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YAP prevents premature senescence of astrocytes and cognitive decline of Alzheimer's disease through regulating CDK6 signaling
Aging Cell ( IF 8.0 ) Pub Date : 2021-08-20 , DOI: 10.1111/acel.13465 Xingxing Xu 1 , Xiya Shen 1 , Jiaojiao Wang 1 , Wenjin Feng 2 , Mianxian Wang 1 , Xuemeng Miao 3 , Qian Wu 3 , Lihao Wu 4 , Xiaoning Wang 4 , Yimin Ma 3 , Shuang Wu 4 , Xiaomei Bao 1, 5 , Wei Wang 3 , Ying Wang 6 , Zhihui Huang 1, 3, 7
Aging Cell ( IF 8.0 ) Pub Date : 2021-08-20 , DOI: 10.1111/acel.13465 Xingxing Xu 1 , Xiya Shen 1 , Jiaojiao Wang 1 , Wenjin Feng 2 , Mianxian Wang 1 , Xuemeng Miao 3 , Qian Wu 3 , Lihao Wu 4 , Xiaoning Wang 4 , Yimin Ma 3 , Shuang Wu 4 , Xiaomei Bao 1, 5 , Wei Wang 3 , Ying Wang 6 , Zhihui Huang 1, 3, 7
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Senescent astrocytes accumulate with aging and contribute to brain dysfunction and diseases such as Alzheimer's disease (AD), however, the mechanisms underlying the senescence of astrocytes during aging remain unclear. In the present study, we found that Yes-associated Protein (YAP) was downregulated and inactivated in hippocampal astrocytes of aging mice and AD model mice, as well as in D-galactose and paraquat-induced senescent astrocytes, in a Hippo pathway-dependent manner. Conditional knockout of YAP in astrocytes significantly promoted premature senescence of astrocytes, including reduction of cell proliferation, hypertrophic morphology, increase in senescence-associated β-galactosidase activity, and upregulation of several senescence-associated genes such as p16, p53 and NF-κB, and downregulation of Lamin B1. Further exploration of the underlying mechanism revealed that the expression of cyclin-dependent kinase 6 (CDK6) was decreased in YAP knockout astrocytes in vivo and in vitro, and ectopic overexpression of CDK6 partially rescued YAP knockout-induced senescence of astrocytes. Finally, activation of YAP signaling by XMU-MP-1 (an inhibitor of Hippo kinase MST1/2) partially rescued the senescence of astrocytes and improved the cognitive function of AD model mice and aging mice. Taken together, our studies identified unrecognized functions of YAP-CDK6 pathway in preventing astrocytic senescence in vitro and in vivo, which may provide further insights and new targets for delaying brain aging and aging-related neurodegenerative diseases such as AD.
中文翻译：
YAP 通过调节 CDK6 信号传导防止星形胶质细胞过早衰老和阿尔茨海默病认知衰退
衰老的星形胶质细胞随着衰老而积累，并导致脑功能障碍和阿尔茨海默病 (AD) 等疾病，然而，衰老过程中星形胶质细胞衰老的机制仍不清楚。在本研究中，我们发现在衰老小鼠和 AD 模型小鼠的海马星形胶质细胞中，以及在 D-半乳糖和百草枯诱导的衰老星形胶质细胞中，Yes 相关蛋白 (YAP) 在 Hippo 通路依赖中被下调和失活方式。条件性敲除星形胶质细胞中的 YAP 可显着促进星形胶质细胞的过早衰老，包括细胞增殖减少、肥大形态、衰老相关 β-半乳糖苷酶活性增加以及几种衰老相关基因如 p16、p53 和 NF-κB 的上调，和 Lamin B1 的下调。对潜在机制的进一步探索表明，体内和体外 YAP 敲除星形胶质细胞中细胞周期蛋白依赖性激酶 6 (CDK6) 的表达降低，而 CDK6 的异位过表达部分挽救了 YAP 敲除诱导的星形胶质细胞衰老。最后，XMU-MP-1（Hippo 激酶 MST1/2 的抑制剂）激活 YAP 信号通路部分挽救了星形胶质细胞的衰老，并改善了 AD 模型小鼠和衰老小鼠的认知功能。总之，我们的研究确定了 YAP-CDK6 通路在体外和体内预防星形胶质细胞衰老中未被识别的功能，这可能为延缓大脑衰老和与衰老相关的神经退行性疾病（如 AD）提供进一步的见解和新的靶点。
更新日期：2021-09-15
中文翻译：
YAP 通过调节 CDK6 信号传导防止星形胶质细胞过早衰老和阿尔茨海默病认知衰退
衰老的星形胶质细胞随着衰老而积累，并导致脑功能障碍和阿尔茨海默病 (AD) 等疾病，然而，衰老过程中星形胶质细胞衰老的机制仍不清楚。在本研究中，我们发现在衰老小鼠和 AD 模型小鼠的海马星形胶质细胞中，以及在 D-半乳糖和百草枯诱导的衰老星形胶质细胞中，Yes 相关蛋白 (YAP) 在 Hippo 通路依赖中被下调和失活方式。条件性敲除星形胶质细胞中的 YAP 可显着促进星形胶质细胞的过早衰老，包括细胞增殖减少、肥大形态、衰老相关 β-半乳糖苷酶活性增加以及几种衰老相关基因如 p16、p53 和 NF-κB 的上调，和 Lamin B1 的下调。对潜在机制的进一步探索表明，体内和体外 YAP 敲除星形胶质细胞中细胞周期蛋白依赖性激酶 6 (CDK6) 的表达降低，而 CDK6 的异位过表达部分挽救了 YAP 敲除诱导的星形胶质细胞衰老。最后，XMU-MP-1（Hippo 激酶 MST1/2 的抑制剂）激活 YAP 信号通路部分挽救了星形胶质细胞的衰老，并改善了 AD 模型小鼠和衰老小鼠的认知功能。总之，我们的研究确定了 YAP-CDK6 通路在体外和体内预防星形胶质细胞衰老中未被识别的功能，这可能为延缓大脑衰老和与衰老相关的神经退行性疾病（如 AD）提供进一步的见解和新的靶点。
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