Blockade of EphA4 Signaling Alleviates the Impairment of Hippocampal Synaptic Plasticity Associated With Alzheimer's Disease

Impairment of hippocampal synaptic plasticity is associated with learning and memory deficit in Alzheimer’s disease. It is therefore important to understand the molecular mechanisms underlying synaptic dysfunctions. We found that activity of a receptor tyrosine kinase EphA4 was increased in hippocampal synaptic fractions of APP/PS1 Alzheimer’s disease mouse model at 3 months, an early stage when the deposition of amyloid plaques s is observed. Furthermore, deletion of postsynaptic EphA4 was able to alleviate the suppression of hippocampal long-term potentiation in the Schaffer collateral-CA1 pathway of APP/PS1 mice. Thus, our findings suggest that EphA4 is a potential target for disease-modifying strategies for Alzheimer’s disease. Using docking analysis, we identified various small molecule inhibitors for EphA4, which were able to inhibit the binding between EphA4 and its endogenous ligands in cultured neurons. Further analysis showed that oral administration of an EphA4 inhibitor blocked the EphA4 signaling in APP/PS1 mice, and rescued the impaired synaptic plasticity observed in those mice. Taken together, blockade of the EphA4-ligand interaction is a promising approach to developing effective treatments for Alzheimer’s disease.