E2F4 gene therapy reverses established synaptic and cognitive deficits and remodels learning-associated signaling in Alzheimer's disease mice

Neuronal AAV delivery of the phosphorylation-resistant human E2F4 variant (hE2F4DN) restores hippocampal long-term potentiation and memory in homozygous 5xFAD mice after impairment is established.

• Why it matters: Advanced AD models show progressive synaptic and cognitive decline, but therapies that reverse already-established deficits are limited.
• What they did: In homozygous 5xFAD mice, hE2F4DN gene therapy was given after functional impairment, and outcomes included synaptic physiology, memory testing, pathology measures, and integrated proteomic/phosphoproteomic profiling.
• The result: hE2F4DN reduces amyloid-{beta} and phospho-tau pathology, prevents hippocampal neuronal loss, and remodels learning-associated metabolic, redox, neuroimmune, synaptic-vesicle, and GSK3{beta}-linked signaling after contextual fear conditioning.

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