Alzheimer-associated a Beta oligomers impact the central nervous system to induce peripheral metabolic deregulation
Julia R. Clarke, Natalia M. Lyra e Silva, Claudia P. Figueiredo, Rudimar L. Frozza, Jose H. Ledo, Danielle Beckman, Carlos K. Katashima, Daniela Razolli, Bruno M. Carvalho, Renata Frazao, Marina A. Silveira, Felipe C. Ribeiro, Theresa R. Bomfim, Fernanda S. Neves, William L. Klein, Rodrigo Medeiros,...
Julia R. Clarke, Natalia M. Lyra e Silva, Claudia P. Figueiredo, Rudimar L. Frozza, Jose H. Ledo, Danielle Beckman, Carlos K. Katashima, Daniela Razolli, Bruno M. Carvalho, Renata Frazao, Marina A. Silveira, Felipe C. Ribeiro, Theresa R. Bomfim, Fernanda S. Neves, William L. Klein, Rodrigo Medeiros, Frank M. LaFerla, Jose B. Carvalheira, Mario J. Saad, Douglas P. Munoz, Licio A. Velloso, Sergio T. Ferreira, Fernanda G. De Felice
ARTIGO
Inglês
Agradecimentos: Human Frontier Science Program; National Institute for Translational Neuroscience (INNT/Brazil); Canadian Institutes of Health Research (CIHR); Canada Research Chairs
Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated A beta oligomers (A beta Os) in mice triggered peripheral glucose...
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Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated A beta oligomers (A beta Os) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected A beta Os failed to induce glucose intolerance, suggesting A beta Os target brain regions involved in peripheral metabolic control. Accordingly, we show that A beta Os affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2 alpha phosphorylation (eIF2 alpha-P). A beta Os further induced eIF2 alpha-P and activated proinflammatory IKK beta/NF-kappa B signaling in the hypothalamus of mice and macaques. A beta Os failed to trigger peripheral glucose intolerance in tumor necrosis factor-alpha (TNF-alpha) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that A beta Os act via a central route to affect peripheral glucose homeostasis. While the hypothalamus has been largely ignored in the AD field, our findings indicate that A beta Os affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD
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FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP
2012/12202-4
COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPES
CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ
FUNDAÇÃO CARLOS CHAGAS FILHO DE AMPARO À PESQUISA DO ESTADO DO RIO DE JANEIRO - FAPERJ
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Alzheimer-associated a Beta oligomers impact the central nervous system to induce peripheral metabolic deregulation
Julia R. Clarke, Natalia M. Lyra e Silva, Claudia P. Figueiredo, Rudimar L. Frozza, Jose H. Ledo, Danielle Beckman, Carlos K. Katashima, Daniela Razolli, Bruno M. Carvalho, Renata Frazao, Marina A. Silveira, Felipe C. Ribeiro, Theresa R. Bomfim, Fernanda S. Neves, William L. Klein, Rodrigo Medeiros,...
Julia R. Clarke, Natalia M. Lyra e Silva, Claudia P. Figueiredo, Rudimar L. Frozza, Jose H. Ledo, Danielle Beckman, Carlos K. Katashima, Daniela Razolli, Bruno M. Carvalho, Renata Frazao, Marina A. Silveira, Felipe C. Ribeiro, Theresa R. Bomfim, Fernanda S. Neves, William L. Klein, Rodrigo Medeiros, Frank M. LaFerla, Jose B. Carvalheira, Mario J. Saad, Douglas P. Munoz, Licio A. Velloso, Sergio T. Ferreira, Fernanda G. De Felice
Alzheimer-associated a Beta oligomers impact the central nervous system to induce peripheral metabolic deregulation
Julia R. Clarke, Natalia M. Lyra e Silva, Claudia P. Figueiredo, Rudimar L. Frozza, Jose H. Ledo, Danielle Beckman, Carlos K. Katashima, Daniela Razolli, Bruno M. Carvalho, Renata Frazao, Marina A. Silveira, Felipe C. Ribeiro, Theresa R. Bomfim, Fernanda S. Neves, William L. Klein, Rodrigo Medeiros,...
Julia R. Clarke, Natalia M. Lyra e Silva, Claudia P. Figueiredo, Rudimar L. Frozza, Jose H. Ledo, Danielle Beckman, Carlos K. Katashima, Daniela Razolli, Bruno M. Carvalho, Renata Frazao, Marina A. Silveira, Felipe C. Ribeiro, Theresa R. Bomfim, Fernanda S. Neves, William L. Klein, Rodrigo Medeiros, Frank M. LaFerla, Jose B. Carvalheira, Mario J. Saad, Douglas P. Munoz, Licio A. Velloso, Sergio T. Ferreira, Fernanda G. De Felice
Fontes
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EMBO Molecular Medicine Vol. 7, no. 2 (Feb., 2015), p. 190-210 |