Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)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 2 alpha (eIF2 alpha-P), and AD brains exhibit elevated phospho-PKR and eIF2 alpha-P levels. Whether and how PKR and eIF2 alpha-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 eIF2 alpha-P, neuronal insulin receptor substrate (IRS-1) inhibition, synapse loss, and memory impairment. Brain phospho-PKR and eIF2 alpha-P were elevated in AD animal models, including monkeys given intracerebroventricular oligomer infusions. Oligomers failed to trigger eIF2 alpha-P and cognitive impairment in PKR-/- and TNFR1(-/-) mice. Bolstering insulin signaling rescued phospho-PKR and eIF2 alpha-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.186831843Human Frontiers Science Program (HFSP)National Institute for Translational Neuroscience (INNT/Brazil)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)Canadian Institutes for Health Research (CIHR)Canada Research Chair ProgramConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)