糖尿病对阿尔茨海默病（Alzheimer’s Disease，AD）的促进作用已经得到大量研究的证实。糖尿病脑内发生的AD样病变包括Aβ 生成增加、Tau蛋白磷酸化加剧、氧化损伤蛋白质增多甚至聚集和认知功能减退等。蛋白酶体是真核细胞内参与异常蛋白质降解最重要的结构，推测糖尿病脑内AD样病变的发生可能与蛋白酶体功能异常有关。为验证上述假设，本项目拟建立糖尿病大鼠模型，在此基础上采用多种研究手段系统检测脑内蛋白酶体的含量和功能是否发生改变；并通过在体蛋白酶体功能干预的方法进行研究蛋白酶体功能改变与AD样病变的相关性。同时，初步探讨糖尿病病理状态下可能导致蛋白酶体功能变化的分子机制。通过本项目的研究我们希望明确蛋白酶体所介导的蛋白质代谢途径在糖尿病促进AD样病变中的作用，从蛋白质代谢的角度加深对AD的发生机制的了解。

It is well verified by many studies that diabetes can accelerate Alzheimer disease pathology. Alzheimer like changes occurred in diabetic brain include increased Aβ generation, facilitated Tau protein phosphorylation, aggragation of oxidatively modified proteins and impaired cognitive function etc. The proteasome is the most important protein quality control structure in eukaryotic cells, function in degrading abnormally modified proteins. Now, we speculate that proteasome degeneration pathway may change in diabetes conditions, which plays a role in Alzheimer like changes in diabetic brain. To verify above hypothesis, we want to establish diabetic rat model and investigate possible changes about content and function of proteasome by multiple detecting methods in brain. Further, aiming to study the role of proteasome in diabetes induced Alzheimer pathological process, intervening studies will be conducted to inhibit proteasome proteolytic activity in vivo, and then detect Alzheimer like changes. Beside, candidate moleculars that may regulate proteasome function in diabetic brain were also detected. Though this study, we hope to determine the role of proteasome in diabetes induced Alzheimer like change and expand understanding of AD pathology from aspect of protein degeneration.

研究表明糖尿病是阿尔茨海默病的易感因素，糖尿病脑内发生不同程度的阿尔茨海默样病理改变，包括淀粉样蛋白Aβ通路生成激活，微管相关蛋白Tau磷酸化加剧，氧化损伤蛋白质增多和轻度认知功能减退。蛋白酶体是细胞内蛋白质代谢的主要途径之一，推测糖尿病脑内阿尔茨海默样病变的发生可能与蛋白酶体功能异常有关。为验证上述假设，本研究首先建立了能模拟人类2型糖尿病多种典型特征的大鼠模型，包括高血糖，高甘油三酯、高胆固醇，有胰岛素抵抗症状，表现为多饮多尿和体重下降。在此基础上检测发现糖尿病大鼠海马区20S蛋白酶体催化活性的亚基表达轻度改变，蛋白酶体活性有升高趋势；通过立体定位方法抑制海马区蛋白酶体功能活性，检测发现未显著影响Aβ生成途径，轻度加重磷酸化Tau蛋白聚集，显著影响氧化损伤蛋白质在海马区的聚集，提示蛋白酶体代谢途径异常主要影响脑内蛋白质氧化聚集；进一步研究发现，糖尿病脑内20S蛋白酶体功能调节相关蛋白PSME1、PSME2和ECM29发生表达改变，提示上述调节因子的表达变化可能是糖尿病病理状态下导致蛋白酶体功能变化的分子机制。