卡介苗对Aβ所致的海马突触功能损伤的保护作用及机制的研究

Alzheimer's disease (AD) is a neurodegenerative disease and its immune therapy is the important aspect of clinical treatment. Bacillus Calmette Guerin, as an immune regulator, has been applied to Parkinson syndrome and other diseases of the nervous system. The latest research has shown that BCG can improve cognitive deficits in AD transgenic mice and reduce neuroinflammatory responses, however, it is unclear about the underlying mechanism. Our previous research found BCG can enhance hippocampal synaptic plasticity in rats,however,Whether BCG can improve synaptic function in AD model mice has not been reported. The results of pre-experimentshowed that amyloid beta 1-42 inhibited the hippocampal LTP; moreover, this inhibition was protected against by BCG. In addition to this, BCG increased the expression of IFN-γ, P-JAK2 and P-STAT3. Accordingly, We propose the hypotheses that BCG play a protective role through IFN-γ/JAK/STAT signaling pathway in AD mice. On the basis of the above research, this project intends to research the protective effects of BCG against amyloid beta-induced synaptic deficits and damages in the aspects of LTP, dendritic spine morphology changes and related receptor currents change, and investigate the possible mechanism in the level of JAK/STAT signaling pathway, which will provide new way for the immunotherapy of AD.

免疫治疗是临床治疗阿尔茨海默症（AD）的重要方式。卡介苗作为一种免疫调节剂，已被应用到帕金森综合征等神经系统疾病的治疗当中。最新研究报道卡介苗可改善AD转基因小鼠的认知缺陷并减轻神经炎症反应，但具体机制尚不清楚。申请者已发表文章报道，新生期注射卡介苗可以增强大鼠海马突触的可塑性，然而卡介苗是否可以改善AD模型鼠的突触功能还未见报道。申请者预实验结果显示卡介苗可以显著改善Aβ所致的海马突触功能的损伤；卡介苗增加了IFN-γ、P-JAK2和P-STAT3的表达，据此，我们提出假说，卡介苗通过IFN-γ/JAK/STAT信号通路改善AD模型鼠的突触可塑性。在上述研究的基础上，本申请项目拟从LTP、树突棘形态的变化、相关受体通道电流的改变三个方面研究卡介苗对Aβ所致的海马突触功能损伤的保护作用，并在IFN-γ/JAK/STAT信号通路水平探讨其可能的机制，为AD的免疫治疗提供新的思路。

免疫治疗是临床治疗阿尔茨海默症（AD）的重要方式。卡介苗作为一种免疫调节剂，已被应用到帕金森综合征等神经系统疾病的治疗当中。最新研究报道卡介苗可改善AD转基因小鼠的认知缺陷并减轻神经炎症反应，但具体机制尚不清楚。申请者已发表文章报道，新生期注射卡介苗可以增强大鼠海马突触的可塑性，然而卡介苗是否可以改善AD模型鼠的突触功能还未见报道。本课题研究发现卡介苗可以显著改善AD小鼠的海马突触功能的损伤，具体表现在卡介苗增强了AD小鼠海马LTP的诱导，增加了树突的复杂性，树突棘的密度和表面积均显著增加，此外，申请者发现卡介苗增加了IFN-γ、P-JAK2和P-STAT3的表达，而干扰掉IFN-γ后，卡介苗对AD的突触保护作用显著减弱。据此，我们得出结论，卡介苗通过IFN-γ/JAK/STAT信号通路改善AD小鼠的突触可塑性，我们的研究为AD的免疫治疗提供了新的思路。