Dysregulation of insulin signaling pathway with reduced downstream neuronal survival and plasticity mechanisms is a fundamental abnormality observed in Alzheimer's disease (AD) brain. This phenomenon, known as brain insulin resistance, is associated with poor cognitive performance and is driven by the uncoupling of insulin receptor (IR) from its direct substrate (IRS1). Considering that Down syndrome (DS) and AD neuropathology share many common features, we investigated metabolic aspects of neurodegeneration, i.e., brain insulin resistance, in DS and whether it would contribute to early onset AD in DS population. Changes of levels and activation of main brain proteins belonging to the insulin signaling pathway (i.e., IR, IRS1, PTEN, GSK3β, PKCζ, AS160, GLUT4) were evaluated. Furthermore, we analyzed whether changes of these proteins were associated with alterations of: (i) proteins regulating brain energy metabolism; (ii) APP cleavage; and (ii) regulation of synaptic plasticity mechanisms in post-mortem brain samples collected from people with DS before and after the development of AD pathology (DSAD) compared with their age-matched controls. We found that DS cases were characterized by key markers of brain insulin resistance (reduced IR and increased IRS1 inhibition) early in life. Furthermore, downstream from IRS1, an overall uncoupling among the proteins of insulin signaling was observed. Dysregulated brain insulin signaling was associated with reduced hexokinase II (HKII) levels and proteins associated with mitochondrial complexes levels as well as with reduced levels of syntaxin in DS cases. Tellingly, these alterations precede the development of AD neuropathology and clinical presentations in DS. We propose that markers of brain insulin resistance rise earlier with age in DS compared with the general population and may contribute to the cognitive impairment associated with the early development of AD in DS.

中文翻译：

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脑胰岛素抵抗会触发唐氏综合症中的早发性阿尔茨海默氏病。

具有降低的下游神经元存活和可塑性机制的胰岛素信号通路失调是在阿尔茨海默氏病（AD）脑中观察到的基本异常。这种现象称为脑胰岛素抵抗，与较差的认知表现有关，并且是由胰岛素受体（IR）从其直接底物（IRS1）解偶联驱动的。考虑到唐氏综合症（DS）和AD神经病理学具有许多共同特征，我们研究了DS中神经变性的代谢方面，即脑胰岛素抵抗，以及它是否会导致DS人群早期AD。评估了属于胰岛素信号通路的主要脑蛋白（即IR，IRS1，PTEN，GSK3β，PKCζ，AS160，GLUT4）的水平和激活水平的变化。此外，我们分析了这些蛋白质的变化是否与以下方面的变化有关：（i）调节大脑能量代谢的蛋白质；（ii）APP切割；（ii）与年龄匹配的对照组相比，在AD病理学发展之前和之后从DS人群中收集的死后脑样本中突触可塑性机制的调控。我们发现DS病例的特征在于生命早期大脑胰岛素抵抗（IR降低和IRS1抑制增加）的关键标志物。此外，在IRS1的下游，观察到胰岛素信号转导蛋白之间的整体解偶联。在DS病例中，脑胰岛素信号失调与己糖激酶II（HKII）水平降低以及与线粒体复合物水平相关的蛋白质以及语法素水平降低相关。显然，这些改变先于AD神经病理学的发展和DS中的临床表现。我们建议与一般人群相比，DS中脑胰岛素抵抗的标志物随着年龄的增长而上升，并且可能与DS中AD的早期发展有关。