Reduced brain insulin signaling: A seminal process in Alzheimer's disease pathogenesis.
Reduced brain insulin signaling: A seminal process in Alzheimer's disease pathogenesis.
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DOI：
10.1016/j.neuropharm.2017.09.016
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发表时间：
2018-07-01
影响因子：
4.7
通讯作者：
Norambuena A
中科院分区：
文献类型：
--
作者：
Bloom GS;Lazo JS;Norambuena A
突触功能障碍和介导记忆和认知的神经元的死亡共同解释了阿尔茨海默病（AD）的行为症状。大脑中胰岛素信号的减少是AD患者的一个标志，即使没有系统性1型或2型糖尿病，也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的这种特征性特征出现的一个关键问题是“如果有的话，大脑利用胰岛素的能力受损如何促成与AD相关的行为缺陷？”2型糖尿病是AD的危险因素，这一事实表明胰岛素反应性受损在AD发病机制中发挥着致病作用，但在详细的分子水平上这种情况是如何发生的一直难以捉摸。在这里，我们回顾了最近的研究结果，在机械上连接可溶性形式的淀粉样蛋白-β（Aβ）和tau，淀粉样蛋白斑块和神经元缠结的相应构建模块，积累在AD患者的大脑中，与神经元衰退，与胰岛素反应性差，可能开始早在AD症状变得明显。我们讨论了Aβ和tau蛋白如何协同工作，剥夺神经元功能可及的胰岛素受体，并通过蛋白激酶mTOR失调正常信号。最后，我们建议如何利用新获得的知识，减少脑胰岛素信号传导引起的致病信号，以改善早期检测和治疗干预AD。
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.
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影响因子：
3.7
作者：
Sanphui P;Pramanik SK;Chatterjee N;Moorthi P;Banerji B;Biswas SC
通讯作者：
Biswas SC
DOI：
10.1523/jneurosci.2441-08.2008
发表时间：
2008-10-22
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Varvel NH;Bhaskar K;Patil AR;Pimplikar SW;Herrup K;Lamb BT
通讯作者：
Lamb BT
影响因子：
5.6
作者：
de la Monte, Suzanne M.
通讯作者：
de la Monte, Suzanne M.
影响因子：
4
作者：
Claxton, Amy;Baker, Laura D.;Craft, Suzanne
通讯作者：
Craft, Suzanne
DOI：
10.1073/pnas.0809158106
发表时间：
2009-02-10
影响因子：
11.1
作者：
De Felice, Fernanda G.;Vieira, Marcelo N. N.;Klein, William L.
通讯作者：
Klein, William L.