经鼻吸入胰岛素对阿尔茨海默病tau病理扩散的抑制作用及其机制研究

Alzheimer’s Disease (AD) is the most common form of dementia in the eldly population. However, no treatment by far can slow down the progression of the disease. As evidence shows the correlation between the severity of dementia and the extent of tau pathology load in the brain, tau has been selected as a target for therapeutic intervention. Recent studies suggest prion-like propagation of pathologic tau in AD, in which the hyperphophorylation of tau plays a vitol role. We previously have shown that intranasal delivery of insulin, which enters the brain without affecting the peripheral blood glucose level, can effectively prevent the hyperphosphorylation of tau, leading to improved cognition of the AD transgenic mice. Therefore, we propose that preventing the propagation of tau pathology in the initial stage with the treatment of intranasal insulin could be an effective disease modifying therapy. Thus, in the present project, we plan to employ intracerebral injection of AD P-tau and recombinant tau fibrils into P301S mice to investigate the role of intranasal insulin in the propagation of tau pathology. In vitro studies using tau seeding assay will be applied to investigate the underlying mechanisms and the key phosphorylation site of tau involved in the tau propagation. The accomplishment of this project would provide a new therapeutic strategy to AD.

阿尔茨海默病（AD）是老年痴呆最常见的病因，目前无有效治疗药物可以延缓疾病进展。Tau在AD致病中起重要作用，病理性tau蛋白在脑内以朊蛋白样方式扩散。近期研究发现tau的过度磷酸化在tau病理扩散中起关键作用。申请人前期研究发现，经鼻吸入胰岛素可以有效抑制AD小鼠脑内tau的过度磷酸化，改善小鼠的认知水平。据此推测，在疾病早期通过经鼻吸入胰岛素抑制tau的过度磷酸化，可能抑制tau病理扩散，阻断AD病理进展，延缓疾病进程。本项目拟建立小鼠tau病理扩散模型，研究经鼻吸入胰岛素对tau病理扩散的抑制作用及对小鼠认知的影响。同时，还将利用tau病理扩散细胞模型，研究胰岛素对小鼠脑组织提取物tau扩散活性的影响以及胰岛素抑制tau病理扩散的相关信号通路和关键tau磷酸化位点，深入探讨胰岛素抑制tau病理扩散的机制，为AD治疗提供新策略。

阿尔茨海默病（AD）的病理性标志物包括以淀粉样蛋白-β（Aβ）为主要成分的淀粉样斑块和高度磷酸化tau为主要成分的神经原纤维缠结（NFTs）。AD脑内异常聚集的蛋白在疾病早期就以类似朊病毒的方式传播。而AD早期即存在着胰岛素信号通路异常。因此本项目通过经鼻吸入胰岛素和胰岛素增敏剂二甲双胍增强AD脑内胰岛素信号通路，探究对tau病理和Aβ病理传播的影响。我们研究发现经鼻吸入胰岛素可以通过抑制tau激酶活性，增强tau磷酸酶活性，从而减轻tau的磷酸化，抑制tau病理的传播，改善AD小鼠认知障碍。此外，我们发现Aβ斑块可促进了NP tau病理的聚集，tau种子则可加重APP/PS1小鼠脑内Aβ沉积，同时减少Aβ斑块周围的小胶质细胞数量，小胶质细胞自噬流受阻。而二甲双胍可改善小胶质细胞自噬障碍，增加了Aβ斑块周围小胶质细胞数量，促进对NP tau病理的吞噬，降低Aβ负荷和NP tau病理的传播。我们还发现二甲双胍可通过降低了mTORC1蛋白水平，升高PP2A的活性，降低了不可溶性tau的磷酸化水平，进而抑制了tau病理在PS19小鼠脑内传播，改善了小鼠的学习和记忆缺陷。这些发现提示了经鼻吸入胰岛素以及胰岛素增敏剂二甲双胍可改善AD病理的传播，为靶向脑内胰岛素信号通路异常治疗AD提供基础研究结果支持。