E2F4 gene therapy reverses established synaptic and cognitive deficits and remodels learning-associated signaling in Alzheimer's disease mice
Alzheimer's disease (AD) causes progressive synaptic dysfunction, neurodegeneration, and cognitive decline, yet strategies capable of reversing established deficits remain limited. Here, we show that neuronal expression of a p38MAPK phosphorylation-resistant human E2F4 variant (hE2F4DN), delivered by adeno-associated virus, restores hippocampal long-term potentiation and memory in homozygous 5xFAD mice after functional impairment is established. Treatment also reduces amyloid-{beta} and phospho-tau pathology and prevents hippocampal neuronal loss. Integrated proteomic and phosphoproteomic analyses reveal remodeling of metabolic, redox, neuroimmune, synaptic-vesicle, and GSK3{beta}-associated signaling pathways. Following contextual fear conditioning, hE2F4DN-treated mice exhibit broader learning-associated synaptic proteomic signatures and distinct phosphoregulatory responses involving synaptic machinery. These findings demonstrate that E2F4 gene therapy can reverse established synaptic and cognitive deficits while preserving neuronal integrity and reshaping molecular responses to learning, identifying E2F4 phosphorylation as a potential therapeutic target for advanced AD states.