外周組織中胰島素耐受性是2型糖尿病一個標志。大量的證據(jù)表明胰島素耐受性也會在阿茲海默病人的大腦中發(fā)展,。AD病人中,，大腦胰島素及其受體的水平低于正常水平，通過尸檢及AD動物模型證明胰島素信號傳導(dǎo)發(fā)生障礙,。大腦中的胰島素信號對學(xué)習(xí)和記憶是尤其重要的,，這表明胰島素耐受性可能會促進AD病人的認知缺陷。目前,，胰島素耐受性在AD個體大腦中出現(xiàn)的機制還不明確,。近日，巴西里約熱內(nèi)盧聯(lián)邦大學(xué)的Fernanda G. De Felice等人發(fā)現(xiàn),，一種抗糖尿病試劑可以保護老鼠大腦免受與阿茲海默病有關(guān)的Aβ低聚物引起胰島素信號傳導(dǎo)障礙,。相關(guān)研究發(fā)表在3月22日的《臨床研究》（The Journal of Clinical Investigation）上。
研究人員發(fā)現(xiàn),，在糖尿病以及阿茲海默病兩種病人中都出現(xiàn)了IRS-1的絲氨酸磷酸化(IRS-1pSer),。來自AD病人的大腦組織中有升高的IRS-1pSer及激活的JNK水平，這與糖尿病人外周組織所發(fā)生的現(xiàn)象相似,。而且,，淀粉樣β多肽（Aβ）低聚物在AD病人大腦中積聚，激活JNK/TNF-α通路,，引起大量的絲氨酸殘基IRS-1的磷酸化,。在成熟培養(yǎng)的海馬神經(jīng)元抑制了IRS-1位點的Tyr的磷酸化。受損的IRS-1出現(xiàn)在了Tg老鼠模擬了AD環(huán)境的海馬組織中,。重要的是,，在獼猴中，腦內(nèi)注射Aβ低聚物后引起了海馬神經(jīng)元IRS-1pSer及JNK的激活,。體外觀察發(fā)現(xiàn),，這種低聚物引起的神經(jīng)元病理包括受損的軸突運輸,，能夠被一種抗糖尿病試劑exendin-4 (exenatide)所抑制。
在Tg老鼠中,，exendin-4能夠下調(diào)海馬體中IRS-1pSer及活化的JNK的水平,，提升了老鼠的認知能力。通過建立胰島素信號傳導(dǎo)障礙在阿茲海默病及糖尿病人的分子聯(lián)系,，這項研究對阿茲海默?。ˋD）的臨床治療提供了更廣闊的思路。（生物谷Deepblue編譯）
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.
