项目名称: 人胚胎干细胞来源神经前体细胞移植对APP/PS1转基因鼠海马Aβ沉积与神经发生的影响及其机制
项目编号: No.81200849
项目类型: 青年科学基金项目
立项/批准年度: 2013
项目学科: 神经系统疾病、精神疾病
项目作者: 张运
作者单位: 首都医科大学
项目金额: 23万元
中文摘要: 脑内β-淀粉样蛋白(Aβ)的病理积聚是启动阿尔茨海默病症(AD)长期病理级联的关键事件。抑制Aβ沉积以促进海马神经发生成为AD防治的新热点。最新研究报道鼠骨髓间充质干细胞(MSC)移植入APP/PS1转基因AD小鼠模型海马可诱导小胶质细胞选择性激活,从而降低Aβ沉积。其局限性在于:MSC分化为神经细胞较少,具有成瘤性且可发生自身免疫损伤。人胚胎干细胞(hESC)可定向分化为神经前体细胞(NPC),分泌神经生长因子,并最终分化为成熟神经细胞,修复神经网络且成瘤性相对低,有望为干细胞治疗AD提供理想的细胞来源。本课题拟从细胞、组织及整体水平上探讨人胚胎干细胞来源神经前体细胞移植对APP/PS1转基因鼠内源性小胶质细胞活化、Aβ沉积及海马神经发生的影响。通过调控IL-4信号途径,解析内源性小胶质细胞选择性激活的细胞分子机制,为干细胞治疗AD提供新的治疗靶点。
中文关键词: 阿尔茨海默病;β-淀粉样蛋白;人胚胎干细胞;神经前体细胞;小胶质细胞活化
英文摘要: The main pathological hallmark of Alzheimer's disease(AD) is the abnormal increase and deposition of β-amyloid peptide(Aβ).Pathological deposition of Aβ results to the abnormal decrease of neurogenesis in hippocampus. Recent reserch focuses on the elevating neurogenesis by inhibiting deposition of Aβ in hippocampus. Transplanted into APP/PS1 Mice, Bone marrow-derived mesenchymal stem cells (BM-MSCs) can modulate immune/inflammatory responses in AD mice, ameliorate their pathophysiology, and improve the cognitive decline associated with Aβ deposits. But BM-MSCs can lead to oncogenesis and develop adverse effects that were probably a consequence of an autoimmune assault on the brain. In this study, We hypothesize that human Embryonic stem cell derived neuronal progenitor cells(ESC-NPC) not only survive as differentiated neural cells,but activate endogenous microglial population with an alternative phenotype that has neuroprotective effects.Thus, NPCs derived from human ESCs can be a good candidate for AD cell therapy.And a new mechanism of relieving AD by human ESC-NPC can be revealed.
英文关键词: Alzheimer's disease;β-amyloid peptide;human Embryonic stem cell;neuronal progenitor cells;microglial activate