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Tau deletion promotes brain insulin resistance

Lookup NU author(s): Professor Tiago Outeiro

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2017 Marciniak et al.The molecular pathways underlying tau pathology-induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of-function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer's disease patients.


Publication metadata

Author(s): Marciniak E, Leboucher A, Caron E, Ahmed T, Tailleux A, Dumont J, Issad T, Gerhardt E, Pagesy P, Vileno M, Bournonville C, Hamdane M, Bantubungi K, Lancel S, Demeyer D, Eddarkaoui S, Vallez E, Vieau D, Humez S, Faivre E, Grenier-Boley B, Outeiro TF, Staels B, Amouyel P, Balschun D, Buee L, Blum D

Publication type: Article

Publication status: Published

Journal: Journal of Experimental Medicine

Year: 2017

Volume: 214

Issue: 8

Pages: 2257-2269

Print publication date: 07/08/2017

Online publication date: 26/06/2017

Acceptance date: 12/05/2017

Date deposited: 20/12/2017

ISSN (print): 0022-1007

ISSN (electronic): 1540-9538

Publisher: Rockefeller University Press

URL: https://doi.org/10.1084/jem.20161731

DOI: 10.1084/jem.20161731

PubMed id: 28652303


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