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

EMBO Molecular Medicine

Julia R Clarke¹  Natalia M Lyra e Silva¹  Claudia P Figueiredo⁶  Rudimar L Frozza¹  Jose H Ledo¹  Danielle Beckman¹  Carlos K Katashima⁴  Daniela Razolli⁴  Bruno M Carvalho⁴  Renata Frazão⁷  Marina A Silveira⁷  Felipe C Ribeiro¹  Theresa R Bomfim¹  Fernanda S Neves⁶  William L Klein²  Rodrigo Medeiros³  Frank M LaFerla³  Jose B Carvalheira⁴  Mario J Saad⁴  Douglas P Munoz⁵  Licio A Velloso⁴  Sergio T Ferreira¹ 

[1]Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

[2]Department of Neurobiology, Northwestern University, Evanston, IL, USA

[3]Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA

[4]Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil

[5]Center for Neuroscience Studies, Queen's University, Kingston, ON, Canada

[6]School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

[7]Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, SP, Brazil

关键词: Alzheimer's disease;    ER stress;    hypothalamus;    inflammation;    insulin resistance;   

DOI  :  10.15252/emmm.201404183

来源: Wiley

【 摘 要 】

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 Aβ oligomers (AβOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. 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 (eIF2α-P). AβOs further induced eIF2α-P and activated pro-inflammatory IKKβ/NF-κB signaling in the hypothalamus of mice and macaques. AβOs failed to trigger peripheral glucose intolerance in tumor necrosis factor-α (TNF-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 AD field, our findings indicate that AβOs affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD.

Synopsis

Centrally administered Aβ oligomers can trigger insulin resistance by engaging ER stress and inflammatory signals in the central nervous system. This study provides important insights into the link between Alzheimer's disease and diabetes by pointing to a common etiology.

• Aβ oligomers (ΑβOs), toxins that accumulate in the AD brain and have been linked to neuronal dysfunction in brain areas related to learning and memory, impact the hypothalamus of mice and macaques, revealing a novel toxic mechanism of AβOs in the brain.
• Infusion of AβOs in the brain triggers peripheral glucose intolerance, insulin resistance and other diabetes-related metabolic alterations in mice. Similar metabolic alterations were verified in two transgenic mouse models of AD.
• Blockade of brain inflammation or ER stress attenuates peripheral glucose intolerance induced by brain infusion of AβOs, suggesting that AβOs use a central route to disrupt metabolic control in peripheral tissues.
• Current results may explain why AD patients have increased risk of developing diabetes, and suggest that targeting the hypothalamus may constitute an approach to combat peripheral metabolic deregulation in AD.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.