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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; Frazão, 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

Alzheimer‐associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation

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  • Medientyp: E-Artikel
  • Titel: Alzheimer‐associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation
  • Beteiligte: 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; Frazão, 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
  • Erschienen: Springer Science and Business Media LLC, 2015
  • Erschienen in: EMBO Molecular Medicine, 7 (2015) 2, Seite 190-210
  • Sprache: Englisch
  • DOI: 10.15252/emmm.201404183
  • ISSN: 1757-4676; 1757-4684
  • Schlagwörter: Molecular Medicine
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Alzheimer's disease (<jats:styled-content style="fixed-case">AD</jats:styled-content>) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in <jats:styled-content style="fixed-case">AD</jats:styled-content> patients. Here, we show that intracerebroventricular infusion of <jats:styled-content style="fixed-case">AD</jats:styled-content>‐associated Aβ oligomers (AβOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of <jats:styled-content style="fixed-case">AD</jats:styled-content>. Systemically injected AβOs failed to induce glucose intolerance, suggesting AβOs target brain regions involved in peripheral metabolic control. Accordingly, we show that AβOs affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2α phosphorylation (<jats:styled-content style="fixed-case">eIF</jats:styled-content>2α‐P). AβOs further induced <jats:styled-content style="fixed-case">eIF</jats:styled-content>2α‐P and activated pro‐inflammatory <jats:styled-content style="fixed-case">IKK</jats:styled-content>β/<jats:styled-content style="fixed-case">NF</jats:styled-content>‐κB signaling in the hypothalamus of mice and macaques. AβOs failed to trigger peripheral glucose intolerance in tumor necrosis factor‐α (<jats:styled-content style="fixed-case">TNF</jats:styled-content>‐α) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that AβOs act via a central route to affect peripheral glucose homeostasis. While the hypothalamus has been largely ignored in the <jats:styled-content style="fixed-case">AD</jats:styled-content> field, our findings indicate that AβOs affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD.</jats:p>
  • Zugangsstatus: Freier Zugang