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

Antoine Leboucher, Tariq Ahmed, Emilie Caron, Anne Tailleux, Sylvie Raison, Aurélie Joly-Amado, Elodie Marciniak, Kevin Carvalho, Malika Hamdane, Kadiombo Bantubungi, Steve Lancel, Sabiha Eddarkaoui, Raphaelle Caillierez, Emmanuelle Vallez, Bart Staels, Didier Vieau, Detlef Balschun, Luc Buee, David Blum

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)14-22
Number of pages9
JournalNeurobiology of Disease
Volume125
DOIs
Publication statusPublished - 1 May 2019

Fingerprint

Transgenic Mice
Insulin
Brain
Insulin Resistance
Tauopathies
Pathology
Alzheimer Disease
Body Weight
tau Proteins
Aptitude
High Fat Diet
Transgenes
Weight Gain
Weight Loss
Hippocampus
Homeostasis

Keywords

  • Alzheimer's disease
  • Insulin resistance
  • Metabolism
  • Tau
  • THY-Tau22
  • Transgenic mice

ASJC Scopus subject areas

  • Neurology

Cite this

Brain insulin response and peripheral metabolic changes in a Tau transgenic mouse model. / Leboucher, Antoine; Ahmed, Tariq; Caron, Emilie; Tailleux, Anne; Raison, Sylvie; Joly-Amado, Aurélie; Marciniak, Elodie; Carvalho, Kevin; Hamdane, Malika; Bantubungi, Kadiombo; Lancel, Steve; Eddarkaoui, Sabiha; Caillierez, Raphaelle; Vallez, Emmanuelle; Staels, Bart; Vieau, Didier; Balschun, Detlef; Buee, Luc; Blum, David.

In: Neurobiology of Disease, Vol. 125, 01.05.2019, p. 14-22.

Research output: Contribution to journalArticle

Leboucher, A, Ahmed, T, Caron, E, Tailleux, A, Raison, S, Joly-Amado, A, Marciniak, E, Carvalho, K, Hamdane, M, Bantubungi, K, Lancel, S, Eddarkaoui, S, Caillierez, R, Vallez, E, Staels, B, Vieau, D, Balschun, D, Buee, L & Blum, D 2019, 'Brain insulin response and peripheral metabolic changes in a Tau transgenic mouse model', Neurobiology of Disease, vol. 125, pp. 14-22. https://doi.org/10.1016/j.nbd.2019.01.008
Leboucher, Antoine ; Ahmed, Tariq ; Caron, Emilie ; Tailleux, Anne ; Raison, Sylvie ; Joly-Amado, Aurélie ; Marciniak, Elodie ; Carvalho, Kevin ; Hamdane, Malika ; Bantubungi, Kadiombo ; Lancel, Steve ; Eddarkaoui, Sabiha ; Caillierez, Raphaelle ; Vallez, Emmanuelle ; Staels, Bart ; Vieau, Didier ; Balschun, Detlef ; Buee, Luc ; Blum, David. / Brain insulin response and peripheral metabolic changes in a Tau transgenic mouse model. In: Neurobiology of Disease. 2019 ; Vol. 125. pp. 14-22.
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