Acupuncture ameliorates neurodamage in STZ-induced AD rat model, accompanied by BNIP3/NIX-related mitophagy signals

Background Mitochondrial dysfunction and defective mitophagy are closely tied to the pathology of Alzheimer's disease (AD). Although acupuncture exerts neuroprotective effects in AD, whether it acts via BNIP3/NIX-mediated mitophagy remains unclear. Methods Male Sprague-Dawley rats underwent ICV streptozotocin (STZ) modeling and were evaluated after 7, 14, or 21 days of acupuncture at GV20, GV22, and bilateral GB20, with or without Mdivi-1. After acupuncture intervention, spatial learning performance was evaluated with the Morris water maze (MWM) acquisition task. The mitophagy-related mechanisms underlying the therapeutic effects were investigated via TUNEL staining, transmission electron microscopy (TEM), western blotting, and double immunofluorescence. Results In the Morris water maze test, acupuncture intervention markedly shortened the escape latency of AD rats. TUNEL staining revealed a reduction in TUNEL-positive cells in the hippocampus following acupuncture treatment. TEM demonstrated that acupuncture alleviated mitochondrial ultrastructural abnormalities in the hippocampal region. Western blotting demonstrated that acupuncture increased HIF-1α, BNIP3, and LC3 protein expression, while downregulating caspase-3. Double immunofluorescence staining revealed enhanced co-localization of LC3 and combined BNIP3/NIX lableling in the acupuncture group. Moreover, administration of Mdivi-1 exacerbated cognitive dysfunction, partially reversed the neuroprotective effects, and attenuated the upregulation of BNIP3 and LC3. Conclusion Acupuncture exerts neuroprotective effects in this AD rat model, at least in part, through activation of mitophagy-related signaling potentially involving BNIP3/NIX.