Metformin attenuates diabetes-induced tau hyperphosphorylation in vitro and in vivo by enhancing autophagic clearance
Metformin attenuates diabetes-induced tau hyperphosphorylation in vitro and in vivo by enhancing autophagic clearance
复制标题
二甲双胍通过增强自噬清除作用在体外和体内减轻糖尿病诱导的 tau 蛋白过度磷酸化
DOI：
10.1016/j.expneurol.2018.09.008
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发表时间：
2019-01-01
影响因子：
5.3
通讯作者：
Xiao, Qian
中科院分区：
文献类型：
--
作者：
Chen, Jin-Liang;Luo, Cheng;Xiao, Qian
糖尿病（DM）可增加患者患阿尔茨海默病（AD）的风险。然而，没有有效的方法来防止其进展和发展。近年来，自噬功能障碍被认为与神经退行性疾病的发病机制有关。本研究旨在探讨二甲双胍通过调节自噬清除对糖尿病性脑病（DE）过度磷酸化tau蛋白的影响。Db / Db小鼠随机分为4组，Db /+小鼠为对照组。12周龄雄性db/db小鼠连续腹腔注射200 mg/kg/d二甲双胍或（和）10 mg/kg/d氯喹，连续8周。Morris水迷宫（MWM）试验在小鼠安乐死前进行认知功能测试。二甲双胍减轻了db/db小鼠的认知障碍，降低了过度磷酸化的tau蛋白，恢复了糖尿病小鼠受损的自噬，所有这些都通过抑制自噬活性而逆转。在高糖培养的HT22细胞中，二甲双胍以剂量依赖的方式增加自噬。此外，二甲双胍以依赖AMPK的方式增强自噬活性。这些数据表明，二甲双胍可能通过AMPK依赖途径调节自噬，从而减轻db/db小鼠的tau病并改善认知功能障碍。这些发现强调了二甲双胍作为治疗DE的一种新的治疗策略。
Diabetes mellitus (DM) can increase the risk of Alzheimer's disease (AD) in patients. However, no effective approaches are available to prevent its progression and development. Recently, autophagy dysfunction was identified to be involved in the pathogenesis of neurodegenerative diseases. This study was designed to investigate the effect of metformin on hyperphosphorylated tau proteins in diabetic encephalopathy (DE) by regulating autophagy clearance. db/db mice were randomly divided into four groups, db/+ mice were used as control group. Twelve-week old male db/db mice received consecutive intraperitoneal injection of 200 mg/kg/d metformin or (and) 10 mg/kg/d chloroquine for eight weeks. Morris water maze (MWM) tests were performed to test cognitive functions before the mice were euthanized. Metformin attenuated cognitive impairment in db/db mice, reduced hyperphosphorylated tau proteins, restored the impaired autophagy in diabetic mice, all of which were reversed by inhibiting of autophagy activity. In high glucose-cultured HT22 cells, metformin increased autophagy in a dose-dependent manner. Besides, metformin enhanced autophagy activity in an AMPK dependent manner. These data show that metformin may reduce tauopathy and improve cognitive impairment in db/db mice by modulating autophagy through the AMPK dependent pathway. These findings highlight metformin as a new therapeutic strategy for the treatment of DE.