中枢胰岛素抵抗在硫胺素代谢障碍导致AD病变中的作用及机制

Growing evidence indicates the promising role of central insulin resistance in the development of Alzheimer’s disease (AD). Yet, the mechanism underlying insulin resistance in AD brain is still elusive. Our previous work showed the lesions in a thiamine dysbolism mouse resulting from diet of thiamine deficiency (TD), including impairment of learning and memory, disruption of cerebral glucose metabolism, elevation of Aβ production and Tau pathology, in which insulin resistance in the brain was determined to play an essential role. Suppressor of cytokine signaling 3 (SOCS3) is a member of the SOCS protein family that acting as a negative regulator. Our preliminary studies showed that the expression of SOCS3 was significant elevated both TD and AD mouse. Furthermore, we also observed that insulin resistance induced by TD was attenuated by genetic interference of SOCS3, suggesting the critical role of SOCS3 in the development of insulin resistance in the central nerve system (CNS). Thus, we speculate that SOCS3 is an pivotal modulator in the generation of insulin resistance induced by thiamine dysbolism, which then initiates the development of AD. Subsequently, more research methods will be employed and more details will be investigated in our next study to determine the mechanisms of SOCS3 in thiamine dysbolism-resulted pathologies of AD, so as to present novel experimental evidence in the strategies for AD treatment.

中枢胰岛素抵抗与阿尔茨海默病（AD）关系十分密切，但调控机制未明。本项目前期已明确硫胺素代谢障碍通过介导中枢胰岛素抵抗引起小鼠学习记忆功能损伤、脑葡萄糖代谢水平降低、Aβ生成增加、Tau蛋白病理等AD病变。细胞因子信号抑制物3（SOCS3）参与细胞信号通路负反馈调节机制，我们前期发现硫胺素代谢障碍动物或AD动物脑内均有SOCS3表达上调，干扰SOCS3基因表达能抑制硫胺素代谢障碍引起的神经元胰岛素信号通路传导损害。据此我们提出科学假说，硫胺素代谢障碍通过SOCS3介导中枢胰岛素抵抗，继而引起AD病变。本项目拟通过在体小鼠及体外脑片与细胞培养等不同层面，研究硫胺素代谢障碍通过SOCS3引起中枢胰岛素抵抗的调控作用，探讨SOCS3介导硫胺素代谢障碍致AD病变的运作方式，为发展新的AD防治措施提供实验依据。

项目的背景：硫胺素代谢障碍参与阿尔茨海默病（AD）发病，但调控机制未明。细胞因子信号抑制物3（SOCS3）属于SOCS家族，是一类对细胞信号通路发挥负反馈调节的蛋白分子，能抑制和阻断信号传导途径，项目前期发现SOCS3在硫胺素代谢障碍介导中枢胰岛素抵抗形成过程中可能发挥关键作用，提示硫胺素代谢障碍通过SOCS3介导中枢胰岛素抵抗，继而引起AD病变，据此提出本项目科学假说：硫胺素代谢障碍通过上调SOCS3蛋白表达诱发中枢胰岛素抵抗，继而导致脑葡萄糖代谢异常、Aβ生成增加、Tau蛋白病理等病变，从而促使AD发生发展。.主要研究内容：利用在体小鼠及体外脑片与细胞培养等不同层面，进一步明确硫胺素代谢障碍对SOCS3及胰岛素信号通路的影响，确定SOCS3在硫胺素代谢障碍引起中枢胰岛素抵抗中的作用机制及其在AD病变中的作用。.重要结果：1、硫胺素代谢障碍介导的中枢胰岛素抵抗参与脑葡萄糖代谢损害以及Aβ、Tau蛋白等AD病理形成。2、硫胺素代谢障碍激活调控Tau蛋白异常磷酸化GSK3βpS9激酶系统。3、经鼻胰岛素改善硫胺素代谢障碍引起的小鼠学习记忆功能损害。4、中枢胰岛素抵抗在铁沉积介导Tau蛋白病理中作用关键。5、硫胺素缺乏小鼠中枢胰岛素及PI3K/Akt信号通路活性降低。6、硫胺素缺乏激活IRS-1相关炎症信号通路。7、硫胺素代谢障碍动物或AD动物脑内均有SOCS3表达上调。8、干扰SOCS3基因表达能抑制硫胺素代谢障碍引起的神经元胰岛素信号通路传导损害。.关键数据及其科学意义：脑糖代谢异常是AD早期特征，但发生机制及参与AD病变的机制未明。本项目基于前期团队发现的AD硫胺素代谢障碍，进一步研究提示SOCS3是硫胺素代谢障碍引起的中枢胰岛素抵抗的重要环节，本项目发现 SOCS3介导硫胺素代谢障碍致AD病变的运作方式，进一步阐述硫胺素代谢障碍通过介导中枢性胰岛素抵抗导致AD病变的分子机制，从而为AD防治研究提供实验依据和新思路。