title: Alzheimer-associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation.
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.
authors.affiliation: 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.
authors.forename: Julia R
authors.initials: JR
authors.lastname: Clarke
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Natalia M
authors.initials: NM
authors.lastname: Lyra E Silva
authors.affiliation: School of Pharmacy Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Claudia P
authors.initials: CP
authors.lastname: Figueiredo
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Rudimar L
authors.initials: RL
authors.lastname: Frozza
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Jose H
authors.initials: JH
authors.lastname: Ledo
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Danielle
authors.initials: D
authors.lastname: Beckman
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Carlos K
authors.initials: CK
authors.lastname: Katashima
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Daniela
authors.initials: D
authors.lastname: Razolli
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Bruno M
authors.initials: BM
authors.lastname: Carvalho
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences University of São Paulo, SP, Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: Frazão
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences University of São Paulo, SP, Brazil.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Silveira
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Felipe C
authors.initials: FC
authors.lastname: Ribeiro
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Theresa R
authors.initials: TR
authors.lastname: Bomfim
authors.affiliation: School of Pharmacy Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Fernanda S
authors.initials: FS
authors.lastname: Neves
authors.affiliation: Department of Neurobiology, Northwestern University, Evanston, IL, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Klein
authors.affiliation: Institute for Memory Impairments and Neurological Disorders University of California, Irvine, CA, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Medeiros
authors.affiliation: Institute for Memory Impairments and Neurological Disorders University of California, Irvine, CA, USA.
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Jose B
authors.initials: JB
authors.lastname: Carvalheira
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Mario J
authors.initials: MJ
authors.lastname: Saad
authors.affiliation: Center for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Munoz
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.
authors.forename: Licio A
authors.initials: LA
authors.lastname: Velloso
authors.affiliation: 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.
authors.forename: Sergio T
authors.initials: ST
authors.lastname: Ferreira
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil felice@bioqmed.ufrj.br.
authors.forename: Fernanda G
authors.initials: FG
authors.lastname: De Felice
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D008251:Macaca; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics / Q000378:metabolism*; D010525:Peripheral Nerves / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D009841:Oligonucleotides; D014409:Tumor Necrosis Factor-alpha; D005947:Glucose
keywords: Alzheimer's disease; ER stress; hypothalamus; inflammation; insulin resistance