经鼻给予神经生长因子通过NF-κB/BACE1信号通路治疗脑外伤相关的认知功能障碍

项目名称： 经鼻给予神经生长因子通过NF-κB/BACE1信号通路治疗脑外伤相关的认知功能障碍

项目编号： No.81500939

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 郭芮兵

作者单位： 中国人民解放军东部战区总医院

项目金额： 17.5万元

中文摘要： 创伤性颅脑外伤是青少年和青壮年的头号致死致残原因，伤后认知功能下降，痴呆患病率增高，为社会带来巨大负担。研究证实，紧随脑外伤后出现的β-淀粉样蛋白（Aβ）沉积是影响认知功能的主要原因，其中Aβ所致突触损伤是认知功能受损的主要原因之一。Aβ由BACE1（β分泌酶）切割淀粉样蛋白前体所产生，近期研究认为脑外伤后Aβ的产生主要受BACE1调控，而BACE1的启动子上有NF-κB的结合位点，.我们前期研究发现，经鼻给予神经生长因子（NGF）可以有效抑制脑外伤后Aβ的沉积，改善脑外伤后认知功能，同时抑制脑外伤后NF-κB活性。由此推测，NGF很有可能通过NF-κB信号转导通路调控BACE1活性，从而减少Aβ的产生，保护创伤性颅脑外伤后突触功能。本研究旨在探讨此调控机制存在的可能，以期找到创伤性颅脑外伤新的治疗靶点，减少痴呆的发生，减轻社会负担。

中文关键词： 认知障碍；信号通路；核因子-κB；经鼻给药；神经生长因子

英文摘要： As we all known,traumatic brain injury (TBI) is the leading cause of mortality and disability among children and young individuals. After the primary injury, the continuing cognitive disfunction constitutes a major health and socioeconomic burden, including the risk for developing of Alzheimer's disease (AD). Immediately after TBI, the level of amyloid-β (Aβ) increases remarkably in animal and human brain tissue . The over-production of Aβ is widely believed to be the cognitive disfunction after TBI.It had been investgated that declines in synaptic plasticity of β-amyloid correlated with cognitive function defects.Aβ is derived from the initial cleavage of amyloid precursor protein(APP) by the aspartyl protease BACE1. BACE1 is the main enzyme required for production of Aβ from APP. To increase NF-κB activation, NF-κB binding to the BACE1 promoter, and subsequent increase in BACE1 transcription and Aβ production...Nerve growth factor (NGF) could be delivered into brain intranasally. In our previous study ,we had found that intranasal administration of NGF significantly attenuated NF-κB expression and Aβ42 deposits, and improved cognitive functional outcome after TBI. Thus, intranasal delivery of NGF provides a potential strategy for reducing the risk of developing AD in the later life of TBI patients.But the mechanism of which had not been verified.

英文关键词： cognition dysfunction;signal pathway;nuclear factor-κB;intranasal;nerve growth factor