Department of Biology, University of Virginia, Charlottesville, VA, USA; Department of Cell Biology, University of Virginia, Charlottesville, VA, USA; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.
Department of Pharmacology, University of Virginia, Charlottesville, VA, USA; Department of Chemistry, University of Virginia, Charlottesville, VA, USA.
Neuropharmacology. 2018 Jul 1;136(Pt B):192-195. doi: 10.1016/j.neuropharm.2017.09.016. Epub 2017 Sep 29.
The synaptic dysfunction and death of neurons that mediate memory and cognition account together for the behavioral symptoms of Alzheimer's disease (AD). Reduced insulin signaling in the brain is a hallmark of AD patients, even in the absence of systemic type 1 or type 2 diabetes, prompting some researchers to refer to AD as brain-specific, or type 3 diabetes. A key question that arises about this signature feature of AD is "how, if at all, does the brain's impaired ability to utilize insulin contribute to the behavioral deficits associated with AD?" The fact that type 2 diabetes is a risk factor for AD suggests a causative role for impaired insulin responsiveness in AD pathogenesis, but how that might occur at a detailed molecular level had been elusive. Here we review recent findings that mechanistically link soluble forms of amyloid-β (Aβ) and tau, the respective building blocks of the amyloid plaques and neurofibrillary tangles that accumulate in the brains of AD patients, with neuronal decline that is associated with poor insulin responsiveness and may begin long before AD symptoms become evident. We discuss how Aβ and tau work coordinately to deprive neurons of functionally accessible insulin receptors and dysregulate normal signaling by the protein kinase, mTOR. Finally, we suggest how newly gained knowledge about pathogenic signaling caused by reduced brain insulin signaling might be exploited for improved early detection and therapeutic intervention for AD. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'
介导记忆和认知的神经元的突触功能障碍和死亡共同导致了阿尔茨海默病（AD）的行为症状。即使在没有系统性 1 型或 2 型糖尿病的情况下，大脑中的胰岛素信号降低也是 AD 患者的一个标志，这促使一些研究人员将 AD 称为脑特异性，或 3 型糖尿病。关于 AD 的这个特征，出现了一个关键问题，“大脑利用胰岛素的能力受损，如果确实有影响，如何导致与 AD 相关的行为缺陷？”2 型糖尿病是 AD 的一个风险因素，这表明胰岛素反应受损在 AD 发病机制中起因果作用，但在详细的分子水平上，这种情况如何发生一直难以捉摸。在这里，我们回顾了最近的发现，这些发现从机制上将可溶性形式的淀粉样蛋白-β（Aβ）和 tau 联系起来，Aβ 和 tau 分别是在 AD 患者大脑中积累的淀粉样斑块和神经原纤维缠结的组成部分，与与胰岛素反应不良相关的神经元衰退有关，并且可能在 AD 症状明显之前很久就开始了。我们讨论了 Aβ 和 tau 如何协调作用，使神经元失去功能上可接近的胰岛素受体，并使蛋白激酶 mTOR 的正常信号失调。最后，我们提出了如何利用关于大脑胰岛素信号降低引起的致病信号的新知识，来改善 AD 的早期检测和治疗干预。本文是题为“代谢障碍作为神经退行性疾病的风险因素”的特刊的一部分。
