外周组织中胰岛素耐受性是2型糖尿病一个标志。大量的证据表明胰岛素耐受性也会在阿兹海默病人的大脑中发展。AD病人中，大脑胰岛素及其受体的水平低于正常水平，通过尸检及AD动物模型证明胰岛素信号传导发生障碍。大脑中的胰岛素信号对学习和记忆是尤其重要的，这表明胰岛素耐受性可能会促进AD病人的认知缺陷。目前，胰岛素耐受性在AD个体大脑中出现的机制还不明确。近日，巴西里约热内卢联邦大学的Fernanda G. De Felice等人发现，一种抗糖尿病试剂可以保护老鼠大脑免受与阿兹海默病有关的Aβ低聚物引起胰岛素信号传导障碍。相关研究发表在3月22日的《临床研究》（The Journal of Clinical Investigation）上。
研究人员发现，在糖尿病以及阿兹海默病两种病人中都出现了IRS-1的丝氨酸磷酸化(IRS-1pSer)。来自AD病人的大脑组织中有升高的IRS-1pSer及激活的JNK水平，这与糖尿病人外周组织所发生的现象相似。而且，淀粉样β多肽（Aβ）低聚物在AD病人大脑中积聚，激活JNK/TNF-α通路，引起大量的丝氨酸残基IRS-1的磷酸化。在成熟培养的海马神经元抑制了IRS-1位点的Tyr的磷酸化。受损的IRS-1出现在了Tg老鼠模拟了AD环境的海马组织中。重要的是，在猕猴中，脑内注射Aβ低聚物后引起了海马神经元IRS-1pSer及JNK的激活。体外观察发现，这种低聚物引起的神经元病理包括受损的轴突运输，能够被一种抗糖尿病试剂exendin-4 (exenatide)所抑制。
在Tg老鼠中，exendin-4能够下调海马体中IRS-1pSer及活化的JNK的水平，提升了老鼠的认知能力。通过建立胰岛素信号传导障碍在阿兹海默病及糖尿病人的分子联系，这项研究对阿兹海默病（AD）的临床治疗提供了更广阔的思路。（生物谷Deepblue编译）
doi: 10.1172/JCI57256
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An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers
Theresa R. Bomfim, Leticia Forny-Germano, Luciana B. Sathler, Jordano Brito-Moreira, Jean-Christophe Houzel, Helena Decker, Michael A. Silverman, Hala Kazi4, Helen M. Melo, Paula L. McClean, Christian Holscher, Steven E. Arnold, Konrad Talbot, William L. Klein, Douglas P. Munoz, Sergio T. Ferreira and Fernanda G. De Felice.
Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer’s disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases.Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD.Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent.In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.
