Electroacupuncture Ameliorates Cognitive Impairment by Modulating the Hippo–YAP Pathway in 5 × FAD Mice

Background Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Neuroinflammation is a major contributor to its pathogenesis. The Hippo–Yes-associated protein (YAP) signaling pathway is closely associated with AD progression and neuroinflammatory regulation. Electroacupuncture (EA) exerts neuroprotective effects in AD; however, its mechanism of action via the Hippo–YAP pathway remains unclear. Therefore, we aimed to investigate whether EA ameliorates cognitive dysfunction by modulating the Hippo–YAP signaling pathway to suppress hippocampal neuroinflammation and alleviate amyloid-beta (Aβ) pathological lesions. Methods AD model five familial Alzheimer’s disease (5 × FAD) mice were classified into 5 × FAD, EA, and non-acupoint groups. Age- and sex-matched wild-type C57 mice from the same litter served as controls. The EA and non-acupoint groups received the respective interventions for 4 weeks. Cognitive function was evaluated using behavioral tests. Inflammatory cytokine levels were measured using real-time quantitative polymerase chain reaction. Hippocampal Aβ deposition was detected using immunohistochemistry. YAP nucleocytoplasmic shuttling and microglial activation were examined using immunofluorescence. Hippo–YAP pathway-related proteins were assessed using Western blotting. Results EA significantly ameliorated cognitive dysfunction, reduced hippocampal Aβ deposition, and inhibited microglial activation and neuroinflammation in 5 × FAD mice. Mechanistically, EA increased the phosphorylation of mammalian Ste20-like kinase 1/2, large tumor suppressor kinase 1/2, and YAP, thereby inhibiting YAP nuclear translocation through activation of the Hippo pathway. Conclusions EA may improve cognitive function and alleviate pathological changes in this AD model by regulating the Hippo–YAP signaling pathway, supporting further investigation of EA as a potential therapeutic approach for AD.