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.细胞衰老（cellular senescence）以不可逆的细胞周期退出、促炎分泌表型获得、大分子损伤以及代谢失调为特征。衰老细胞已被证实与多种年龄相关性疾病相关，包括神经退行性疾病。我们既往的研究表明，通过药理学与遗传学手段选择性清除衰老细胞，可在tau（MAPTP301S;PS19）突变小鼠中阻断神经退行性疾病表型。本研究显示，遗传学敲除衰老介质p16Ink4a（一种细胞周期蛋白依赖性激酶抑制剂，cyclin-dependent kinase inhibitor），足以减弱PS19小鼠体内的衰老特征谱。在p16Ink4a缺失的情况下，依赖于衰老细胞积累的神经退行性疾病表型——包括神经炎症、磷酸化tau负荷、神经退行性变以及认知障碍——均得到显著缓解。此外，我们发现PS19小鼠存在异常的神经血管特征，包括血管扩张、血管密度升高、内皮细胞细胞外基质失调以及星形胶质细胞终足去极化，上述异常在p16Ink4a被敲除后同样得到缓解。最后，我们通过p16Ink4a的细胞类型特异性敲除实验证实，仅在内皮细胞与小胶质细胞中删除p16Ink4a，即可减弱诸多与p16Ink4a全身性敲除相同的tau依赖性表型。综上，上述结果表明，PS19小鼠神经退行性疾病的发生与进展，至少部分由表达p16Ink4a的内皮细胞和小胶质细胞所驱动。