The Role And The Molecular Regulatory Mechanism Of Hippo Pathway In AD Models

Alzheimer’s disease(AD)is a progressive and irreversible neurodegenerative disease characterized by progressive deterioration of memory and cognition decline.The neuropathologic hallmark of AD are characterized by neuronal loss accompanied by extracellular amyloid-rich senile plaques and intracellular neurofibrillary tangles(NFTs).The Hippo pathway is a main regulator of cell proliferation and apoptosis,and it has attracted much attention for its tumor-suppressing function.However,the pathological studies from brain tissue of AD patients have found that an abnormal enrichment of Hippo signal pathway in the entorhinal cortex whose function is closely associated with memory formation and consolidation.Meanwhile,a few recently reports have shown that Hippo pathway-dependent TRIAD necrosis and apoptosis are involved in AD pathogenicity.However,based on the functional diversity of Hippo pathway,it is possible that this signaling pathway is also involved through the additional downstream functional outputs besides the known apoptosis and necrosis?And how Aβ regulates the switch of Hippo signal pathway remains to be further elucidated.The AD model of Caenorhabditis elegans has been revealed to imitate the pathological features and have the conservative signaling pathways to the mammals,which makes it has been intensively investigated for drug screening and better understanding of the molecular mechanisms.So in our current study,because of the evolutionary conservation of Hippo pathway in different species,we used both C.elegans and mammalian cell AD models to exploring the role and the molecular regulatory mechanism of Hippo pathway in the pathogenic process of AD.The main results were as follows:1.The core components within Hippo signaling pathway are involved in the pathogenic process of AβOur current data suggested that the Hippo core components,including cst-1,mob-1,sav-1,wts-1,yap-1 and egl-44 were involved in the pathogenesis of C.elegans AD model through RNAi,overexpression and mutation assay.It was found that the phosphorylation levels of CST-1 and WTS-1 were decreased in C.elegans AD model,which in turn promoted YAP-1 translocation into the nucleus.Binding with EGL-44,the transcriptional complex YAP-1/EGL-44 activated expression of the downstream genes.At the same time,the similar roles of LATS1 and TAZ were confirmed in AD mammalian cell model.2.Inactivation of Hippo pathway accelerates the AD pathogenesis in C.elegans model via inhibiting the autophagy-lysosomal pathwayIn order to identify the downstream output of Hippo signaling pathway,we examined Aβ aggregation caused by the disturbed Hippo pathway using the method of dot blotting.q PCR and autophagosome observation showed that Hippo pathway changed autophagy-related gene expression and autophagosome accumulation induced by Aβ.Morphological observation and V-ATPases analysis showed that Hippo pathway affected lysosomal morphology and activity.Furthermore,the transcriptional complex YAP-1/EGL-44 increased the expressional levels of let-363 and then downregulated the transcription factors hlh-30 and pha-4,which caused the inhibition of the autophagy-lysosome pathway.3.Aβ-induced nuclear translocation of YAP-1 depends on the involvement of LIN-10.According to the previous report that YAP/TAZ transcriptional activity was controlled by the scaffold protein Mint3 during APP cleavage in mammals,we further investigated if LIN-10,the homolog of Mint3 in C.elegans functioned in YAP-1translocation into the nucleus.It was found that Aβ enhanced the expressional level of LIN-10.Meanwhile,the direct interaction between LIN-10 and YAP-1 was identified,which promoted YAP-1 to enter the nucleus and consequently inhibited the autophagy-lysosome pathway.Collectively,our investigation here suggested that,in AD models,the expression of Aβ can promoted YAP-1 entry into the nucleus by the reduced phosphorylation level of CST-1/WTS-1 or increased the interaction of LIN-10/YAP-1.Once entering the nucleus and binding with EGL-44,the transcriptional complex YAP-1/EGL-44 accelerates the Aβ-mediated pathogenesis by affecting the downstream autophagy-lysosome pathway.And the innovations of our study are included as below:1.Hippo signaling pathway can participate in AD pathogenesis through inhibiting autophagy-lysosomal pathway and accumulating Aβ.2.Direct interaction between LIN-10 and YAP-1 regulates Aβ-induced nuclear translocation of YAP-1.