基于Rab5-NGF/TrkA轴调控胆碱能神经环路探讨电针延缓AD早期学习记忆功能减退的机制

阿尔茨海默病（AD）是老年难治疾病，病理复杂且潜伏期长。目前国际上已将治疗重心转移至发病早期、甚至前期阶段。电针能改善AD学习记忆功能，但作用机制有待完善。Rab5蛋白是NGF/TrkA受体复合物进入“溶酶体降解”还是“维持信号传递”选择的关键调控“开关”。在AD中，Rab5蛋白过表达导致NGF信号丢失，可抑制基底前脑-海马胆碱能神经环路突触可塑性。基于此，本课题提出研究假说：电针“神庭”、“百会”穴可能通过下调Rab5蛋白，减少NGF/TrkA受体复合物降解，维持NGF信号，增强基底前脑-海马胆碱能神经环路突触可塑性，从而延缓AD早期学习记忆功能减退。本课题首先采用RNA干扰技术明确早期电针通过增加NGF信号改善AD学习记忆能力；在此基础之上，结合AAV病毒转染和CRE/LOXP基因编辑技术在基底前脑胆碱能神经元过表达Rab5蛋白。研究结果将进一步揭示早期电针改善阿尔茨海默病的分子机制。

Alzheimer's disease, which presents complicated pathologies and long incubation period, is hard to be cured. In recent years, the focus of AD has been shifted to the early stage. Electroacupuncture can improve learning and memory ability of Alzheimer's disease, but the mechanism needs to be further elucidated. Rab5 protein is a key regulatory "switch" for the choice of whether the NGF/TrkA receptor complex entered "lysosomal degradation" or "maintains signal transmission". In AD, Rab5 protein overexpression leads to loss the signal of NGF, which could inhibit synaptic plasticity of basal forebrain-hippocampus cholinergic neural circuit. Based on this, we proposed a hypothesis: electroacupuncture at "GV24" and "GV20" points may reduce the degradation of NGF/TrkA receptor complex by down-regulating Rab5 protein, maintain the signal of NGF, and enhance the synaptic plasticity of basal forebrain-hippocampus cholinergic neural circuit, thereby delaying the decline of learning and memory in the early stage of AD. In order to verify the hypothesis, RNA interference technology would be applied to demonstrate that electroacupuncture could improve learning and memory ability by increasing the signal of NGF; then AAV virus transfection technology and CRE/LOXP gene editing technology would be combined to overexpress Rab5 protein in basal forebrain cholinergic neurons. The results will further reveal the molecular mechanism of early electroacupuncture in ameliorating the progress of Alzheimer's disease.