Department of Geriatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210011, China.
School of Stomatology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Brain Res. 2019 May 1;1710:61-73. doi: 10.1016/j.brainres.2018.12.034. Epub 2018 Dec 23.
Alzheimer's disease (AD) is an age-related neurodegenerative disease and the most common type of dementia. Although it is still incurable, stem cell replacement therapy provides new hope for AD. Human umbilical cord mesenchymal stem cells (hUC-MSCs) have multiple differentiation potentials, which can differentiate into cholinergic-like neurons and promote the release of acetylcholine. Brain-derived neurotrophic factor (BDNF) can also promote neurogenesis and synaptic formation, reduce oxidative stress and cell death. Therefore, we investigated the therapeutic effects of BDNF modified hUC-MSCs-derived cholinergic-like neurons in AD rats in this study. To make AD models, 1 μl beta amyloid (Aβ) was injected into the right hippocampus of the rats. After two weeks, the hUC-MSCs-derived cholinergic-like neurons null cells or overexpressing BDNF cells delivered by lentiviralvectors were slowly injected into the right hippocampus of the AD rats. After 8 weeks of transplantation, Morris water maze test, Western blotting, Immunohistochemistry, Immunofluorescence assay and TdT mediated dUTP Nick End Labeling (TUNEL) detection were performed. Transplantation of BDNF modified hUC-MSCs-derived cholinergic-like neurons significantly improved spatial learning and memory abilities in the AD rats, increased the release of acetylcholine and ChAT expression in the hippocampus, enhanced the activation of astrocytes and microglia, reduced the expression of Aβ and recombinant human beta-site APP-cleaving enzyme1 (BACE1), inhibited neuronal apoptosis, and promoted neurogenesis. Our results demonstrate that BDNF modified hUC-MSCs-derived cholinergic-like neurons might be a promising therapeutic strategy for AD.
阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，也是最常见的痴呆症类型。尽管它仍然无法治愈，但干细胞替代疗法为 AD 提供了新的希望。人脐带间充质干细胞（hUC-MSCs）具有多种分化潜能，可分化为胆碱能样神经元，并促进乙酰胆碱的释放。脑源性神经营养因子（BDNF）还可以促进神经发生和突触形成，减少氧化应激和细胞死亡。因此，我们在这项研究中研究了 BDNF 修饰的 hUC-MSCs 衍生的胆碱能样神经元在 AD 大鼠中的治疗效果。为了制作 AD 模型，将 1 µl β淀粉样蛋白（Aβ）注入大鼠右侧海马。两周后，通过慢病毒载体将 hUC-MSCs 衍生的胆碱能样神经元空细胞或过表达 BDNF 的细胞缓慢注入 AD 大鼠的右侧海马。移植 8 周后，进行 Morris 水迷宫测试、Western blot、免疫组织化学、免疫荧光检测和末端转移酶介导的 dUTP 缺口末端标记（TUNEL）检测。BDNF 修饰的 hUC-MSCs 衍生的胆碱能样神经元移植显著改善了 AD 大鼠的空间学习和记忆能力，增加了海马中乙酰胆碱和 ChAT 的释放，增强了星形胶质细胞和小胶质细胞的激活，减少了 Aβ和重组人β位淀粉样前体蛋白裂解酶 1（BACE1）的表达，抑制了神经元凋亡，并促进了神经发生。我们的结果表明，BDNF 修饰的 hUC-MSCs 衍生的胆碱能样神经元可能是治疗 AD 的一种有前途的治疗策略。
