School of Medicine, Yunnan University, Kunming 650091, China; College of Biological Resource and Food Engineering, Qujing Normal University, Qujing 655011, China.
School of Medicine, Yunnan University, Kunming 650091, China.
Neurobiol Aging. 2024 Feb;134:9-20. doi: 10.1016/j.neurobiolaging.2023.09.015. Epub 2023 Sep 28.
Although there is increasing evidence for the involvement of Hippo signaling in Alzheimer's disease (AD), the detailed functions and regulatory mechanisms are not fully understood, given the diverse biological effects of this pathway. In the present work, we used Caenorhabditis elegans and mammalian cell models to investigate changes in the Hippo signaling pathway in response to Aβ and the downstream effects on AD development. Aβ production in the AD models decreased phosphorylation of the upstream CST-1/WTS-1 kinase cascade and promoted an interaction between LIN-10 and YAP-1, leading to the nuclear translocation of YAP-1 and inducing gene transcription in conjunction with the transcription factor EGL-44. The YAP-1/EGL-44 complex suppressed the autophagy-lysosome pathway by modulating mTOR signaling, which enhanced Aβ accumulation and promoted AD progression. These results demonstrate for the first time that crosstalk between Hippo and mTOR signaling contributes to AD development by enhancing Aβ production, resulting in inhibition of Hippo signaling and autophagy-lysosome pathway and Aβ accumulation, suggesting potential therapeutic targets for the treatment or prevention of AD.
尽管越来越多的证据表明 Hippo 信号通路参与了阿尔茨海默病（AD），但其详细功能和调控机制尚不完全清楚，因为该途径具有多种生物学效应。在本研究中，我们使用秀丽隐杆线虫和哺乳动物细胞模型来研究 Hippo 信号通路对 Aβ 的反应变化及其对 AD 发展的下游影响。AD 模型中 Aβ 的产生降低了上游 CST-1/WTS-1 激酶级联的磷酸化，并促进了 LIN-10 和 YAP-1 之间的相互作用，导致 YAP-1 的核易位，并与转录因子 EGL-44 一起诱导基因转录。YAP-1/EGL-44 复合物通过调节 mTOR 信号来抑制自噬-溶酶体途径，从而增强 Aβ 的积累并促进 AD 的进展。这些结果首次表明，Hippo 和 mTOR 信号之间的串扰通过增强 Aβ 的产生促进 AD 的发展，从而导致 Hippo 信号通路和自噬-溶酶体途径的抑制和 Aβ 的积累，为 AD 的治疗或预防提供了潜在的治疗靶点。
