Alzheimer-associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation
Authors: Douglas P Munoz
Mario J Saad
Rudimar L Frozza
Fernanda G De Felice
Natalia M Lyra E Silva
Rodrigo Medeiros
Claudia P Figueiredo
Jose H Ledo
Danielle Beckman
Renata Frazão
Marina A Silveira
Sergio T Ferreira
Licio A Velloso
Bruno M Carvalho
William L Klein
Jose B Carvalheira
Theresa R Bomfim
Fernanda S Neves
Felipe C Ribeiro
Frank M LaFerla
Julia R Clarke
Daniela Razolli
Carlos K Katashima
Journal: EMBO molecular medicine (2015)
Discipline: CLINICAL MEDICINE
Keywords: Alzheimer's disease; ER stress; hypothalamus; inflammation; insulin resistance.
Affiliations: 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., 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., Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil., Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil., Department of Anatomy, Institute of Biomedical Sciences University of São Paulo, SP, Brazil., Department of Neurobiology, Northwestern University, Evanston, IL, USA., Institute for Memory Impairments and Neurological Disorders University of California, Irvine, CA, USA., Center for Neuroscience Studies, Queen's University, Kingston, ON, Canada., 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., Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil .

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. 

Retracted: No

PubPeer comments:
 The authors state in legends of Figure 2C that they measured leptin mRNA in white adipose tissue of **mice**. However, the leptin pair of primers used in this work was originally designed for measuring in rats, not in mice . If you blast the provided forward primer against Mus musculus transcriptome (TGAGCTATCTGCAGCACGTT), you donu2019t get any similarity with leptin mRNA. ![file] You can find some matching with leptin mRNA acting as a reverse primer at the beginning of the gene. This PCR reaction canu2019t work with mice cDNA. ![file] I would like to know whether authors can provide an explanation and or the raw data of this qPCR? , 
 Thank you for alerting the journal to this discrepancy. As a canonical first step to resolve the discrepancy, have you tried contacting the authors directly? Failing that, you are welcome to submit a formal refutation to the journal. ,