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Type: Artigo
Title: Alzheimer-associated a Beta oligomers impact the central nervous system to induce peripheral metabolic deregulation
Author: Clarke, Julia R.
Lyra e Silva, Natalia M.
Figueiredo, Claudia P.
Frozza, Rudimar L.
Ledo, Jose H.
Beckman, Danielle
Katashima, Carlos K.
Razolli, Daniela
Carvalho, Bruno M.
Frazao, Renata
Silveira, Marina A.
Ribeiro, Felipe C.
Bomfim, Theresa R.
Neves, Fernanda S.
Klein, William L.
Medeiros, Rodrigo
LaFerla, Frank M.
Carvalheira, Jose B.
Saad, Mario J.
Munoz, Douglas P.
Velloso, Licio A.
Ferreira, Sergio T.
De Felice, Fernanda G.
Abstract: 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
Subject: Hipotálamo
Resistência à insulina
Doença de Alzheimer
Country: Alemanha
Editor: EMBO Press
Rights: Aberto
Identifier DOI: 10.15252/emmm.201404183
Date Issue: 2015
Appears in Collections:FCM - Artigos e Outros Documentos

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