基于Dectin-1/TLR4/GSK3β信号轴协同调控神经免疫和突触可塑性改善学习记忆的药理新机制

It is an urgent task to study and develop drug that for the improvement of memory and cognitive decline for Alzheimer disease (AD) patients. In our previous study, we found that Proteo-β-glucan from Maitake (PGM) which is the ligand of Dectin-1(Innate immunity receptor) could ameliorate the AlCl3-induced learning and memory impairments in C57 BL/6J mice, but the mechanism through which PGM may ameliorate the learning and memory impairments is still unknown. Our previous studies showed that treatment with PGM significantly decreased the protein level of p-Tau Ser396, while significantly increased the protein levels of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and brain derived neurotrophic factor (BDNF) in the hippocampus of the AlCl3-treated mice. However, the underlying mechanism triggered by PGM/Dectin-1 that related to the role of PGM on the AlCl3-treated mice are not well understood. In this study, we aimed to investigate the roles and mechanism of action of PGM against learning and memory impairments and the effect on regulation of Dectin-1/TLR4/GSK3β signaling pathway in APP/PS1 transgenic mouse and microglial–neuronal cocultured model. Meanwhile, the Dectin-1/TLR4/GSK3β signaling pathway-based mechanism study on the co-regulation of neuroimmune and synaptic plasticity should be confirmed. Thus, this project finding might provide further evidence and scientific basis to affirm the potential of PGM as a worthy candidate for further development into a therapeutic agent for AD and to exploit the potential value of Dectin-1 receptor.

目前仍无治疗阿尔兹海默症（AD）的有效药物，研究抗AD药物迫在眉睫。团队近年围绕抗AD靶标AMPA受体进行了系列研究，但仅在众多调控AMPA受体分子中发现免疫受体Dectin-1配体灰树花多糖PGM具有显著改善AD样小鼠学习记忆能力。前期研究揭示PGM可有效降低AD样小鼠Tau蛋白磷酸化并增强AMPA受体和BDNF分子表达，但上述信号事件如何从Dectin-1触发并发挥改善学习记忆的作用机制仍未阐明。基于此，本项目拟从Dectin-1介导的神经免疫和突触可塑性协同作用途径深入研究PGM改善学习记忆的作用机制。通过APP/PS1转基因鼠，小胶质-神经元细胞模型研究PGM对Dectin-1/TLR4/GSK3β信号轴调控作用，研究基于该信号轴协同作用神经免疫和突触可塑性的机理，明确Dectin-1介导的上述途径和抗AD之间新关系，阐明Dectin-1受体新价值，为抗AD机制和药理研究提供新思路。

目前治疗阿尔兹海默症（AD）的有效靶标和药物十分缺乏，研究抗AD药物和新靶标迫在眉睫。团队前期围绕抗AD靶标AMPA受体的活性成分进行了系列研究并发现免疫受体Dectin-1配体灰树花多糖PGM具有显著改善AD样小鼠学习记忆能力。项目结合前期研究基础，开展了PGM发挥对AD模型小鼠学习记忆的作用和潜在分子机制研究。研究结合药物造模和APP/PS1转基因AD模型小鼠模型，采用多种分子生物学，迷宫行为学等研究手段评测了PGM对AD模型小鼠学习记忆的作用和AD特征性病理标志物的作用，对Dectin-1介导的有关分子信号通路的调控和相关免疫效应的作用。研究表明，PGM可有效改善AD模型小鼠学习记忆行为学，减少AD模型小鼠脑内Aβ沉积并改善脑组织相关结构的形态学。初步机制研究表明上述作用可能与PGM调控Dectin-1受体，AMPA受体，GSK3β等信号通路以及激活小胶质细胞发挥免疫吞噬Aβ效应有关。本研究为AD的药理研究提供新发现，为AD和免疫的关系研究提供了新支撑。