突变型神经生长因子NGFR100W治疗阿尔茨海默病作用及相关机制的研究

One of the main hallmarks of AD pathology is early and severe degeneration of BFCN neurons. NGF exerts potent trophic support for BFCNs in the central nervous system. NGF deficiency can thus be directly linked to cognitive defects in AD. An attractive therapeutic strategy to prevent or slow down cognitive decline in AD would be to restore NGF to provide long-lasting cholinergic trophic support. The severe pain in animals and humans caused by NGF infusion is a major obstacle for NGF-based therapy. The discovery of a “painless” human mutant NGF（NGFR100W）offers great hope to circumvent the pain-causing issue associated with the NGF-based approach，however the biological characteristics of NGFR100W remains unclear. This project will focus on the study of biological characteristics of NGFR100W，to identify whether or not NGFR100W retains TrkA-dependent trophic support as well as the pain side-effect of wild type NGF. Furthermore we want to show in AD mouse models that administration of NGFR100Wmay rescues degeneration of BFCNs and enhances their cognition. Our project would offer a novel effective treatment strategy for AD.

AD主要表现为基底前脑（BFCNs）胆碱能神经元的变性死亡，NGF在中枢神经系统中能维持BFCNs的生存和正常生理功能，因此其临床应用被认为可帮助阻断BFCNs的变性死亡、减缓AD的临床进展，但NGF导致疼痛的副作用极大限制了NGF的临床治疗，阻碍了NGF用于AD的临床治疗。“无痛性”人神经生长因子NGFR100W的发现为NGF的临床应用带来了极大的希望,但其生物学特性尚不明了。本项目将重点研究无痛性NGF突变体—NGFR100W的生物学特性，观察NGFR100W是否能保持野生型NGF的神经营养作用且避免野生型NGF治疗所导致的疼痛，并进一步通过组织及动物行为学观察NGFR100W治疗是否能有效阻断AD动物模型中BFCNs的变性死亡、改善AD动物的病理损伤及认知功能。课题的开展将对NGFR100W作为一种安全有效AD治疗药物的可行性提供实验及理论依据。

AD主要表现为基底前脑胆碱能神经元的变性死亡，NGF在中枢神经系统中能维持神经元的生存和正常生理功能，被认为可以减缓AD的进展，但是，NGF所导致的疼痛副作用的出现大大限制了NGF 的临床应用。我们的研究发现突变体NGFR100W能够有效维持神经元的生长并促使其分化，突变体NGFR100W通过与TrkA受体结合，通过内吞作用入胞，并进一步激活TrkA受体及其下游大部分信号通路，而不能与p75NTR受体结合，不能激活p75NTR信号通路以及削弱TrkA 下游与致痛功能密切相关的PLC 激活，从而影响NGFR100W致痛功能。我们进一步在动物实验中发现，突变体NGFR100W Knock-in小鼠会产生严重的痛觉障碍，其脑内海马结构及基底前脑未见明显结构异常，NGFR100W Knock-in小鼠认知功能与野生小鼠认知功能无明显差异。我们研究的结果提示突变体NGFR100W能选择性丢失介导痛觉的功能，而保留其外周及中枢神经系统的营养功能，这一结果的发现不仅为研究NGF 神经营养和介导痛觉的功能提供了重要工具，也可能为NGF 临床应用寻求新的治疗突破点特别是阿尔茨海默病和周围神经损伤的治疗中提供新的思路和方法。