Abstract

The incidence of Alzheimer’s disease (AD) increases significantly following chronic stress and brain ischemia which, over the years, cause accumulation of toxic amyloid species and brain damage. The effects of global 15-min ischemia and 120-min reperfusion on the levels of expression of the amyloid precursor protein (APP) and its processing were investigated in the brain cortex (Cx) of male Wistar rats. Additionally, the levels of expression of the amyloid-degrading enzymes neprilysin (NEP), endothelin-converting enzyme-1 (ECE-1), and insulin-degrading enzyme (IDE), as well as of some markers of oxidative damage were assessed. It was shown that the APP mRNA and protein levels in the rat Cx were significantly increased after the ischemic insult. Protein levels of the soluble APP fragments, especially of sAPPβ produced by β-secretase, (BACE-1) and the levels of BACE-1 mRNA and protein expression itself were also increased after ischemia. The protein levels of APP and BACE-1 in the Cx returned to the control values after 120-min reperfusion. The levels of NEP and ECE-1 mRNA also decreased after ischemia, which correlated with the decreased protein levels of these enzymes. However, we have not observed any changes in the protein levels of insulin-degrading enzyme. Contents of the markers of oxidative damage (di-tyrosine and lysine conjugates with lipid peroxidation products) were also increased after ischemia. The obtained data suggest that ischemia shifts APP processing towards the amyloidogenic β-secretase pathway and accumulation of the neurotoxic Aβ peptide as well as triggers oxidative stress in the cells. These results are discussed in the context of the role of stress and ischemia in initiation and progression of AD.

中文翻译：

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全脑缺血对大鼠皮层淀粉样蛋白前体蛋白代谢和淀粉样蛋白降解酶表达的影响：在阿尔茨海默病发病机制中的作用

摘要

阿尔茨海默病 (AD) 的发病率在慢性压力和脑缺血后显着增加，多年来，这会导致有毒淀粉样蛋白物质的积累和脑损伤。在雄性 Wistar 大鼠的大脑皮层 (Cx) 中研究了全局 15 分钟缺血和 120 分钟再灌注对淀粉样前体蛋白 (APP) 表达水平及其加工的影响。此外，还评估了淀粉样蛋白降解酶脑啡肽酶 (NEP)、内皮素转化酶-1 (ECE-1) 和胰岛素降解酶 (IDE) 以及一些氧化损伤标志物的表达水平。结果表明，缺血性损伤后大鼠Cx中APP mRNA和蛋白质水平显着增加。可溶性 APP 片段的蛋白质水平，尤其是由 β-分泌酶产生的 sAPPβ，(BACE-1) 以及 BACE-1 mRNA 和蛋白质表达本身的水平也在缺血后增加。再灌注 120 分钟后，Cx 中 APP 和 BACE-1 的蛋白质水平恢复到对照值。缺血后 NEP 和 ECE-1 mRNA 的水平也降低，这与这些酶的蛋白质水平降低有关。然而，我们没有观察到胰岛素降解酶的蛋白质水平有任何变化。缺血后氧化损伤标志物（二酪氨酸和赖氨酸结合物与脂质过氧化产物）的含量也增加。获得的数据表明，缺血将 APP 加工转向淀粉样蛋白生成 β-分泌酶途径和神经毒性 Aβ 肽的积累，并引发细胞中的氧化应激。