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

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.

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。

创伤性颅脑外伤（TBI）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）沉积是影响脑外伤后认知功能的主要原因，其中Aβ所致突触损伤和神经元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（APP）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，NF-κB的活性影响BACE1的表达。我们的前期研究中发现，经鼻给予神经生长因子（NGF） 可以有效抑制脑外伤后脑组织中Aβ的沉积，改善脑外伤后的认知功能障碍和运动功能障碍，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。. 本研究旨在观察经鼻给予 NGF 后对脑外伤大鼠神经功能的保护作用是否与 NF-κB /BACE1信号通路密切相关，及其对该通路相关产物表达的影响。同时观察脑外伤前预先给予NGF有无对神经元的预保护作用，以期最终为指导临床医生，选择适宜时机利用经鼻给予 NGF 治疗脑外伤提供理论依据，从而最大限度为脑外伤患者神经功能改善提供有效地治疗手段，尽可能减少脑外伤后遗症的发生。经过动物在体实验与细胞离体实验不同层面的研究，我们发现经鼻给予 NGF可以减轻脑外伤后脑神经元的损伤，减少伤后BACE1、NF-κB、APP、 Aβ以及炎症因子TNF-α、IL-6的表达。在NGF干预的环境下，抑制BACE1活性时，Aβ表达明显减少；抑制NF-κB活性 时，BACE1和Aβ表达明显减少；提示NF-κB /BACE1信号通路与NGF的这种保护作用密切相关。同时研究发现，在脑外伤发生前预先给予NGF可以更好的保护神经功能，抑制脑外伤后炎症反应。同时经鼻给药这种方式的给药操作非常便捷，可在救援人员到达的第一时间就地给药，不容易受时间和环境的限制。故而本研究成果容易转化并具有很强的临床应用前景。