TNF在AD早期胆碱能神经元损伤机制的研究

The hallmark in the early stage of Alzheimer's disease is the basal forebrain cholinergic neuron deficits and its-induced behavioral and cognitive dysfunctions. However, the mechanism of cholinergic neuron damages in the early stage of AD still maintains unclear. A number of studies have reported that tumor necrosis factor alpha (TNF) plays a predominant role not only in the initiation of immunity and inflammation but also in neurodegenerative disorders: elevated expression of TNF aggravates neurodegeneration. Our previous studies in vivo and in vitro have shown that TNF/TNFR1 signalling pathway can induce neuron death while TNF/TNFR2 signalling pathway can be neuroprotective. We hypothesized that TNF-mediated cholinergic neuron damages in the early stage of AD could be due to TNFR1 overactivation. Therefore, we propose a research project in AD mouse models (APP1/PS1 transgenic mice & j20 transgenic mice ) in which present the early AD symptoms: 1) to analyze the TNF role in NBM cholinergic neuron deficits and behavioral dysfunctions via selectively targeting two distinct TNF receptors; 2) to anatomy AD-related NBM cholinergic neural circuits and the possible role of TNF in the neural circuits via using TRIO methods; 3) whether manipulating TNF signalling pathways dependent on its two distinct receptors via TNFR targets could alter the deficits of cholinergic neurons, neural circuits and behavioral functions towards to amelioration. This could provide a potential therapeutic approach against AD.

AD早期的标志病症是基底前脑胆碱能神经元损伤及其导致的认知功能障碍，然而其损伤机制仍不清楚。研究已证实肿瘤坏死因子（TNF）会导致神经元死亡。那么，TNF是否会介导AD早期胆碱能神经元损伤？我们在细胞和NBM急性损伤鼠模型中已证实TNF受体一（TNFR1）活化导致神经元死亡而TNFR2活化却保护神经元免于损伤。进一步在AD鼠模型中发现抑制TNFR1活化改善了胆碱能神经元损伤。据此我们提出TNF介导AD胆碱能神经元损伤是与其两个不同受体的活化有关。本项目拟利用AD转基因小鼠：1）针对TNF两个不同受体选择性干预研究TNF对AD早期胆碱能神经元损伤及其诱导的功能障碍的作用；2）解析基底前脑胆碱能神经环路在AD发生中的结构及功能改变并研究TNF在其中的可能性作用；3）探讨利用药物调控TNF两受体活性对胆碱能神经元分子/细胞、环路及功能水平损伤的潜在治疗作用，为AD的可能治疗策略提供科学依据。

阿尔茨海默病(Alzheimer’s disease，AD)是一种进行性的中枢神经系统退行性疾病，其临床主要表现为记忆力的下降及其认知功能的减退。AD早期的主要病理标志是基底核的胆碱能神经元的丢失及其所释放的乙酰胆碱显著减少。我们前期研究发现，肿瘤坏死因子TNF在神经退行性疾病中扮演者重要的角色：TNF/TNFR1加剧神经退行性而TNF/TNFR2介导神经保护作用。那么，TNF的信号在AD早期的作用及机制并不清楚。本项目利用APP/PS1转基因AD小鼠，发现TNFR1受体的抑制剂可以显著改善包括细胞水平和功能水平的AD早期的症状；而TNFR2激动剂亦可显著改善包括细胞水平和功能水平的AD早期的症状。进一步实验证实TNFR1通过MAPK信号通路调控炎症因子的释放而改善AD症状。本研究为AD的治疗提供了新的潜在作用靶点。为相应药物治疗AD的临床进一步应用提供了实验依据。本课题目前已顺利完成。已发表2篇sci论文，还有一篇正在返修，并申请一项专利。