TY - JOUR
T1 - TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's β-amyloid oligomers in mice and monkeys
AU - Lourenco, Mychael V.
AU - Clarke, Julia R.
AU - Frozza, Rudimar L.
AU - Bomfim, Theresa R.
AU - Forny-Germano, Letícia
AU - Batista, André F.
AU - Sathler, Luciana B.
AU - Brito-Moreira, Jordano
AU - Amaral, Olavo B.
AU - Silva, Cesar A.
AU - Freitas-Correa, Léo
AU - Espírito-Santo, Sheila
AU - Campello-Costa, Paula
AU - Houzel, Jean Christophe
AU - Klein, William L.
AU - Holscher, Christian
AU - Carvalheira, José B.
AU - Silva, Aristobolo M.
AU - Velloso, Lício A.
AU - Munoz, Douglas P.
AU - Ferreira, Sergio T.
AU - De Felice, Fernanda G.
N1 - Funding Information:
This work was supported by grants from Human Frontiers Science Program (HFSP) (to F.G.D.F.), National Institute for Translational Neuroscience (INNT/Brazil), the Brazilian funding agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (to S.T.F. and F.G.D.F.), Canadian Institutes for Health Research (CIHR), and Canada Research Chair Program (to D.P.M.). M.V.L., L.B.S., L.F.-G., A.F.B., T.R.B., J.B.-M., and L.F.-C. were supported by CNPq predoctoral fellowships. We thank Drs. Matthias Gralle, Wagner Seixas, and Claudio A. Masuda (Federal University of Rio de Janeiro, Brazil) for insightful discussions and Dr. Claudia P. Figueiredo (Federal University of Rio de Janeiro, Brazil) for advice on immunohistochemical analysis of monkey brains. W.L.K. is a cofounder of Acumen Pharmaceuticals, which has been licensed by Northwestern University to develop ADDL technology for Alzheimer’s therapeutics and diagnostics.
PY - 2013/12/3
Y1 - 2013/12/3
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2013.11.002
DO - 10.1016/j.cmet.2013.11.002
M3 - Article
C2 - 24315369
AN - SCOPUS:84889656503
SN - 1550-4131
VL - 18
SP - 831
EP - 843
JO - Cell Metabolism
JF - Cell Metabolism
IS - 6
ER -
