Holloway Kristopher, Neherin Kashfia, Song Yingduo, Sato Kazuhito, Houston Andrew, Chen Feng, Ding Li, Zhang Hong
Department of Pediatrics, 3 NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
Department of Medicine, McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA.
Aging Cell. 2025 May;24(5):e14472. doi: 10.1111/acel.14472. Epub 2025 Jan 5.
Increased expression of the cyclin-dependent kinase inhibitor p16Ink4a (p16) is detected in neurons of human Alzheimer's disease (AD) brains and during normal aging. Importantly, selective eliminating p16-expressing cells in AD mouse models attenuates tau pathologies and improves cognition. But whether and how p16 contributes to AD pathogenesis remains unclear. To address this question, we tested whether induction of p16 expression in neurons exacerbates AD pathologies. We created a doxycycline-inducible system to trigger p16 up-regulation in human-induced pluripotent stem cells (iPSCs) and neurons differentiated from iPSCs. We demonstrated that up-regulated p16 expression in iPSCs reduces cell proliferation, down-regulates cell cycle genes, and up-regulates genes involved in focal adhesion, interferon α response and PI3K-Akt signaling. Our approach enables temporal control of p16 induction upon differentiation from iPSCs to neurons. In differentiated cortical neurons, we found that up-regulation of p16 increases tau phosphorylation at Ser202/Thr205 and Thr231 in a cell-autonomous manner, while amyloid beta secretion is not affected. These data suggest a critical role of p16 in regulating tau phosphorylation in neurons, and thereby contributing to pathological progression of AD. As pathological tau tangles have been shown to induce p16 expression, our studies suggest a positive feedback loop between p16 and tau to exacerbate tau pathologies.
在人类阿尔茨海默病（AD）大脑的神经元以及正常衰老过程中，细胞周期蛋白依赖性激酶抑制剂p16Ink4a（p16）的表达增加。重要的是，在AD小鼠模型中选择性清除表达p16的细胞可减轻tau病理变化并改善认知。但p16是否以及如何促成AD发病机制仍不清楚。为解决这个问题，我们测试了神经元中p16表达的诱导是否会加剧AD病理变化。我们创建了一个强力霉素诱导系统，以触发人诱导多能干细胞（iPSC）以及由iPSC分化而来的神经元中p16的上调。我们证明，iPSC中上调的p16表达会减少细胞增殖、下调细胞周期基因，并上调参与粘着斑、干扰素α反应和PI3K-Akt信号传导的基因。我们的方法能够在从iPSC分化为神经元的过程中对p16的诱导进行时间控制。在分化的皮质神经元中，我们发现p16的上调以细胞自主方式增加Ser202/Thr205和Thr231位点的tau磷酸化，而淀粉样β分泌不受影响。这些数据表明p16在调节神经元中tau磷酸化方面起关键作用，从而促成AD的病理进展。由于病理性tau缠结已被证明可诱导p16表达，我们的研究表明p16与tau之间存在正反馈回路，从而加剧tau病理变化。
