Rab5a-GTP Impairs NGF Transduction and Synaptic Plasticity of the Basal Forebrain Hippocampal Circuit in AD and Electroacupuncture

Nerve growth factor (NGF) loss is a potential factor for the degeneration of basal forebrain cholinergic neurons (BFCNs) in Alzheimer’s disease (AD), and Rab5a is a key regulatory molecule of NGF signaling transduction. However, the underlying mechanism of how Rab5a affects NGF and BFCNs in AD remains unclear. We found that Rab5a and Rin3, a guanine nucleotide exchange factor of Rab5 were hyperactivated, and rab5a-GTP increased significantly in the hippocampus of 5-month-old 5×FAD mice. Notably, electroacupuncture (EA) treatment reduced the levels of Rin3 and Rab5a in the hippocampus in the early stage of 5×FAD mice. Using CRE/LOXP gene editing to overexpress Rab5a and knockout NGF in the basal forebrain hippocampal circuit, we confirmed that EA improved learning memory by reducing Rab5a and increasing NGF. Moreover, EA suppress Rab5a-GTP to increase NGF transduction by promoting the phosphorylation of TrkA, AKT, and ERK, and increasing cholinergic-related proteins, ChAT, m1AchR, and m2AchR in the basal forebrain and hippocampus in the early stage of 5×FAD mice. These suggest that Rab5a hyperactivation is an early pathological manifestation, and EA could suppress Rab5a-GTP to promote the transduction of NGF signaling improving synaptic plasticity of the basal forebrain hippocampal circuit in the early stage of 5×FAD mice.Funding: This study was supported by grants from the National Natural Science Foundation of China (ref. 82104966) and the Natural Science Foundation of Fujian Province (ref.2021J01131553).Declaration of Interests: The authors declare that they have no conflicts of interest.Ethics Approval: The animal experimental study was carried out in compliance with the ethical regulations approved by the Animal Ethics Committee of Fujian University of Traditional Chinese Medicine (Fuzhou, Fujian province, China).