Mechanisms underlying insulin deficiency-induced acceleration of β-amyloidosis in a mouse model of Alzheimer's disease.
Mechanisms underlying insulin deficiency-induced acceleration of β-amyloidosis in a mouse model of Alzheimer's disease.
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DOI：
10.1371/journal.pone.0032792
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ohno M
中科院分区：
文献类型：
--
作者：
Devi L;Alldred MJ;Ginsberg SD;Ohno M
虽然越来越多的证据表明糖尿病是散发性阿尔茨海默病(AD)的重要危险因素，但胰岛素信号转导缺陷导致AD进展加速的机制尚不清楚。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)实验性糖尿病，并研究胰岛素缺乏对淀粉样前体蛋白(APP)的β-淀粉样蛋白生成过程的影响。给5XFAD小鼠灌胃STZ(90 mg/kg，每天一次，连续两天)两个半月后，它们的脑胰岛素水平显著降低，但胰岛素受体表达没有变化。注射链脲佐菌素的5XFAD小鼠脑内淀粉样蛋白β多肽(Aβ40和Aβ42)的浓度显著高于赋形剂对照组。重要的是，链脲佐菌素诱导的胰岛素缺乏上调了5XFAD小鼠脑中β位点APP裂解酶1(BACE1)和全长APP的水平，同时伴随着β裂解的C末端片段(C99)的显著升高。有趣的是，BACE1mRNA水平没有受到影响，而翻译起始因子eIF2α的磷酸化，一种被认为介导BACE1转录后上调的机制，在STZ处理的5XFAD小鼠中显著增加。同时，GGA3的水平，一种负责将BACE1分类为溶酶体降解的适配器蛋白，在STZ治疗的5XFAD小鼠和赋形剂治疗的5XFAD小鼠之间是无法区分的。此外，STZ处理不影响5XFAD大脑中Aβ降解酶的水平，如Neprilysin和胰岛素降解酶。综上所述，我们的发现为糖尿病和AD之间的联系提供了机制基础，证明了胰岛素缺乏可能通过BACE1的翻译上调及其底物APP的升高而改变APP的处理，有利于β-淀粉样蛋白的发生。
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.
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影响因子：
4.8
作者：
Kang, Eugene L.;Cameron, Andrew N.;Tesco, Giuseppina
通讯作者：
Tesco, Giuseppina
影响因子：
4.2
作者：
Cotel, Marie-Caroline;Jawhar, Sadim;Wirths, Oliver
通讯作者：
Wirths, Oliver
影响因子：
9.9
作者：
Beeri, M. S.;Schmeidler, J.;Haroutunian, V.
通讯作者：
Haroutunian, V.
影响因子：
5.3
作者：
Jolivalt, Corinne G.;Hurford, Rosemarie;Lee, Corinne A.;Dumaop, Wilmar;Rockenstein, Edward;Masliah, Eliezer
通讯作者：
Masliah, Eliezer
DOI：
10.1111/j.1460-9568.2009.07031.x
发表时间：
2010-01
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Devi L;Ohno M
通讯作者：
Ohno M