Department of Radiation Oncology, University of California Irvine, Irvine, CA, 92697, USA.
Department of Medicine, University of California Irvine, Irvine, CA, 92697, USA.
Alzheimers Res Ther. 2021 Mar 6;13(1):57. doi: 10.1186/s13195-021-00791-x.
Regenerative therapies to mitigate Alzheimer's disease (AD) neuropathology have shown very limited success. In the recent era, extracellular vesicles (EVs) derived from multipotent and pluripotent stem cells have shown considerable promise for the treatment of dementia and many neurodegenerative conditions.
Using the 5xFAD accelerated transgenic mouse model of AD, we now show the regenerative potential of human neural stem cell (hNSC)-derived EVs on the neurocognitive and neuropathologic hallmarks in the AD brain. Two- or 6-month-old 5xFAD mice received single or two intra-venous (retro-orbital vein, RO) injections of hNSC-derived EVs, respectively.
RO treatment using hNSC-derived EVs restored fear extinction memory consolidation and reduced anxiety-related behaviors 4-6 weeks post-injection. EV treatment also significantly reduced dense core amyloid-beta plaque accumulation and microglial activation in both age groups. These results correlated with partial restoration of homeostatic levels of circulating pro-inflammatory cytokines in the AD mice. Importantly, EV treatment protected against synaptic loss in the AD brain that paralleled improved cognition. MiRNA analysis of the EV cargo revealed promising candidates targeting neuroinflammation and synaptic function.
Collectively, these data demonstrate the neuroprotective effects of systemic administration of stem cell-derived EVs for remediation of behavioral and molecular AD neuropathologies.
减轻阿尔茨海默病（AD）神经病理学的再生疗法取得的效果非常有限。在最近的一段时间里，源自多能和多能干细胞的细胞外囊泡（EVs）在治疗痴呆症和许多神经退行性疾病方面显示出了相当大的前景。
使用 AD 的 5xFAD 加速转基因小鼠模型，我们现在展示了源自人神经干细胞（hNSC）的 EV 对 AD 大脑中的神经认知和神经病理学特征的再生潜力。2 或 6 个月大的 5xFAD 小鼠分别接受单次或两次静脉内（眶后静脉，RO）注射 hNSC 衍生的 EV。
RO 处理使用 hNSC 衍生的 EV 恢复了恐惧性遗忘记忆的巩固，并减少了注射后 4-6 周的焦虑相关行为。EV 治疗还显著减少了两个年龄组中密集核心淀粉样β斑块的积累和小胶质细胞的激活。这些结果与 AD 小鼠中循环促炎细胞因子的稳态水平部分恢复相关。重要的是，EV 治疗可防止 AD 大脑中的突触丢失，同时改善认知。对 EV 货物的 miRNA 分析显示了针对神经炎症和突触功能的有希望的候选物。
总的来说，这些数据表明系统给予干细胞衍生的 EV 对修复 AD 神经病理学的行为和分子具有神经保护作用。
