Brain-derived neurotrophic factor modified human umbilical cord mesenchymal stem cells-derived cholinergic-like neurons improve spatial learning and memory ability in Alzheimer's disease rats
Brain-derived neurotrophic factor modified human umbilical cord mesenchymal stem cells-derived cholinergic-like neurons improve spatial learning and memory ability in Alzheimer's disease rats
复制标题
DOI：
10.1016/j.brainres.2018.12.034
复制
发表时间：
2019-05-01
期刊：
影响因子：
2.9
通讯作者：
Feng, Meijiang
中科院分区：
文献类型：
--
作者：
Hu, Weiwei;Feng, Zehua;Feng, Meijiang
阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，也是最常见的痴呆类型。虽然目前尚无法治愈，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（human umbilical cord mesenchymal stem cells，hUC-MSCs）具有多向分化潜能，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，我们在本研究中研究BDNF修饰的hUC-MSCs衍生的胆碱能样神经元对AD大鼠的治疗作用。为了制作AD模型，将1 μ l β淀粉样蛋白（A β）（1-42）注射到大鼠的右侧海马中。两周后，将hUC-MSCs衍生的胆碱能样神经元空细胞或过表达BDNF细胞缓慢注射到AD大鼠的右侧海马中。移植8周后行Morris水迷宫实验、Western blotting、免疫组化、免疫荧光及TUNEL检测。BDNF修饰的hUC-MSCs来源的胆碱能样神经元移植能显著改善AD大鼠的空间学习记忆能力，增加海马乙酰胆碱释放和ChAT表达，增强星形胶质细胞和小胶质细胞的活化，降低A β和重组人β-APP裂解酶1（BACE 1）的表达，抑制神经元凋亡，促进神经发生。我们的研究结果表明，BDNF修饰的hUC-MSCs衍生的胆碱能样神经元可能是一个有前途的治疗AD的策略。
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 mu l beta amyloid (A beta)(1-42) 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 lentiviral vectors 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 A beta and recombinant human betasite APP-cleaving enzymel (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.