Overexpression of WNT3a in the Hippocampus Can Partly Alleviate Deficits in Animal Models of Alzheimer's Disease.

Dysregulation of the WNT signaling pathway is implicated in the synaptic dysfunction underlying Alzheimer's disease (AD). This study investigates whether enhancing WNT signaling through hippocampal overexpression of the WNT3a ligand can mitigate functional deficits in two distinct animal models of AD pathology. We used a rat model of cholinergic deficit, induced by intraseptal 192IgG-saporin injections, and a transgenic 5XFAD mouse model of amyloidosis. Adeno-associated viruses were used to overexpress WNT3a in the hippocampal CA1 region. We assessed cognitive and sensorimotor behavior, synaptic plasticity (long-term potentiation, LTP) in vivo (rats) and in vitro (mice), and analyzed key proteins of the WNT signaling pathway. In rats with cholinergic deficit, WNT3a overexpression ameliorated sensorimotor coordination deficits and restored the initial phase of hippocampal LTP in vivo, without preventing the loss of cholinergic neurons or the decrease in acetylcholinesterase activity. In 5XFAD mice, which exhibited impaired LTP in vitro, WNT3a overexpression significantly enhanced the early phase of potentiation. This functional rescue was associated with a recovery of elevated phospho-β-catenin levels in the 5XFAD hippocampus. WNT3a did not affect behavior in the 5XFAD model and its benefits were independent of changes in cholinergic markers in both models. Our findings demonstrate that targeted WNT3a overexpression in the hippocampus can partially alleviate synaptic and functional deficits in AD models by directly modulating synaptic plasticity, primarily through the restoration of the Wnt/β-catenin pathway. This positions WNT3a gene therapy as a promising strategy for counteracting synaptic failure in Alzheimer's disease.