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Repurposing beta3-adrenergic receptor agonists for Alzheimer's disease: Beneficial effects on recognition memory and amyloid pathology in a mouse model.
bioRxiv - Pharmacology and Toxicology Pub Date : 2020-05-25 , DOI: 10.1101/2020.05.25.114454
Marine Tournissac , Tra-My Vu , Nika Vrabic , Clara Hozer , Cyntia Tremblay , Koralie Mélançon , Emmanuel Planel , Fabien Pifferi , Frédéric Calon

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. Here, we show that β3AR agonist administration (CL-316,243, 1 mg/kg/day i.p., from 15 to 16 months of age) 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. 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.

中文翻译:

重新使用β3-肾上腺素能受体激动剂治疗阿尔茨海默氏病:对小鼠模型中识别记忆和淀粉样蛋白病理的有益影响。

老年是阿尔茨海默氏病(AD)最重要的危险因素,它与体温调节缺陷有关。棕色脂肪组织(BAT)是哺乳动物的主要生热驱动因子,通过β3-肾上腺素能受体(β3AR)激动剂或冷驯化对其进行刺激,可以抵消啮齿动物和人类的代谢缺陷。动物模型研究表明,AD神经病理学可导致体温调节功能障碍,而冷诱导的BAT刺激可预防冷诱导的tau过度磷酸化。由于代谢紊乱和AD具有很强的致病性联系,我们假设通过β3AR激动剂进行的BAT刺激也可以在AD中发挥作用。在这里,我们显示了β3AR激动剂的给药方式(CL-316,243、1 mg / kg /天ip,15至16个月大)可降低体重,改善非转基因和3xTg-AD小鼠的外周葡萄糖代谢和BAT生热。与治疗前(14个月大)相比,使用β3AR激动剂进行1个月治疗可使16个月大的3xTg-AD小鼠的识别指数提高19%。运动,焦虑和tau病理未改变。最后,在注射CL-316,243的3xTg-AD小鼠的海马中,不溶性Aβ42/Aβ40的比率降低了27%。总体而言,我们的结果表明,β3AR刺激可以逆转记忆力不足,并使16个月大的3xTg-AD小鼠的不溶性Aβ42/Aβ40比值向下移动。随着β3AR激动剂在临床上针对代谢紊乱的发展,在AD中重新使用它们可能是一种有价值的治疗策略。与治疗前(14个月大)相比,使用β3AR激动剂进行1个月治疗可使16个月大的3xTg-AD小鼠的识别指数提高19%。运动,焦虑和tau病理未改变。最后,在注射CL-316,243的3xTg-AD小鼠的海马中,不溶性Aβ42/Aβ40的比率降低了27%。总体而言,我们的结果表明,β3AR刺激可以逆转记忆力不足,并使16个月大的3xTg-AD小鼠的不溶性Aβ42/Aβ40比值向下移动。随着β3AR激动剂在临床上针对代谢紊乱的发展,在AD中重新使用它们可能是一种有价值的治疗策略。与治疗前(14个月大)相比,在16个月大的3xTg-AD小鼠中使用β3AR激动剂进行一个月的治疗可使识别指数提高19%。运动,焦虑和tau病理未改变。最后,在注射CL-316,243的3xTg-AD小鼠的海马中,不溶性Aβ42/Aβ40的比率降低了27%。总体而言,我们的结果表明,β3AR刺激可以逆转记忆力不足,并使16个月大的3xTg-AD小鼠的不溶性Aβ42/Aβ40比值向下移动。随着β3AR激动剂在临床上针对代谢紊乱的发展,在AD中重新使用它们可能是一种有价值的治疗策略。注射243只的3xTg-AD小鼠。总体而言,我们的结果表明,β3AR刺激可逆转记忆力不足,并在16个月大的3xTg-AD小鼠中向下移动不溶性Aβ42/Aβ40比例。随着β3AR激动剂在临床上针对代谢紊乱的发展,在AD中重新使用它们可能是一种有价值的治疗策略。注射243只的3xTg-AD小鼠。总体而言,我们的结果表明,β3AR刺激可以逆转记忆力不足,并使16个月大的3xTg-AD小鼠的不溶性Aβ42/Aβ40比值向下移动。随着β3AR激动剂在临床上针对代谢紊乱的发展,在AD中重新使用它们可能是一种有价值的治疗策略。
更新日期:2020-05-25
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