Repeated cold exposures protect a mouse model of Alzheimer's disease against cold-induced tau phosphorylation

Marine Tournissac,Philippe Bourassa,Ruben D Martinez-Cano,Tra-My Vu,Sébastien S Hébert,Emmanuel Planel,Frédéric Calon

doi:10.1016/j.molmet.2019.01.008

Marine Tournissac, Philippe Bourassa + Show 5 more

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https://doi.org/10.1016/j.molmet.2019.01.008

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Journal: Molecular Metabolism	Publication Date: Jan 26, 2019
Citations: 26	License type: cc-by

Affiliation: Université Laval

Abstract

ObjectiveOld age is associated with a rise in the incidence of Alzheimer's disease (AD) but also with thermoregulatory deficits. Indicative of a link between the two, hypothermia induces tau hyperphosphorylation. The 3xTg-AD mouse model not only develops tau and amyloid pathologies in the brain but also metabolic and thermoregulatory deficits. Brown adipose tissue (BAT) is the main thermogenic driver in mammals, and its stimulation counteracts metabolic deficits in rodents and humans. We thus investigated whether BAT stimulation impedes AD neuropathology. Methods15-month-old 3xTg-AD mice were subjected to repeated short cold exposures (RSCE), consisting of 4-hour sessions of cold exposure (4 °C), five times per week for four weeks, compared to animals kept at housing temperature. ResultsFirst, we confirmed that 3xTg-AD RSCE-trained mice exhibited BAT thermogenesis and improved glucose tolerance. RSCE-trained mice were completely resistant to tau hyperphosphorylation in the hippocampus induced by a 24-hour cold challenge. Finally, RSCE increased plasma levels of fibroblast growth factor 21 (FGF21), a batokine, which inversely correlated with hippocampal tau phosphorylation. ConclusionsOverall, BAT stimulation through RSCE improved metabolic deficits and completely blocked cold-induced tau hyperphosphorylation in the 3xTg-AD mouse model of AD neuropathology. These results suggest that improving thermogenesis could exert a therapeutic effect in AD.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by disrupted cognitive functions and is diagnosed neuropathologically by the presence of tau-laden neurofibrillary tangles and Ab-loaded plaques [1,2]
Overall, Brown adipose tissue (BAT) stimulation through repeated short cold exposures (RSCE) improved metabolic deficits and completely blocked cold-induced tau hyperphosphorylation in the 3xTg-AD mouse model of AD neuropathology. These results suggest that improving thermogenesis could exert a therapeutic effect in AD
We confirmed that Ucp1 mRNA expression in BAT was increased by cold exposure, after a single acute episode (24 h at 4-hour sessions of cold exposure (4 C)) or at the end of the RSCE session (Figure 1C), while b3 adrenergic receptors (b3AR) were not affected by RSCE (Figure 1E,G)

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by disrupted cognitive functions and is diagnosed neuropathologically by the presence of tau-laden neurofibrillary tangles and Ab-loaded plaques [1,2]. Animal studies are providing new lines of evidence suggesting that thermoregulatory deficits contribute to AD pathogenesis. It has been repeatedly shown in the rodent brain that a decrease in body temperature induces tau hyperphosphorylation [8e12], one of the main neuropathological markers of the disease [1,2]. Our studies in animal models show that both aging and AD pathology potentiate the rise in tau phosphorylation following acute exposure to cold (4 C, 24 h) [11,12]. Mouse models of diabetes and obesity display thermoregulatory deficits associated with higher tau phosphorylation, further supporting a close relationship between type 2 diabetes and AD [19,20].

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