胰岛素改善阿尔茨海默病相关病变的分子机制研究

A connection has been established between Alzheimer’s disease (AD) and type 2 diabetes, since insulin resistance, a hallmark of type 2 diabetes, also develops in Alzheimer brains. Recently, studies have shown that intranasal insulin treatment improves memory in healthy participants, as well as in patients with mild cognitive impairment and Alzheimer’s disease. However, the mechanisms underlying improved memory with insulin treatment remain unclear. We recently found that intranasal administration of insulin ameliorates defective brain insulin signaling, improves cognitive deficits, reduces amyloid β-protein plaque depositin and prevents anesthesia-induced hyperphosphorylation of tau in AD transgenic mice. Based on our previous findings, in this project we are going to further study how insulin regulates the generation, degradation, and removal of amyloid β-protein and how insulin regulates the proteins participate in tau hyperphosphorylation, with the use of different animal and cell models. Besides, we will also explore the effect of insulin on other pathological changes related to AD and screen the major intracellular pathway involved in the protective functions downstream of insulin receptor. Our project may provide new understanding to the pathogenesis of AD and offer preclinical evidence that intranasal insulin is potentially an effective therapeutic method for the prevention and treatment of AD.

阿尔茨海默病（AD）与2型糖尿病的关系密切，胰岛素信号通路的异常被认为是这两种疾病的共同特征。近年来研究发现，经鼻吸入胰岛素不仅可以改善健康受试者的记忆功能，对轻度认知功能障碍和AD患者也有改善认知的作用，然而其确切的机制不明。我们前期研究发现，AD转基因小鼠脑内存在胰岛素信号通路蛋白的表达异常，经鼻吸入胰岛素可以增强胰岛素信号通路，并改善AD小鼠的记忆障碍。进一步研究发现，胰岛素减轻AD小鼠脑内的Aβ淀粉样斑块沉积和经麻醉诱导的Tau蛋白过度磷酸化，但具体机制仍有待研究。本课题根据前期研究基础，拟采用转基因小鼠模型和侧脑室内注射链脲佐菌素大鼠模型，以及细胞模型研究胰岛素调节Aβ的产生、降解与清除，减轻Tau蛋白过度磷酸化的具体机制；以及胰岛素对AD相关的其他病变的作用，并筛选出胰岛素作用的关键下游信号通路，从而为深入探索AD的发病机制打下基础，为胰岛素在临床治疗AD提供理论依据。

阿尔茨海默病（AD）与2型糖尿病的关系密切，胰岛素信号通路的异常被认为是这两种疾病的共同特征。本课题旨在深入研究经鼻吸入胰岛素对阿尔茨海默病主要病理变化以及脑内其他相关病变的作用及机制。通过本课题的研究,有以下主要结果：1，进一步明确了经鼻吸入胰岛素对阿尔茨海默病有疾病改善作用 2，经鼻吸入胰岛素可以通过调节Tau蛋白的磷酸酶和激酶的活性来改善AD主要病理变化之一Tau蛋白过度磷酸化。3，同时胰岛素的吸入也参与调节AD脑内的炎症反应，减轻模型大鼠海马神经元的丢失。这些研究结果为经鼻吸入胰岛素作为潜在的预防和治疗AD的选择增添了新的理论依据。