Activation of Epac2 improves Aβ-induced impairment of memory retrieval in an acute model of Alzheimer's disease

Impaired memory retrieval is one of the cognitive markers in the early stage of Alzheimer's Disease (AD). Previous studies report that exchange protein directly activated by cAMP 2 (Epac2) plays a specific and time-limited role in promoting memory retrieval. In this study, we investigated the effect of a novel Epac2 activator, S220, on neuronal and synaptic activities, and memory impairment in an acute AD mouse model. S220 treatment increased the firing rate of action potential and intracellular calcium in primary neuronal cultures. Moreover, S220 treatment increased synaptic currents in CA1 neurons. In the acute AD mouse model, intrahippocampal injection of amyloid-β (Aβ) oligomers impaired memory performance. Notably, administering S220 20 min before retention of contextual fear conditioning recovered the Aβ-induced memory impairment, suggesting an enhancing effect on memory retrieval. Collectively, our data demonstrate that the novel Epac2 activator S220 promotes synaptic communication and neuronal firing, and thereby improves Aβ-induced memory impairment via enhancing memory retrieval, indicating the role of Epac2 as a potential treatment target for AD.