Alzheimer-associated A beta oligomers impact the central nervous system to induce peripheral metabolic deregulation

Autor(es):Mostrar menos -

Clarke, Julia R. ^{[1, 2]} ; Lyra e Silva, Natalia M. ^[2] ; Figueiredo, Claudia P. ^[1] ; Frozza, Rudimar L. ^[2] ; Ledo, Jose H. ^[2] ; Beckman, Danielle ^[2] ; Katashima, Carlos K. ^[3] ; Razolli, Daniela ^[3] ; Carvalho, Bruno M. ^[3] ; Frazao, Renata ^[4] ; Silveira, Marina A. ^[4] ; Ribeiro, Felipe C. ^[2] ; Bomfim, Theresa R. ^[2] ; Neves, Fernanda S. ^[1] ; Klein, William L. ^[5] ; Medeiros, Rodrigo ^[6] ; LaFerla, Frank M. ^[6] ; Carvalheira, Jose B. ^[3] ; Saad, Mario J. ^[3] ; Munoz, Douglas P. ^[7] ; Velloso, Licio A. ^[3] ; Ferreira, Sergio T. ^{[2, 8]} ; De Felice, Fernanda G. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Fed Rio de Janeiro, Sch Pharm, Rio De Janeiro, RJ - Brazil

^[2] Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, Rio De Janeiro, RJ - Brazil

^[3] Univ Estadual Campinas, Fac Med Sci, Dept Internal Med, Campinas, SP - Brazil

^[4] Univ Sao Paulo, Inst Biomed Sci, Dept Anat, Sao Paulo, SP - Brazil

^[5] Northwestern Univ, Dept Neurobiol, Evanston, IL - USA

^[6] Univ Calif Irvine, Inst Memory Impairments & Neurol Disorders, Irvine, CA - USA

^[7] Queens Univ, Ctr Neurosci Studies, Kingston, ON - Canada

^[8] Univ Fed Rio de Janeiro, Inst Biophys Carlos Chagas Filho, Rio De Janeiro, RJ - Brazil

• Tipo de documento: Artigo Científico
• Fonte: EMBO MOLECULAR MEDICINE; v. 7, n. 2, p. 190-210, FEB 2015.
• Citações Web of Science: 84

Resumo

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. (AU)

• Processo FAPESP: 12/12202-4 - Modulação das propriedades biofísicas de neurônios Kiss1 por fatores circadianos
• Beneficiário: Renata Frazão
• Modalidade de apoio: Auxílio à Pesquisa - Regular