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

Abstract

Objective Old 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. Methods 15-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. Results First, 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. Conclusions Overall, 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.

Repurposing beta3-adrenergic receptor agonists for Alzheimer’s disease: Beneficial effects on recognition memory and amyloid pathology in a mouse model

“…Since tau phosphorylation has been repeatedly shown to follow body temperature modulation (Arendt et al, 2003;Planel et al, 2007;Stieler et al, 2011), we could have expected a protective effect of β3AR stimulation. For example, we recently showed that improved BAT thermogenesis through repeated cold exposure protects old 3xTg-AD mice from cold-induced tau phosphorylation (Tournissac et al, 2019). However, the present study design did not fully explore the hypothesis that β3AR stimulation impacts tau phosphorylation, because the animals were kept at room temperature and not exposed to any frank thermoregulatory challenge (i.e.…”

“…The present study aimed at investigating whether β3AR agonist administration induces BAT thermogenesis and exerts an effect on cognitive behavior and AD neuropathology in a mouse model of the disease. The 3xTg-AD mice was selected to test the effect of β3AR stimulation in AD because this model displays age-dependent metabolic and thermoregulatory deficits and was shown to respond to thermoneutrality and BAT stimulation induced by repeated cold exposure (Knight et al, 2013;Tournissac et al, 2019;Vandal et al, 2016). This led to the hypothesis that pharmacological BAT stimulation could exert benefit on AD-like behavior and neuropathology.…”

“…Accordingly, manipulation of external temperature leads to strong modulation of AD neuropathology in mice: cold exposure increases both tau phosphorylation and β-amyloid (Aβ) pathology and decreases synaptic proteins, while higher temperature reverses memory and anxiety-like behavior and reduced Aβ42 peptide levels in 3xTg-AD mice (Vandal et al, 2016). More recently, our group provided evidence that enhancement of thermogenesis through cold acclimation improves metabolic disorders and protects old 3xTg-AD mice from cold-induced tau phosphorylation (Tournissac et al, 2019). Supporting the link with age, cold-induced tau phosphorylation is potentiated in old mice compared to young mice (Tournissac et al, 2017).…”

“…The discovery of functional BAT in adults in 2009 has revived research on this tissue (Cypess et al, 2009;Virtanen et al, 2009). The ability of BAT thermogenesis to improve main metabolic disorders is now well-established in young (Hanssen et al, 2015;Ravussin et al, 2014;Schrauwen and van Marken Lichtenbelt, 2016) and old mice (Tournissac et al, 2019). Pharmacological tools have been developed in this direction.…”

Cold-induced lipid dynamics and transcriptional programs in white adipose tissue

“…Thermoregulatory deficits coincide with a rise in the incidence of metabolic syndrome and a set of neurodegenerative disorders in old age [103]. A previous study indicated that thermogenesis stimulation improved metabolic deficits and protected a mouse model of AD [104]. Increasing evidence has suggested that adipose tissue influences brain development, cognition, and the risk for neurodegenerative disorders throughout one’s lifespan [105].…”