期刊
PROGRESS IN NEUROBIOLOGY
卷 214, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pneurobio.2022.102280
关键词
MST1; Hippo pathway; Alzheimer's disease; Cognition; Neuronal loss
资金
- National Natural Science Foundation of China [32070988, 31970733]
- 111 Project [B08011]
- China Postdoctoral Science Foundation [2019M651012, 2020T130324]
This study suggests that MST1 is involved in the occurrence and development of AD. Overexpression of MST1 induces AD-like phenotype and accelerates cognitive decline and neuronal apoptosis in 5xFAD mice. MST1 promotes neuronal apoptosis by interacting with p53.
Alzheimer's disease (AD) is the most prevalent form of dementia in the old adult and characterized by progressive cognitive decline and neuronal damage. The mammalian Ste20-like kinase1/2 (MST1/2) is a core component in Hippo signaling, which regulates neural stem cell proliferation, neuronal death and neuroinflammation. However, whether MST1/2 is involved in the occurrence and development of AD remains unknown. In this study we reported that the activity of MST1 was increased with A ss accumulation in the hippocampus of 5xFAD mice. Overexpression of MST1 induced AD-like phenotype in normal mice and accelerated cognitive decline, synaptic plasticity damage and neuronal apoptosis in 2-month-old 5xFAD mice, but did not significantly affect A ss levels. Mechanistically, MST1 associated with p53 and promoted neuronal apoptosis by phosphorylation and activation of p53, while p53 knockout largely reversed MST1-induced AD-like cognitive deficits. Importantly, either genetic knockdown or chemical inactivation of MST1 could significantly improve cognitive deficits and neuronal apoptosis in 7-month-old 5xFAD mice. Our results support the idea that MST1mediated neuronal apoptosis is an essential mechanism of cognitive deficits and neuronal loss for AD, and manipulating the MST1 activity as a potential strategy will shed light on clinical treatment for AD or other diseases caused by neuronal injury.
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