Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo
Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo
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DOI：
10.1073/pnas.0230450100
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发表时间：
2003-04-01
影响因子：
11.1
通讯作者：
Guénette, S
中科院分区：
文献类型：
--
作者：
Farris, W;Mansourian, S;Guénette, S
胰岛素降解酶（IDE）的两种底物淀粉样β蛋白（Abeta）和胰岛素分别在阿尔茨海默病（AD）和2型糖尿病（DM 2）的发病机制中起着至关重要的作用。我们以前确定IDE是神经元和小胶质细胞中Abeta水平的主要调节因子。在DM 2大鼠模型中，含有突变IDE等位基因的小染色体区域与高胰岛素血症和葡萄糖耐受不良相关。人类遗传学研究表明，AD和DM 2都与10号染色体的IDE区域有关。为了确定IDE功能减退是否会降低体内Abeta和胰岛素降解并长期增加其水平，我们对IDE基因纯合缺失（IDE -/-）的小鼠进行了表征。IDE缺乏导致脑膜组分和原代神经元培养物中的Abeta降解降低>50%，并且肝脏中的胰岛素降解出现类似缺陷。IDE -/-小鼠显示内源性Abeta的脑蓄积增加，这是AD的标志，并且具有高胰岛素血症和葡萄糖耐受不良，这是DM 2的标志。此外，小鼠的β-淀粉样前体蛋白的细胞内信号结构域水平升高，最近发现IDE在体外降解。结合新出现的遗传证据，我们的体内研究结果表明IDE功能减退可能是某些形式的AD和DM 2的基础或促成因素，并为最近认识到的高胰岛素血症、糖尿病和AD之间的关联提供了机制。
Two substrates of insulin-degrading enzyme (IDE), amyloid beta-protein (Abeta) and insulin, are critically important in the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2), respectively. We previously identified IDE as a principal regulator of Abeta levels in neuronal and microglial cells. A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2. Human genetic studies have implicated the IDE region of chromosome 10 in both AD and DM2. To establish whether IDE hypofunction decreases Abeta and insulin degradation in vivo and chronically increases their levels, we characterized mice with homozygous deletions of the IDE gene (IDE -/-). IDE deficiency resulted in a >50% decrease in Abeta degradation in both brain membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The IDE -/- mice showed increased cerebral accumulation of endogenous Abeta, a hallmark of AD, and had hyperinsulinemia and glucose intolerance, hallmarks of DM2. Moreover, the mice had elevated levels of the intracellular signaling domain of the beta-amyloid precursor protein, which was recently found to be degraded by IDE in vitro. Together with emerging genetic evidence, our in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD.