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Lookup NU author(s): Professor Tiago OuteiroORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 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.
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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