| Full text | |
| Author(s): Show less - |
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 |