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J Exp Med. 2017 Aug 7;214(8):2257-2269. doi: 10.1084/jem.20161731. Epub 2017 Jun 26.

Tau deletion promotes brain insulin resistance.

Author information

1
Université de Lille, Institut National de la Santé et de la Recherche Medicale (INSERM), CHU Lille, UMR-S 1172 JPArc, Lille, France.
2
LabEx DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease), Lille, France.
3
Laboratory of Biological Psychology, Faculty of Psychology and Educational Sciences, KU Leuven, Leuven, Belgium.
4
Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar.
5
Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011EGID, Lille, France.
6
Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167 RID-AGE Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, Lille, France.
7
INSERM U1016, CNRS UMR8104, Université Paris Descartes Sorbonne Paris Cité, Institut Cochin, Paris, France.
8
Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Goettingen, Goettingen, Germany.
9
Université de Lille, Institut National de la Santé et de la Recherche Medicale (INSERM), CHU Lille, UMR-S 1172 JPArc, Lille, France david.blum@inserm.fr.

Abstract

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.

PMID:
28652303
PMCID:
PMC5551570
DOI:
10.1084/jem.20161731
[Indexed for MEDLINE]
Free PMC Article

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