胰岛素抵抗大鼠脑组织APP代谢及其相关酶的表达及吡格列酮的干预效果

目的观察胰岛素抵抗（IR）大鼠脑组织β 淀粉样蛋白（Aβ）、淀粉样前体蛋白（APP）及其代谢相关酶的表达及吡格列酮(PIO)的干预效果。方法从45只Wistar大鼠中随机选取10只作为对照组（NC组），35只给予10%果糖水诱发胰岛素抵抗，4周后根据胰岛素抵抗指数（IRI），将制作成功的胰岛素抵抗模型26只大鼠随机分为IR组、PIO组。PIO组灌服吡格列酮（10?mg·kg-1·d-1）12周，IR组和NC组给予相同体积的生理盐水。免疫组化法观察大鼠海马Aβ42的表达；免疫印迹法检测大鼠脑APP、β 分泌酶( BACE1)、γ 分泌酶（PS1）的变化。结果IR组和PIO组大鼠海马Aβ42的表达明显高于NC组，与IR组相比，PIO组表达明显减低（P<0.01）；与NC组相比，IR组和PIO组大鼠脑组织APP、BACE1及PS1的表达增高，PIO组表达较IR组减少(P<0.05)。 结论胰岛素抵抗大鼠脑组织通过上调BACE1、PS1活性，使Aβ42生成增加；吡格列酮能抑制BACE1、PS1的表达，减少Aβ42生成。

Metabolism ofβ amyloid precursor protein,expressions of its related enzymes and effect of pioglitazone intervention in the brain of insulin resistance rats

Objective To investigate the expressions of β-amyloid (Aβ), amyloid precmsor protein (APP) and its metabohsm-related enzymes, and to explore the effect of pioglitazone (PIO) intervention in the brain of insulin resistance rats. Methods Of 45 Wistar male rats, 10 were randomly chosen as the control group (NC group), and the others were given 10% fructose for 4 weeks to develop the insulin resistance (IR) model. 26 IR rats were randomly divided into the IR group(n = 13) and the PIO group (n= 13). The PIO group was given pioglitazone(10 mg·kg~(-1)·d~(-1) by gavage for 12 weeks, and the IR and NC groups were given an identical volume of physiological saline. Immunohistochemistry and Western blotting were employed to examine the level of Aβ42 in the hippoeampus and the changes of APP, β-secretase (BACE1) and γ-secretase (PSI) in the brain tissue, Re-suits Immunohistoehemistry results indicated that the optical density of Aβ42 in the hippocampus of the IR and PIO groups was significantly higher than that of the NC group, and was lower in the PIO grpup than that of the IR group(P<0.01). Western blotting showed that APP, BACE1 and PS1 levels in the rat brain were elevated in the IR and PIO groups compared with that in the normal controls, and the concentration in the PIO group was lower than that of the IR group (P<0.05). Conclusion Insu-lin resistance promotes Aβ42 by up-regulating the activities of BACE1, PS1 and pioglitazone inhibits the activities of BACE1 and PS1 to deerease the expression of Aβ42.