p75NTR介导Aβ神经毒性的机制研究

The abberant accumulation of toxic amyloid-beta (Aβ) in the cerebral cortex and hippocampus is one of the initial pathological factors of Alzheimer's disease (AD). Aβ plays an important role in the development of AD. The binding of Aβ to neurotrophin receptor p75NTR has been proposed to mediate Aβ-induced neurotoxicity; however, its role in the development of AD remains to be clarified. In the present study, we used AD (Tg2576) mice, p75NTR gene deletion (p75NTR −/−) mice, and AD mice with deletion of p75NTR gene（Tg2576/p75NTR−/−）to investigate the role of p75NTR in mediating the neurotoxicity of amyloid-beta in astrocytes and neurons and the related mechanisms. Asctrocytes and neurons only or mixed culture as well as conditioned medium culture combined with molecular biology, immunohistochemistry and electrophysiological technology were performed in this study. These studies will shed light on the understanding the pathogenesis of AD and the development of related drugs.

β 淀粉样蛋白（Amyloid-beta, Aβ）作为阿尔茨海默病(Alzheimer's disease, AD)的源头致病因子，在AD的发生发展过程中起到了重要作用。p75神经营养因子受体(p75 neurotrophin receptor，p75NTR)作为Aβ的受体，参与介导了 Aβ引起的神经元变性死亡，但详细机制仍不清楚。本项目在过去研究的基础上应用AD模型 (Tg2576) 小鼠、p75NTR基因敲除 (p75NTR −/−)小鼠、p75NTR基因敲除AD (Tg2576/p75NTR−/−)小鼠，通过纯胶质细胞培养、纯神经元培养、胶质细胞与神经共培养、条件性介质培养结合分子生物学、免疫组化和电生理手段来确定胶质细胞与神经元的p75NTR在介导Aβ神经毒性过程的作用及在此过程中这两种细胞间的相互通讯。这些研究将为认识AD的发病机制和相关药物的研发提供重要的参考。

阿尔茨海默病(Alzheimer’s disease, AD)作为一种神经系统退行性疾病,其主要临床表现为认知障碍、记忆力衰退、言语失调等,且常常伴随有人格分裂、精神失常，最终神经系统功能遭到严重破坏，导致死亡。因此，系统深入的了解AD的发病机制有着重要的理论与临床意义。本项目应用膜片钳技术、钙成像技术结合细胞生物学与动物行为学技术就这一问题进行了系统深入的研究。项目研究发现AD模型小鼠L-型钙通道的活性明显增强，而敲除p75NTR后L-型钙通道的活性恢复正常。Aβ处理培养的海马神经元可明显的增加L-型钙通道的活性。Aβ处理海马神经后可减弱突触形成，突触传递效能并加强神经元胞内自发性钙振荡。进一步研究发现，Aβ可引起小胶质细胞中与AD相关基因表达明显增加并与神经元存在相互通讯。其中，小胶质细胞CXCR4, EGFR, MAP4K4, IGF1R基因参与了这一过程。这些研究将为认识AD 的发病机制和AD 治疗提供重要的参考。