Table_1_Platycodin D and voluntary running synergistically ameliorate memory deficits in 5 × FAD mice via mediating neuromodulation and neuroinflammation.DOCX

IntroductionAlzheimer’s disease (AD) is the leading cause of dementia, and currently, no effective treatments are available to reverse or halt its progression in clinical practice. Although a plethora of studies have highlighted the benefits of physical exercise in combating AD, elder individuals often have limited exercise capacity. Therefore, mild physical exercise and nutritional interventions represent potential strategies for preventing and mitigating neurodegenerative diseases. Our research, along with other studies, have demonstrated that platycodin D (PD) or its metabolite, platycodigenin, derived from the medicinal plant Platycodon grandiflorus, exerts neuroprotective effects against amyloid β (Aβ)-induced neuroinflammation. However, the combined effects of PD and physical exercise on alleviating AD have yet to be explored. The current study aimed to investigate whether combined therapy could synergistically ameliorate memory deficits and AD pathology in 5 × FAD mice.MethodsFive-month-old 5 × FAD mice were randomly assigned to four groups, and received either PD (5 mg/kg/day, p.o.), voluntary running, or a combination of both for 47 days. Nest building test, locomotion test, and Morris water maze test were used to evaluate the cognitive function. Immunohistochemical and ELISA analysis was performed to determine Aβ build-up, microglia and astrocytes hyperactivation, and survival neurons in the hippocampus and perirhinal cortex. Real-time quantitative PCR analysis was used to assess the polarization of microglia and astrocytes. HPLC analysis was performed to measure monoamine neurotransmitters in the hippocampus.Results and discussionThe combination of PD and voluntary running synergistically restored nest-building behavior, alleviated recognition and spatial memory deficits, and showed superior effects compared to monotherapy. In addition, the PD and voluntary running combination reduced Aβ build-up, decreased hyperactivation of microglia and astrocytes in the hippocampus and perirhinal cortex, promoted the polarization of inflammatory M1 microglia and reactive astrocytes toward beneficial phenotypes, and lowered systemic circulating pro-inflammatory cytokines while increasing anti-inflammatory cytokines in 5 × FAD mice. Furthermore, combined therapy effectively protected neurons and increased levels of 5-hydroxytryptamine (5-HT) and dopamine (DA) in the hippocampus of 5 × FAD mice. In conclusion, the combination of PD and voluntary running holds great potential as a treatment for AD, offering promise for delaying onset or progression of AD.

阿尔茨海默病（AD）是痴呆症的首要病因，目前临床实践中尚无有效治疗方法能够逆转或阻止其进展。尽管众多研究已证实体育锻炼在对抗AD方面的益处，老年个体往往具有有限的运动能力。因此，轻度体育锻炼和营养干预成为预防和减轻神经退行性疾病的潜在策略。本研究与其他研究一致，证实了从药用植物桔梗（Platycodon grandiflorus）中提取的桔梗苷D（PD）及其代谢产物桔梗苷，对β-淀粉样蛋白（Aβ）诱导的神经炎症具有神经保护作用。然而，PD与体育锻炼相结合对缓解AD的联合作用尚未得到充分研究。本研究旨在探究联合治疗是否能够协同改善5×FAD小鼠的记忆缺陷和AD病理。方法：将5个月大的5×FAD小鼠随机分为四组，分别给予PD（5 mg/kg/天，口服）、自愿跑步或两者的联合治疗，持续47天。通过筑巢测试、运动测试和莫里斯水迷宫测试评估认知功能。通过免疫组化和ELISA分析确定Aβ的积累、小胶质细胞和星形胶质细胞的过度激活以及海马体和颞下回皮层的存活神经元。实时定量PCR分析用于评估小胶质细胞和星形胶质细胞的极化。高效液相色谱分析用于测量海马体中的单胺神经递质。结果与讨论：PD与自愿跑步的结合协同恢复了筑巢行为，减轻了识别和空间记忆缺陷，并显示出优于单一治疗的效果。此外，PD与自愿跑步的结合减少了Aβ的积累，降低了海马体和颞下回皮层中小胶质细胞和星形胶质细胞的过度激活，促进了炎症M1小胶质细胞和反应性星形胶质细胞向有益表型的极化，并在5×FAD小鼠中降低了系统性循环的促炎细胞因子，同时增加了抗炎细胞因子。此外，联合治疗有效地保护了神经元，并增加了5-羟色胺（5-HT）和多巴胺（DA）在海马体中的水平。综上所述，PD与自愿跑步的结合在AD治疗方面具有巨大潜力，为延缓AD的发生或进展提供了希望。