Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil.
Cell Metab. 2013 Dec 3;18(6):831-43. doi: 10.1016/j.cmet.2013.11.002.
Alzheimer's disease (AD) and type 2 diabetes appear to share similar pathogenic mechanisms. dsRNA-dependent protein kinase (PKR) underlies peripheral insulin resistance in metabolic disorders. PKR phosphorylates eukaryotic translation initiation factor 2α (eIF2α-P), and AD brains exhibit elevated phospho-PKR and eIF2α-P levels. Whether and how PKR and eIF2α-P participate in defective brain insulin signaling and cognitive impairment in AD are unknown. We report that β-amyloid oligomers, AD-associated toxins, activate PKR in a tumor necrosis factor α (TNF-α)-dependent manner, resulting in eIF2α-P, neuronal insulin receptor substrate (IRS-1) inhibition, synapse loss, and memory impairment. Brain phospho-PKR and eIF2α-P were elevated in AD animal models, including monkeys given intracerebroventricular oligomer infusions. Oligomers failed to trigger eIF2α-P and cognitive impairment in PKR(-/-) and TNFR1(-/-) mice. Bolstering insulin signaling rescued phospho-PKR and eIF2α-P. Results reveal pathogenic mechanisms shared by AD and diabetes and establish that proinflammatory signaling mediates oligomer-induced IRS-1 inhibition and PKR-dependent synapse and memory loss.
阿尔茨海默病 (AD) 和 2 型糖尿病似乎具有相似的发病机制。双链 RNA 依赖性蛋白激酶 (PKR) 是代谢紊乱中外周胰岛素抵抗的基础。PKR 磷酸化真核翻译起始因子 2α (eIF2α-P)，AD 大脑中表现出升高的磷酸化 PKR 和 eIF2α-P 水平。PKR 和 eIF2α-P 是否以及如何参与 AD 中脑胰岛素信号转导和认知障碍尚不清楚。我们报告说，β-淀粉样寡聚体，AD 相关毒素，以肿瘤坏死因子 α (TNF-α) 依赖的方式激活 PKR，导致 eIF2α-P、神经元胰岛素受体底物 (IRS-1) 抑制、突触丢失和记忆损伤。AD 动物模型中的大脑磷酸化 PKR 和 eIF2α-P 升高，包括给予脑室寡聚体输注的猴子。寡聚体未能在 PKR(-/-)和 TNFR1(-/-)小鼠中引发 eIF2α-P 和认知障碍。增强胰岛素信号转导可挽救磷酸化 PKR 和 eIF2α-P。结果揭示了 AD 和糖尿病共有的发病机制，并确立了促炎信号转导介导了寡聚体诱导的 IRS-1 抑制和 PKR 依赖性突触和记忆丧失。
