Role and molecular regulatory mechanisms of Hippo signaling pathway in Caenorhabditis elegans and mammalian cell models of Alzheimer’s disease

Abstract

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. Aβ1–42 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 Aβ1–42 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.