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

Cellular senescence is characterized by irreversible cell cycle exit, acquisition of a pro-inflammatory secretory phenotype, macromolecular damage, and deregulated metabolism. Senescent cells have been implicated in many age-related diseases, including neurodegenerative disease. We have previously demonstrated that selective elimination of senescent cells, both pharmacologically and genetically, prevents neurodegenerative disease phenotypes in tau (MAPTP301S;PS19) mutant mice. Here, we show that genetically knocking out the senescence mediator p16Ink4a, a cyclin-dependent kinase inhibitor, is sufficient to attenuate senescence signatures in PS19 mice. Neurodegenerative disease phenotypes dependent on senescent cell accumulation, including neuroinflammation, phosphorylated tau burden, neurodegeneration, and cognitive impairment were blunted in the absence of p16Ink4a. Additionally, we found that PS19 mice display altered neurovascular features—including vessel dilation, increased vessel density, deregulated endothelial cell extracellular matrix, and astrocytic endfoot depolarization—which were also attenuated when p16Ink4a was knocked out. Finally, we utilized a cell-type specific knockout of p16Ink4a to show that p16Ink4a deletion in endothelial cells and microglia alone attenuates many of the same tau-dependent phenotypes as whole-body knockout of p16Ink4a. Taken together, these results indicate that onset and progression of neurodegenerative disease in PS19 mice is driven, at least in part, by p16Ink4a expressing endothelial cells and microglia.