Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive decline of cognitive function from the degeneration of synapses and axons (Guo et al., 2019). It is estimated that there were 50 million people with AD worldwide in 2018, with the number projected to reach 150 million by 2050 (Patterson, 2018). In AD, neuronal loss is accompanied by the accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles (Deture and Dickson, 2019). Although the underlying mechanisms are not fully understood, there is evidence that multiple signaling pathways involved in apoptosis, including JNK, PI3K/AKT, TNFα, and Hippo, contribute to neurodegeneration in AD (Decourt et al., 2017, Kitagishi et al., 2014).

The Hippo signaling pathway, which is evolutionarily conserved in mammals, is a kinase cascade comprising MST1/2 and LATS1/2 that plays an important role in controlling organ size, tissue homeostasis, and tissue repair. A protein complex composed of MST1/2, SAV, and MOB sequentially phosphorylates LATS1/2 and YAP/TAZ, causing YAP/TAZ to associate with 14-3-3, resulting in their cytoplasmic retention (Bao et al., 2011). Inhibition of the Hippo signaling pathway leads to nuclear translocation of unphosphorylated YAP/TAZ and their binding to TEAD family transcription factors and target gene activation (Meng et al., 2016).

Although much attention was traditionally attracted for its antitumor activity, the Hippo signaling pathway has been implicated in neurodegenerative disorders such as AD, Huntington disease, Alexander disease, and amyotrophic lateral sclerosis owing to its effects on apoptosis (Sahu and Mondal, 2020). Abnormal activation of Hippo signaling has been observed in the entorhinal cortex—which is involved in memory formation and consolidation—in patients with AD (Xu et al., 2018). Furthermore, senile plaques in this brain area are detected early on during AD development (Pennanen et al., 2004). However, the precise role of this pathway in AD is unclear. The translocation of YAP from the cytoplasm to the nucleus facilitates Aβ-induced apoptosis by forming a transcription complex with p73 and inducing BAX and PUMA (Zhang et al., 2011). However, both hyper- and hypophosphorylated Hippo were found to accelerate neurodegeneration (Hamilton and O’neill, 2013). Additionally, Hippo-dependent neuron necrosis and inhibition of dendrite formation were shown to contribute to AD pathogenesis (Sahu and Mondal, 2020, Tanaka et al., 2020). Thus, the conflicting evidence pertaining to Hippo signaling and its diverse biological effects requires clarification.

Overexpressing human Aβ in Caenorhabditis elegans recapitulates some aspects of the AD phenotype such as Aβ plaques formation, neurotransmission impairment, synaptic dysfunction, and behavioral defects, making it a valuable model for investigating the molecular mechanisms of AD and the action of novel drugs (Ahmad, 2022, Diomede et al., 2014, Wu and Luo, 2005). In the present study, C. elegans and mammalian cell-based models were used to investigate the role and regulation of Hippo signaling in AD development. The results suggest that Aβ1–42 production inactivates Hippo signaling and a crosstalk between Hippo and the mTOR signaling pathway further enhances Aβ1–42 accumulation, thereby promoting AD progression.