Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York, United States of America.
PLoS One. 2012;7(3):e32792. doi: 10.1371/journal.pone.0032792. Epub 2012 Mar 5.
Although evidence is accumulating that diabetes mellitus is an important risk factor for sporadic Alzheimer's disease (AD), the mechanisms by which defects in insulin signaling may lead to the acceleration of AD progression remain unclear. In this study, we applied streptozotocin (STZ) to induce experimental diabetes in AD transgenic mice (5XFAD model) and investigated how insulin deficiency affects the β-amyloidogenic processing of amyloid precursor protein (APP). Two and half months after 5XFAD mice were treated with STZ (90 mg/kg, i.p., once daily for two consecutive days), they showed significant reductions in brain insulin levels without changes in insulin receptor expression. Concentrations of cerebral amyloid-β peptides (Aβ40 and Aβ42) were significantly increased in STZ-treated 5XFAD mice as compared with vehicle-treated 5XFAD controls. Importantly, STZ-induced insulin deficiency upregulated levels of both β-site APP cleaving enzyme 1 (BACE1) and full-length APP in 5XFAD mouse brains, which was accompanied by dramatic elevations in the β-cleaved C-terminal fragment (C99). Interestingly, BACE1 mRNA levels were not affected, whereas phosphorylation of the translation initiation factor eIF2α, a mechanism proposed to mediate the post-transcriptional upregulation of BACE1, was significantly elevated in STZ-treated 5XFAD mice. Meanwhile, levels of GGA3, an adapter protein responsible for sorting BACE1 to lysosomal degradation, are indistinguishable between STZ- and vehicle-treated 5XFAD mice. Moreover, STZ treatments did not affect levels of Aβ-degrading enzymes such as neprilysin and insulin-degrading enzyme (IDE) in 5XFAD brains. Taken together, our findings provide a mechanistic foundation for a link between diabetes and AD by demonstrating that insulin deficiency may change APP processing to favor β-amyloidogenesis via the translational upregulation of BACE1 in combination with elevations in its substrate, APP.
尽管越来越多的证据表明糖尿病是散发性阿尔茨海默病（AD）的一个重要危险因素，但胰岛素信号缺陷如何导致 AD 进展加速的机制仍不清楚。在这项研究中，我们应用链脲佐菌素（STZ）诱导 AD 转基因小鼠（5XFAD 模型）发生实验性糖尿病，并研究了胰岛素缺乏如何影响淀粉样前体蛋白（APP）的β-淀粉样肽生成加工。在 STZ（90mg/kg，腹腔注射，每天一次，连续两天）处理 5XFAD 小鼠 2 个半月后，它们的大脑胰岛素水平显著降低，而胰岛素受体表达没有变化。与载体处理的 5XFAD 对照相比，STZ 处理的 5XFAD 小鼠大脑中脑淀粉样β肽（Aβ40 和 Aβ42）的浓度显著增加。重要的是，STZ 诱导的胰岛素缺乏增加了 5XFAD 小鼠大脑中 BACE1 和全长 APP 的水平，这伴随着β切割的 C 端片段（C99）的急剧升高。有趣的是，BACE1 mRNA 水平不受影响，而翻译起始因子 eIF2α 的磷酸化，一种被提出介导 BACE1 的转录后上调的机制，在 STZ 处理的 5XFAD 小鼠中显著升高。同时，GGA3 的水平，一种负责将 BACE1 分拣到溶酶体降解的衔接蛋白，在 STZ 和载体处理的 5XFAD 小鼠之间没有区别。此外，STZ 处理不会影响 5XFAD 大脑中 Aβ 降解酶如 Neprilysin 和胰岛素降解酶（IDE）的水平。总之，我们的研究结果为糖尿病和 AD 之间的联系提供了一个机制基础，表明胰岛素缺乏可能通过 BACE1 的翻译上调与增加其底物 APP 一起改变 APP 加工，从而有利于β-淀粉样肽生成。
