The Hippo signaling pathway as a target of intervention for Alzheimer’s disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease afflicting millions of Americans. At present, most AD treatments only manage symptoms, but don’t slow the underlying progression of the disease. The root cause of dementia in AD is degeneration and death of neurons important for cognitive function. The Hippo signaling pathway is an evolutionarily conserved signaling pathway involved in controlling organ size. While this pathway is normally studied in the context of a regulatory mechanism of cell proliferation and development, it has also been shown to be a potent regulator of cell survival. Under circumstances where Hippo signaling activity is attenuated, transcription co-activator YAP and TAZ enter the nucleus and form a complex with TEAD. This allows YAP and TAZ to up-regulate pro-proliferative and pro-survival genes. However, under conditions where Hippo signaling activity is elevated, a cascade of signaling events results in activation of LATS1 and LATS2, which then phosphorylate YAP and TAZ and tag them for sequestration and/or degradation, leading to reduced YAP and TAZ activity. Recently, abnormal activation of Hippo signaling has been implicated in neurodegenerative diseases. We have obtained preliminary data suggesting that Hippo signaling is hyper- activated in AD. In addition, we have shown that inhibition of Hippo signaling by genetic ablation of Lats1 and Lats2 genes in forebrain neurons improved cognition and reduced neurodegeneration in AD mouse model 5xFAD mice. Moreover, we have gathered data indicating that inhibition of Hippo signaling increased neurons’ resilience against ferroptosis, an iron-dependent and lipid peroxidation-driven mode of cell death. This study aims to examine the effectiveness of inhibition of Hippo signaling pathway through genetic approaches at asymptomatic and symptomatic stages in slowing AD onset and progression. The current study will also interrogate the underlying mechanism of increased resilience against ferroptosis in neurons conferred by inhibition of Hippo signaling. Our study seeks to fill the significant gap-of-knowledge on the significance of hyper- activation of Hippo signaling pathway in AD, and to provide the first proof-of-concept evidence on inhibition of the Hippo signaling pathway as a novel therapeutic strategy for AD.