Inhibition of Hippo Signaling Through Ablation of Lats1 and Lats2 Protects Against Cognitive Decline in <scp>5xFAD</scp> Mice via Increasing Neuronal Resilience Against Ferroptosis

The Hippo signaling pathway is a key regulator of cell growth and cell survival, and hyperactivation of the Hippo pathway has been implicated in neurodegenerative diseases such as Huntington's disease. However, the role of Hippo signaling in Alzheimer's disease (AD) remains unclear. We observed that hyperactivation of Hippo signaling occurred in the AD model 5xFAD mice. To determine how inhibition of Hippo signaling might affect disease pathogenesis, we generated 5xFAD mice with conditional neuronal ablation of Lats1 and Lats2, the gatekeepers of Hippo signaling activity. Our results indicated that 5xFAD mice with ablation of Lats1 and Lats2 were protected against cognitive decline compared with control 5xFAD mice, and this protection was correlated with a marked reduction in neurodegeneration. Interestingly, primary culture neurons with ablation of Lats1 and Lats2 had significantly increased survival following treatment with chemical inducers of ferroptosis and exhibited reduced lipid peroxidation, the driving force of ferroptotic cell death. Moreover, 5xFAD mice with ablation of Lats1 and Lats2 showed reduced lipid peroxidation, and transcriptomic analysis revealed that 5xFAD mice with ablation of Lats1 and Lats2 had enriched metabolic pathways associated with ferroptosis. These results indicate that inhibition of Hippo signaling activity confers neural protection in 5xFAD mice by augmenting resilience against ferroptosis.