2型糖尿病与阿尔茨海默病互为发病风险的机制探讨

Common pathogenesis of type 2 diabetes and Alzheimer's disease:a potential mechanism

目的:比较2型糖尿病(T2DM)大鼠和Alzheimer s病(AD)大鼠模型胰腺与海马病变,通过检测糖原合成激酶-3β(GSK-3β)及蛋白酯酶2A(PP2A)变化,探讨两者之间共同的发病基础。方法:用高糖、高脂及高蛋白饮食加小剂量链脲佐菌素(STZ)尾静脉注射建立2型糖尿病模型,海马定位注射STZ建立AD大鼠模型,蛋白质印迹法及免疫组化法检测大鼠大脑和胰腺组织tau蛋白磷酸化及淀粉样β蛋白(Aβ)水平;放射性配体结合实验检测GSK-3β和PP2A活性。结果:T2DM大鼠海马组织中,tau蛋白呈过度磷酸化状态,Aβ水平增加,PP2A活性下降,GSK-3β活性上升,与AD大鼠大脑各项改变相似;在AD大鼠胰腺组织中,Aβ水平增加,PP2A活性下降,GSK-3β活性上升,与2型糖尿病大鼠胰腺组织病变程度相似。但在2组大鼠胰腺组织中均未检出tau蛋白。结论:在T2DM中,由于GSK-3β的活性增高和PP2A的活性降低,导致大脑tau蛋白过度磷酸化及Aβ沉积,是T2DM成为AD发病的重要风险因子的重要原因;在AD中,由于胰岛素抵抗导致胰腺出现Aβ的沉积可能是导致T2DM发病的重要原因。

AIM： Some epidemiologic evidences suggest an association between type 2 diabetes mellitus （T2DM） and Alzheimer disease （AD）. The present study was designed to explore the common pathogenesis in these two diseases by comparing the pathological changes in pancreas and hippocampus, the activity of glucogen synthase kinase 3[5 （ GSK -3β） and protein phosphatase 2A （PP2A） in T2DM rats with those in AD rats. METHODS： The SD rats were fed with high glucose, high fat and high protein for 8 weeks, and then injected with streptozocin （STZ） to establish the T2DM models. The model of AD was made by injection of STZ in hippocampus. The levels of hyperphosphorylated tau protein and β- amyloid protein （Aβ） in hippocampus and pancreas were analyzed by Western blotting and immunochemistry. The activities of GSK -3β and PP2A were determined by using γ-32P -ATP and the specific peptide substrate. RESULTS： In hippocampus of T2DM rats, the tau protein was hyperphosphorylated, the Aβ level was raised, the activity of PP2A was increased and the activity of GSK -3β was decreased, which were also observed in the hippocampus of AD rats. In the AD rats, the Aβ level in pancreas was found to rise, the activity of PP2A decreased and the activity of GSK -3βincreased, which were similar to the changes in pancreas of T2DM rats. However, tau protein was not detected in the pancreas of both groups. CONCLUSION： These findings suggest that there are some common pathological changes between T2DM and AD. The hyperphosohorylation of tau protein in hippocampus, the raised Aβ level in hippocampus and pancreas, as well as the corresponding activities of PP2A and GSK- 3β may contribute to the pathogenesis in the development of T2DM and AD.