    1. Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, Athineos D, Kang TW, Lasitschka F, Andrulis M, et al. (2013). A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 15, 978–990. 10.1038/ncb2784. - DOI - PMC - PubMed

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