摘要Background:Working memory deficits,one of the earliest hallmarks of Alzheimer's disease(AD),are closely linked to abnormal neural activity in the dorsolateral prefrontal cortex(DLPFC).Transcranial direct current stimulation(tDCS),a non-invasive neuromodulation therapy,has been shown to ameliorate early AD working memory deficits by modulating excitatory activity in the DLPFC,yet the underlying mechanisms remain incompletely understood.Methods:This investigation was structured around three experimental phases.We initially applied tDCS to stimulate the left prefrontal cortex(PFC)of transgenic mice with 5 familial AD(5×FAD)5 d per week for 4 weeks.Subsequently,we employed optogenetic(Opt)techniques to modulate left PFC glutamatergic neurons.Finally,we inhibited soluble N-ethylmaleimide-sensitive factor attachment receptor(SNARE)expression in the left PFC to elucidate the essential function of SNARE complex assembly with chaperone molecules in orchestrating synaptic vesicle release.Results:tDCS treatment improved working memory deficits in early-stage AD mice.This was accompanied by increased cerebral blood flow,enhanced neuronal excitability,amelioration of neurochemical metabolic disorders,and reduced amyloid β-protein(Aβ)deposition in the left PFC.Opt stimulation of PFC glutamatergic neurons similarly improved working memory,indicating the association between tDCS's therapeutic effects and synaptic plasticity of excitatory neurons.Crucially,tDCS facilitated synaptic vesicle fusion and release,evidenced by increased vesicle numbers,enhanced release probability,improved synaptic transmission efficacy,and upregulation of the SNARE complex,Snap25,and Syt1.Inhibiting SNARE expression in the left PFC attenuated the tDCS-induced improvements in synaptic vesicle release and working memory.Conclusion:These findings collectively demonstrate that left PFC-targeted tDCS modulates interactions between the SNARE complex and chaperone molecules,thereby promoting synaptic vesicle fusion and release.This mechanism underlies the amelioration of early AD-like working memory impairment by tDCS.