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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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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]
Total Authors: 23
Affiliation:
[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
Total Affiliations: 8
Document type: Journal article
Source: EMBO MOLECULAR MEDICINE; v. 7, n. 2, p. 190-210, FEB 2015.
Web of Science Citations: 84
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. (AU)

FAPESP's process: 12/12202-4 - Kiss1 neurons biophysical properties modulation by circadian factors
Grantee:Renata Frazão
Support Opportunities: Regular Research Grants