Electroacupuncture improves spatial learning and memory functions in triple-transgenic Alzheimer’s disease model mice by enhancing glutamatergic synapse plasticity in the entorhinal cortex–hippocampal CA1 circuit

Alzheimer’s disease is characterized by impairment in episodic memory and visuospatial skills, which is related to the deterioration of glutamatergic synapses within the entorhinal cortex–hippocampal circuit. While electroacupuncture shows therapeutic promise for Alzheimer’s disease, its underlying mechanisms remain poorly understood. This study investigated whether the effects of electroacupuncture on spatial memory involves improving synaptic plasticity in this circuit using triple-transgenic Alzheimer’s disease mice. The intervention consisted of a 4-week daily electroacupuncture treatment at DU20/DU24 acupoints or sham treatment. Our findings revealed that electroacupuncture triggered a cascade of neuroplastic events, leading to significant cognitive improvements. Crucially, these therapeutic effects were completely abrogated by chemogenetic inhibition of the entorhinal cortex–hippocampal CA1 circuit, establishing its causal necessity. Our multi-level analyses revealed that electroacupuncture attenuated tau hyperphosphorylation, restored dendritic spine density, and boosted long-term potentiation. This was accompanied by an increase in crucial synaptic proteins and activation of the NMDAR–CaMKII–CREB signaling cascade. The key findings of this study reveal a multi-level neurorestorative cascade induced by electroacupuncture, by simultaneously reducing tau pathology, rebuilding synaptic architecture, and enhancing synaptic function in the entorhinal-hippocampal circuit, driven by the NMDAR–CaMKII–CREB pathway. Collectively, these results provide evidence that electroacupuncture ameliorates spatial memory deficits in Alzheimer’s disease model mice by specifically enhancing synaptic plasticity in the entorhinal cortex-hippocampal circuit.