Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer's Disease.
Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer's Disease.
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DOI：
10.3389/fnagi.2017.00118
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发表时间：
2017
影响因子：
4.8
通讯作者：
Kapogiannis D
中科院分区：
文献类型：
--
作者：
Mullins RJ;Diehl TC;Chia CW;Kapogiannis D
目前关于阿尔茨海默病（AD）发病机制的假说和理论认为脑胰岛素抵抗（IR）是一个重要因素。尽管系统性IR有许多经过充分验证的指标，但脑特异性IR的生物标志物的缺乏代表了一个翻译空白，阻碍了其在活体人类中的研究。在我们的实验室中，我们一直致力于开发反映脑IR和AD共同机制的生物标志物，这些生物标志物可用于通过实验治疗来跟踪它们的参与。我们提出了两个有前途的生物标志物脑IR在AD：胰岛素级联介质探测细胞外囊泡（EV）丰富的神经元起源，和二维磁共振波谱（MRS）脑葡萄糖的措施。作为脑IR和AD之间的基本联系的进一步证据，我们提供了一种新的分析，证明了与IR有关的基因的脑表达（使用艾伦人脑图谱数据）与tau和β-淀粉样蛋白病理之间的密切空间相关性。我们继续提出大胆的假设，即代谢依赖糖酵解的基线差异以及葡萄糖转运蛋白（GLUT）和胰岛素信号传导基因的表达决定了不同脑区对Tau和/或淀粉样蛋白β（Aβ）病理的脆弱性，IR是定义AD的这两种病理之间的关键联系。最后，我们提供了一个正在进行的临床试验的概述，目标IR作为一个角度来治疗AD，并建议如何生物标志物可用于评估治疗效果和目标的参与。
Current hypotheses and theories regarding the pathogenesis of Alzheimer’s disease (AD) heavily implicate brain insulin resistance (IR) as a key factor. Despite the many well-validated metrics for systemic IR, the absence of biomarkers for brain-specific IR represents a translational gap that has hindered its study in living humans. In our lab, we have been working to develop biomarkers that reflect the common mechanisms of brain IR and AD that may be used to follow their engagement by experimental treatments. We present two promising biomarkers for brain IR in AD: insulin cascade mediators probed in extracellular vesicles (EVs) enriched for neuronal origin, and two-dimensional magnetic resonance spectroscopy (MRS) measures of brain glucose. As further evidence for a fundamental link between brain IR and AD, we provide a novel analysis demonstrating the close spatial correlation between brain expression of genes implicated in IR (using Allen Human Brain Atlas data) and tau and beta-amyloid pathologies. We proceed to propose the bold hypotheses that baseline differences in the metabolic reliance on glycolysis, and the expression of glucose transporters (GLUT) and insulin signaling genes determine the vulnerability of different brain regions to Tau and/or Amyloid beta (Aβ) pathology, and that IR is a critical link between these two pathologies that define AD. Lastly, we provide an overview of ongoing clinical trials that target IR as an angle to treat AD, and suggest how biomarkers may be used to evaluate treatment efficacy and target engagement.