Electroacupuncture alleviates cognitive impairments in APP/PS1 mice via gastric vagal afferent-mediated activation of the nucleus tractus solitarius‒locus coeruleus noradrenergic circuit.

OBJECTIVE: Neuroinflammatory cascades mediated by the locus coeruleus-norepinephrine (LC-NE) system emerge as critical pathophysiological determinants governing the etiology and advancement of neurodegenerative disorders, including Alzheimer's disease (AD). Therapeutic modulation of neuroinflammatory processes may mitigate AD-associated cognitive decline. Electroacupuncture (EA) targeting the Foot Yangming of Stomach Meridian acupoints demonstrates efficacy in ameliorating AD-related cognitive dysfunction through dual peripheral and central anti-inflammatory actions, though the precise neural circuitry linking peripheral interventions to central effects remains undefined. METHODS: In this study, APP/PS1 transgenic mice were administrated with EA stimulation at ST36 and ST37. Cognitive function was assessed via the Morris water maze and novel object recognition tests. Spatial learning capacities and episodic memory retention were quantified through Morris water maze paradigm and object novelty discrimination assays, respectively. Retrograde neural tracing was employed to validate the nucleus tractus solitarius (NTS)-LC noradrenergic projection. Multimodal approaches integrating chemogenetic manipulation, immunofluorescence microscopy, Western blotting, Golgi-Cox neuronal morphology analysis, and Nissl histochemistry elucidated the gastrointestinal vagal afferent fiber (GVAF)-NTS-LC circuit's role in EA-mediated neuroinflammatory regulation. Circuit-specific functional validation was conducted through selective GVAF blockade. RESULTS: EA at ST36 and ST37 attenuated hippocampal synaptic ultrastructural degeneration via NTS-LC noradrenergic circuit activation. This intervention suppressed proinflammatory cytokines expression (IL-6, IL-1β, TNF-α) and microglial hyperactivation through ADRB2/PKA/CREB pathway modulation, effectively rescuing cognitive deficits in AD models. GVAF ablation reversed EA-induced neuroinflammatory suppression, confirming the circuit dependence. CONCLUSIONS: EA at ST36/ST37 alleviates AD-related cognitive impairment through sequential GVAF-NTS-LC circuit activation and downstream ADRB2/PKA/CREB-mediated neuroinflammatory resolution. This work identifies a previously unrecognized peripheral-central neural circuit mechanism underlying EA's therapeutic efficacy in AD pathogenesis.