Oxidative stress is increasingly recognized as a major contributor to the pathophysiology of Alzheimer’s disease (AD), particularly in the early stages of the disease. The multiplicity advantages of stem cell transplantation make it fascinating therapeutic strategy for many neurodegenerative diseases. We herein demonstrated that human dental pulp stem cells (hDPSCs) mediated oxidative stress improvement and neuroreparative effects in in vitro AD models, playing critical roles in regulating the polarization of hyperreactive microglia cells and the recovery of damaged neurons. Importantly, these therapeutic effects were reflected in 10-month-old 3xTg-AD mice after a single transplantation of hDPSCs, with the treated mice showing significant improvement in cognitive function and neuropathological features. Mechanistically, antioxidant and neuroprotective effects, as well as cognitive enhancements elicited by hDPSCs, were at least partially mediated by Nrf2 nuclear accumulation and downstream antioxidant enzymes expression through the activation of the AKT-GSK3β-Nrf2 signaling pathway. In conclusion, our findings corroborated the neuroprotective capacity of hDPSCs to reshape the neuropathological microenvironment in both in vitro and in vivo AD models, which may be a tremendous potential therapeutic candidate for Alzheimer’s disease.

氧化应激越来越被认为是阿尔茨海默病 (AD) 病理生理学的一个主要因素，特别是在该病的早期阶段。干细胞移植的多重优势使其成为许多神经退行性疾病的令人着迷的治疗策略。我们在此证明，人牙髓干细胞（hDPSC）在体外 AD 模型中介导氧化应激改善和神经修复作用，在调节高反应性小胶质细胞的极化和受损神经元的恢复中发挥关键作用。重要的是，这些治疗效果在单次 hDPSC 移植后的 10 个月大的 3xTg-AD 小鼠中得到了体现，治疗后的小鼠在认知功能和神经病理学特征方面表现出显着改善。从机制上讲，hDPSC 引起的抗氧化和神经保护作用以及认知增强至少部分是由 Nrf2 核积累和下游抗氧化酶表达（通过激活 AKT-GSK3β-Nrf2 信号通路）介导的。总之，我们的研究结果证实了 hDPSC 在体外和体内 AD 模型中重塑神经病理微环境的神经保护能力，这可能是阿尔茨海默病的巨大潜在治疗候选者。