First Author | Lourenco MV | Year | 2013 |
Journal | Cell Metab | Volume | 18 |
Issue | 6 | Pages | 831-43 |
PubMed ID | 24315369 | Mgi Jnum | J:206139 |
Mgi Id | MGI:5548002 | Doi | 10.1016/j.cmet.2013.11.002 |
Citation | Lourenco MV, et al. (2013) TNF-alpha mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's beta-amyloid oligomers in mice and monkeys. Cell Metab 18(6):831-43 |
abstractText | 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 2alpha (eIF2alpha-P), and AD brains exhibit elevated phospho-PKR and eIF2alpha-P levels. Whether and how PKR and eIF2alpha-P participate in defective brain insulin signaling and cognitive impairment in AD are unknown. We report that beta-amyloid oligomers, AD-associated toxins, activate PKR in a tumor necrosis factor alpha (TNF-alpha)-dependent manner, resulting in eIF2alpha-P, neuronal insulin receptor substrate (IRS-1) inhibition, synapse loss, and memory impairment. Brain phospho-PKR and eIF2alpha-P were elevated in AD animal models, including monkeys given intracerebroventricular oligomer infusions. Oligomers failed to trigger eIF2alpha-P and cognitive impairment in PKR(-/-) and TNFR1(-/-) mice. Bolstering insulin signaling rescued phospho-PKR and eIF2alpha-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. |