AMPK Activation Ameliorates Alzheimer's Disease-Like Pathology and Spatial Memory Impairment in a Streptozotocin-Induced Alzheimer's Disease Model in Rats
AMPK Activation Ameliorates Alzheimer's Disease-Like Pathology and Spatial Memory Impairment in a Streptozotocin-Induced Alzheimer's Disease Model in Rats
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DOI：
10.3233/jad-140564
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发表时间：
2015-01-01
影响因子：
4
通讯作者：
Zhou, Xin-Wen
中科院分区：
文献类型：
--
作者：
Du, Lai-Ling;Chai, Da-Min;Zhou, Xin-Wen
大量证据表明，2型糖尿病是晚发性阿尔茨海默病（AD）的高危因素，能量代谢障碍被认为是两种疾病的交汇点。然而，糖尿病相关AD的潜在机制仍不清楚。在本研究中，我们研究了AMPK在糖尿病相关AD样病理特征中的作用，在脑室内-链脲佐菌素（ICV-STZ）动物模型中。STZ（3 mg/kg，一次）灌注大鼠后，通过ICV注射AICAR（AMPK激活剂）或溶剂。结果发现，与对照组相比，ICV-STZ组p-AMPK（AMPK的活性型）和SIRT 1活性降低，tau蛋白Ser 396和Thr 231位点磷酸化水平升高。ICV-STZ大鼠线粒体膜电位、复合物I活性、ATP水平和超氧化物歧化酶活性均显著降低，活性氧产生量显著增加。同时，ICV-STZ大鼠的凋亡细胞数量也比对照组强，这是由切割的caspase-3（活性型caspase-3）染色证实的。AMPK特异性激活剂AICAR可通过恢复AMPK活性来减轻ICV-STZ大鼠的生化和认知功能等病理改变。综上所述，这些结果表明AMPK激活通过修复ICV-STZ大鼠的线粒体功能来改善AD样病理变化。
Collecting evidence has shown that type 2 diabetes mellitus is a high risk factor of late-onset Alzheimer's disease (AD); the energy metabolic dysfunction is thought to be a convergent point of the two diseases. However, the underlying mechanisms of diabetes-associated AD are still unclear. In the current study, we investigated the roles of AMPK in diabetes-related AD-like pathologic features in models of intracerebroventricular-streptozotocin (ICV-STZ) animals. Rats infused with STZ (3 mg/kg, once) were followed by injection of AICAR (AMPK activator) or vehicle via ICV. We found that the level of p-AMPK (active type of AMPK) and SIRT1 activity were decreased and the level of phosphorylated tau was increased at Ser396 and Thr231 sites in ICV-STZ rats when compared with control rats. Mitochondria from ICV-STZ rats displayed a significant decrease in mitochondrial membrane potential, complex I activity, ATP level, and superoxide dismutase activity as well as an increase of reactive oxygen species production when compared with that from control rats. Meanwhile the number of apoptotic cell confirmed by cleaved caspase-3 (active type of caspase-3) staining was also stronger in ICV-STZ rats than control rats. All pathological changes including biochemistry and cognitive function could be mitigated through rescuing AMPK activity with its specific activator (AICAR) in ICV-STZ rats. Taken together, these results suggested that AMPK activation improves AD-like pathological changes via repairing mitochondrial functions in ICV-STZ rats.