Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline
Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline
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DOI：
10.1172/jci59903
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发表时间：
2012-04-01
影响因子：
15.9
通讯作者：
Arnold, Steven E.
中科院分区：
文献类型：
--
作者：
Talbot, Konrad;Wang, Hoau-Yan;Arnold, Steven E.
虽然脑胰岛素抵抗是阿尔茨海默病（AD）的潜在致病因素，但尚未直接在该疾病中得到证实。我们在此提供了这样一个证明，即在没有糖尿病的AD病例中，海马结构（HF）和小脑皮质在较小程度上表现出对IR -> IRS-1 -> PI 3 K信号传导途径中胰岛素信号传导的反应显著降低，对IGF-1 R-> IRS-2 -> PI 3 K信号传导途径中IGF-1的反应大大降低。胰岛素反应降低在IRS-1水平最大，并与IRS-1丝氨酸616磷酸化酶（IRS-1 pS（616））和IRS-1 pS（636/639）的基础升高一致。在HF中，这些脑胰岛素抵抗的候选生物标志物通常从正常病例到轻度认知障碍病例再到AD病例逐渐增加，与糖尿病或APOE β 4状态无关。IRS-1 pS（616）和IRS-1 pS（636/639）及其活化激酶的水平与寡聚体A β斑块的水平呈正相关，与情景记忆和工作记忆呈负相关，即使在调整了A β斑块、神经元缠结和APOE β 4之后。因此，脑胰岛素抵抗似乎是AD的早期和常见特征，这是一种伴随IGF-1抵抗的现象，并与可能由A β寡聚体触发的IRS-1功能障碍密切相关，但促进认知下降，与经典AD病理无关。
While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR -> IRS-1 -> PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R -> IRS-2 -> PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylatecl at serine 616 (IRS-1 pS(616)) and IRS-1 pS(636/639). In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE epsilon 4 status. Levels of IRS-1 pS(616) and IRS-1 pS(636/639) and their activated kinases correlated positively with those of oligomeric A beta plaques and were negatively associated with episodic and working memory, even after adjusting for A beta plaques, neurofibrillary tangles, and APOE epsilon 4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by A beta oligomers and yet promoting cognitive decline independent of classic AD pathology.