Brain insulin response and peripheral metabolic changes in a Tau transgenic mouse model.


Journal

Neurobiology of disease
ISSN: 1095-953X
Titre abrégé: Neurobiol Dis
Pays: United States
ID NLM: 9500169

Informations de publication

Date de publication:
05 2019
Historique:
received: 24 10 2018
revised: 14 12 2018
accepted: 15 01 2019
pubmed: 22 1 2019
medline: 18 12 2019
entrez: 22 1 2019
Statut: ppublish

Résumé

Accumulation of hyper-phosphorylated and aggregated Tau proteins is a neuropathological hallmark of Alzheimer's Disease (AD) and Tauopathies. AD patient brains also exhibit insulin resistance. Whereas, under normal physiological conditions insulin signaling in the brain mediates plasticity and memory formation, it can also regulate peripheral energy homeostasis. Thus, in AD, brain insulin resistance affects both cognitive and metabolic changes described in these patients. While a role of Aβ oligomers and APOE4 towards the development of brain insulin resistance emerged, contribution of Tau pathology has been largely overlooked. Our recent data demonstrated that one of the physiological function of Tau is to sustain brain insulin signaling. We postulated that under pathological conditions, hyper-phosphorylated/aggregated Tau is likely to lose this function and to favor the development of brain insulin resistance. This hypothesis was substantiated by observations from patient brains with pure Tauopathies. To address the potential link between Tau pathology and brain insulin resistance, we have evaluated the brain response to insulin in a transgenic mouse model of AD-like Tau pathology (THY-Tau22). Using electrophysiological and biochemical evaluations, we surprisingly observed that, at a time when Tau pathology and cognitive deficits are overt and obvious, the hippocampus of THY-Tau22 mice exhibits enhanced response to insulin. In addition, we demonstrated that the ability of i.c.v. insulin to promote body weight loss is enhanced in THY-Tau22 mice. In line with this, THY-Tau22 mice exhibited a lower body weight gain, hypoleptinemia and hypoinsulinemia and finally a metabolic resistance to high-fat diet. The present data highlight that the brain of transgenic Tau mice exhibit enhanced brain response to insulin. Whether these observations are ascribed to the development of Tau pathology, and therefore relevant to human Tauopathies, or unexpectedly results from the Tau transgene overexpression is debatable and discussed.

Identifiants

pubmed: 30665005
pii: S0969-9961(19)30013-0
doi: 10.1016/j.nbd.2019.01.008
pii:
doi:

Substances chimiques

Insulin 0
tau Proteins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

14-22

Informations de copyright

Copyright © 2019 Elsevier Inc. All rights reserved.

Auteurs

Antoine Leboucher (A)

Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, F-59000 Lille, France; LabEx DISTALZ, F-59000 Lille, France.

Tariq Ahmed (T)

Brain & Cognition, Faculty of Psychology & Educational Sciences, KU Leuven, Belgium; Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar.

Emilie Caron (E)

Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, F-59000 Lille, France.

Anne Tailleux (A)

Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France.

Sylvie Raison (S)

Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France.

Aurélie Joly-Amado (A)

Byrd Alzheimer's Institute, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA.

Elodie Marciniak (E)

Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, F-59000 Lille, France; LabEx DISTALZ, F-59000 Lille, France.

Kevin Carvalho (K)

Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, F-59000 Lille, France; LabEx DISTALZ, F-59000 Lille, France.

Malika Hamdane (M)

Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, F-59000 Lille, France; LabEx DISTALZ, F-59000 Lille, France.

Kadiombo Bantubungi (K)

Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France.

Steve Lancel (S)

Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France.

Sabiha Eddarkaoui (S)

Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, F-59000 Lille, France; LabEx DISTALZ, F-59000 Lille, France.

Raphaelle Caillierez (R)

Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, F-59000 Lille, France; LabEx DISTALZ, F-59000 Lille, France.

Emmanuelle Vallez (E)

Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France.

Bart Staels (B)

Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000 Lille, France.

Didier Vieau (D)

Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, F-59000 Lille, France; LabEx DISTALZ, F-59000 Lille, France.

Detlef Balschun (D)

Brain & Cognition, Faculty of Psychology & Educational Sciences, KU Leuven, Belgium.

Luc Buee (L)

Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, F-59000 Lille, France; LabEx DISTALZ, F-59000 Lille, France.

David Blum (D)

Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc, F-59000 Lille, France; LabEx DISTALZ, F-59000 Lille, France. Electronic address: david.blum@inserm.fr.

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