Mesenchymal stem-cell-derived small extracellular vesicles (MSC-EVs), as a therapeutic agent, have shown great promise in the treatment of neurological diseases. To date, the neurorestorative effects and underlying mechanism of MSC-EVs in Alzheimer’s disease (AD) are not well known. Herein, we aimed to investigate the action of MSC-EVs on the neuronal deficits in β-amyloid protein (Aβ)-stimulated hippocampal neurons, or AD cell (SHSY5Y cell lines) and animal (APPswe / PS1dE9 mice) models. In the present study, the cell and AD models received a single-dose of MSC-EVs, and were then assessed for behavioral deficits, pathological changes, intracellular calcium transients, neuronal morphology alterations, or electrophysiological variations. Additionally, the nuclear factor E2-related factor 2 (Nrf2, a key mediator of neuronal injury in AD) signaling pathway was probed by western blotting in vitro and in vivo models of AD. Our results showed that MSC-EVs therapy improved the cognitive impairments and reduced the hippocampal Aβ aggregation and neuronal loss in AD mice. Markedly, EV treatment restored the calcium oscillations, dendritic spine alterations, action potential abnormalities, or mitochondrial changes in the hippocampus of AD models. Also, we found that the Nrf2 signaling pathway participated in the actions of MSC-EVs in the cell and animal models. Together, these data indicate that MS-EVs as promising nanotherapeutics for restoration of hippocampal neuronal morphology and function in APP / PS1 mice, further highlighting the clinical values of MSC-EVs in the treatment of AD.

间充质干细胞衍生的小细胞外囊泡 (MSC-EVs) 作为一种治疗剂，在神经系统疾病的治疗中显示出巨大的前景。迄今为止，MSC-EVs 在阿尔茨海默病 (AD) 中的神经修复作用和潜在机制尚不清楚。在此，我们旨在研究 MSC-EVs 对 β-淀粉样蛋白 (Aβ) 刺激的海马神经元或 AD 细胞（SHSY5Y 细胞系）和动物（APPswe / PS1dE9 小鼠）模型中神经元缺陷的作用。在本研究中，细胞和 AD 模型接受了单剂量的 MSC-EV，然后评估了行为缺陷、病理变化、细胞内钙瞬变、神经元形态改变或电生理变化。此外，核因子 E2 相关因子 2（Nrf2、通过蛋白质印迹法在体外和体内 AD 模型中探测了 AD 中神经元损伤的关键介质）信号通路。我们的结果表明，MSC-EVs 治疗改善了 AD 小鼠的认知障碍并减少了海马 Aβ 聚集和神经元丢失。值得注意的是，EV 治疗恢复了 AD 模型海马体的钙振荡、树突棘改变、动作电位异常或线粒体变化。此外，我们发现 Nrf2 信号通路参与了 MSC-EVs 在细胞和动物模型中的作用。总之，这些数据表明 MS-EVs 是一种很有前途的纳米疗法，可用于恢复 APP / PS1 小鼠的海马神经元形态和功能，进一步突出了 MSC-EVs 在治疗 AD 中的临床价值。