Repurposing beta-3 adrenergic receptor agonists for Alzheimer’s disease: beneficial effects in a mouse model

Alzheimer’s Research & Therapy

卷:13

Nika Vrabic¹  Cyntia Tremblay¹  Emmanuel Planel¹  Frédéric Calon²  Marine Tournissac²  Tra-My Vu²  Koralie Mélançon²  Fabien Pifferi³  Clara Hozer³ 

[1] Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval (Pavillon CHUL);

[2] Faculté de pharmacie, Université Laval;

[3] UMR CNRS/MNHN 7179, Mécanismes Adaptatifs et Évolution;

关键词: Alzheimer’s disease;    β3 adrenergic receptors;    Drug repurposing;    Thermogenesis;    3xTg-AD mice;    Brown adipose tissue;   

DOI  :  10.1186/s13195-021-00842-3

来源: DOAJ

【 摘 要 】

Abstract 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 β3 adrenergic receptor (β3AR) 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 β3AR agonist could exert benefits in AD as well. Methods CL-316,243, a specific β3AR 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 β3AR 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 β3AR 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 Aβ42/Aβ40 ratio was decreased by 27% in the hippocampus of CL-316,243-injected 3xTg-AD mice. Conclusions Overall, our results indicate that β3AR stimulation reverses memory deficits and shifts downward the insoluble Aβ42/Aβ40 ratio in 16-month-old 3xTg-AD mice. As β3AR agonists are being clinically developed for metabolic disorders, repurposing them in AD could be a valuable therapeutic strategy.

【 授权许可】

Unknown