RESUMO
BACKGROUND: Old age, the most important risk factor for Alzheimer's disease (AD), is associated with thermoregulatory deficits. Brown adipose tissue (BAT) is the main thermogenic driver in mammals and its stimulation, through ß3 adrenergic receptor (ß3AR) agonists or cold acclimation, counteracts metabolic deficits in rodents and humans. Studies in animal models show that AD neuropathology leads to thermoregulatory deficits, and cold-induced tau hyperphosphorylation is prevented by BAT stimulation through cold acclimation. Since metabolic disorders and AD share strong pathogenic links, we hypothesized that BAT stimulation through a ß3AR agonist could exert benefits in AD as well. METHODS: CL-316,243, a specific ß3AR agonist, was administered to the triple transgenic mouse model of AD (3xTg-AD) and non-transgenic controls from 15 to 16 months of age at a dose of 1 mg/kg/day i.p. RESULTS: Here, we show that ß3AR agonist administration decreased body weight and improved peripheral glucose metabolism and BAT thermogenesis in both non-transgenic and 3xTg-AD mice. One-month treatment with a ß3AR agonist increased recognition index by 19% in 16-month-old 3xTg-AD mice compared to pre-treatment (14-month-old). Locomotion, anxiety, and tau pathology were not modified. Finally, insoluble Aß42/Aß40 ratio was decreased by 27% in the hippocampus of CL-316,243-injected 3xTg-AD mice. CONCLUSIONS: Overall, our results indicate that ß3AR stimulation reverses memory deficits and shifts downward the insoluble Aß42/Aß40 ratio in 16-month-old 3xTg-AD mice. As ß3AR agonists are being clinically developed for metabolic disorders, repurposing them in AD could be a valuable therapeutic strategy.
