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

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.

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。

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。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。此外，首次证实老年APP转基因鼠海马存在GRK5缺陷，并导致其胆碱能功能受损。 GRK5功能缺陷可增强APP转基因鼠海马过度磷酸化，其机理可能为GRK5功能缺损引起胆碱能功能障碍，导致PKC活性下降后GSK3β的活性增强相关，揭示了GRK5表达异常引起海马tau蛋白过度磷酸化及轴突转运缺陷的可能原因。有利于完善阿尔茨海默病的发病机制，为AD的早期干预提供理论依据。