TNF-伪 Mediates PKR-Dependent Memory Impairment and Brain IRS-1 Inhibition Induced by Alzheimer鈥檚 尾-Amyloid Oligomers in Mice and Monkeys

详细信息    查看全文

• 作者：Mychael聽V. Lourenco ; Julia聽R. Clarke ; Rudimar聽L. Frozza ; Theresa聽R. Bomfim ; Let铆cia Forny-Germano ; Andr茅聽F. Batista ; Luciana聽B. Sathler ; Jordano Brito-Moreira ; Olavo聽B. Amaral ; Cesar聽A. Silva ; L茅o Freitas-Correa ; Sheila Esp铆rito-Santo ; Paula Campello-Costa ; Jean-Christophe Houzel ; William聽L. Klein ; Christian Holscher ; Jos茅聽B. Carvalheira ; Aristobolo聽M. Silva ; L铆cio聽A. Velloso ; Douglas聽P. Munoz ; et al.
• 刊名：Cell Metabolism
• 出版年：3 December, 2013
• 年：2013
• 卷：18
• 期：6
• 页码：831-843
• 全文大小：3006 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferencescoding="UTF-8"?>

class="h3">Summary

Alzheimer鈥檚 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 2伪 (eIF2伪-P), and AD brains exhibit聽elevated phospho-PKR and eIF2伪-P levels. Whether and how PKR and eIF2伪-P participate in聽defective brain insulin signaling and cognitive impairment in AD are unknown. We report that 尾-amyloid oligomers, AD-associated toxins, activate PKR in a tumor necrosis factor 伪 (TNF-伪)-dependent manner, resulting in eIF2伪-P, neuronal insulin receptor substrate (IRS-1) inhibition, synapse loss, and memory impairment. Brain phospho-PKR and eIF2伪-P were elevated in AD animal models, including monkeys given intracerebroventricular oligomer infusions. Oligomers failed to聽trigger eIF2伪-P and cognitive impairment in PKR^{鈭?鈭?/sup> and TNFR1鈭?鈭?/sup> mice. Bolstering insulin signaling rescued phospho-PKR and eIF2伪-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.}