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EMBO Mol Med. 2015 Feb;7(2):190-210. doi: 10.15252/emmm.201404183.

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

Author information

1
Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil School of Pharmacy Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
2
Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
3
School of Pharmacy Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
4
Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.
5
Department of Anatomy, Institute of Biomedical Sciences University of São Paulo, SP, Brazil.
6
Department of Neurobiology, Northwestern University, Evanston, IL, USA.
7
Institute for Memory Impairments and Neurological Disorders University of California, Irvine, CA, USA.
8
Center for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
9
Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil Institute of Biophysics Carlos Chagas Filho Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
10
Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil felice@bioqmed.ufrj.br.

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.

KEYWORDS:

Alzheimer's disease; ER stress; hypothalamus; inflammation; insulin resistance

PMID:
25617315
PMCID:
PMC4328648
DOI:
10.15252/emmm.201404183
[Indexed for MEDLINE]
Free PMC Article

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