Open AccessYAP prevents premature senescence of astrocytes and cognitive decline of Alzheimer's disease through regulating CDK6 signaling
Author(s) -
Xu Xingxing,
Shen Xiya,
Wang Jiaojiao,
Feng Wenjin,
Wang Mianxian,
Miao Xuemeng,
Wu Qian,
Wu Lihao,
Wang Xiaoning,
Ma Yimin,
Wu Shuang,
Bao Xiaomei,
Wang Wei,
Wang Ying,
Huang Zhihui
Publication year - 2021
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13465
Subject(s) - senescence , biology , microbiology and biotechnology , cyclin dependent kinase 6 , downregulation and upregulation , knockout mouse , cognitive decline , astrocyte , cyclin dependent kinase , alzheimer's disease , kinase , protein kinase a , neuroscience , cyclin dependent kinase 2 , cell cycle , cell , medicine , genetics , dementia , receptor , disease , gene , central nervous system
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.