MST1 mediates neuronal loss and cognitive deficits: A novel therapeutic target for Alzheimer’s disease
MST1 mediates neuronal loss and cognitive deficits: A novel therapeutic target for Alzheimer’s disease
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DOI：
10.1016/j.pneurobio.2022.102280
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发表时间：
2022-05
影响因子：
6.7
通讯作者：
Hui Wang;Yingchun Shang;Enlin Wang;Xinxin Xu;Qiyue Zhang;Chenxi Qian;Zhuo Yang;Shian Wu;
中科院分区：
文献类型：
--
作者：
Hui Wang;Yingchun Shang;Enlin Wang;Xinxin Xu;Qiyue Zhang;Chenxi Qian;Zhuo Yang;Shian Wu;
阿尔茨海默病（AD）是老年人中最常见的痴呆形式，其特征是进行性认知能力下降和神经元损伤。哺乳动物ste20样激酶1/2 （MST1/2）是Hippo信号传导的核心成分，调控神经干细胞增殖、神经元死亡和神经炎症。然而，MST1/2是否参与AD的发生发展尚不清楚。在本研究中，我们报道了5xFAD小鼠海马中MST1的活性随着Aβ的积累而增加。过表达MST1可诱导正常小鼠ad样表型，加速2月龄5xFAD小鼠认知能力下降、突触可塑性损伤和神经元凋亡，但对Aβ水平无显著影响。在机制上，MST1与p53相关，并通过磷酸化和激活p53促进神经元凋亡，而p53敲除在很大程度上逆转了MST1诱导的ad样认知缺陷。重要的是，MST1基因敲除或化学失活均可显著改善7月龄5xFAD小鼠的认知缺陷和神经元凋亡。我们的研究结果支持MST1介导的神经元凋亡是阿尔茨海默病认知缺陷和神经元损失的重要机制，操纵MST1活性作为一种潜在的策略将为阿尔茨海默病或其他由神经元损伤引起的疾病的临床治疗提供线索。
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 Aβ 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 Aβ 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 MST1-mediated 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.