Beclin-1- mediated autophagy may be involved in the elderly cognitive and affective disorders in streptozotocin-induced diabetic mice.
Beclin-1- mediated autophagy may be involved in the elderly cognitive and affective disorders in streptozotocin-induced diabetic mice.
复制标题
Beclin-1介导的自噬可能与链脲佐菌素诱导的糖尿病小鼠老年认知和情感障碍有关
DOI：
10.1186/s40035-016-0070-4
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发表时间：
2016
影响因子：
12.6
通讯作者：
Liu YC
中科院分区：
文献类型：
--
作者：
Guan ZF;Zhou XL;Zhang XM;Zhang Y;Wang YM;Guo QL;Ji G;Wu GF;Wang NN;Yang H;Yu ZY;Zhou HG;Guo JC;Liu YC
背景：糖尿病是最常见的代谢性疾病，慢性并发症较多，认知障碍是糖尿病患者常见的并发症之一。先前的研究表明，自噬在代谢综合征、糖尿病和其他疾病的进展中起着重要作用。因此，我们研究了老年糖尿病小鼠是否容易与认知和情感障碍相关，以及Beclin-1介导的自噬是否可能参与了这一病理过程。方法：采用高脂饮食/链脲佐菌素(STZ)注射诱导的糖尿病C57小鼠。采用Morris水迷宫和恐惧条件测验检测认知功能障碍。采用悬尾试验和强迫游泳试验检测情感性障碍。应用磁共振成像技术观察脑组织形态和代谢的变化。应用18F-脱氧葡萄糖正电子发射断层扫描(FDG-PET)观察老年糖尿病小鼠脑内代谢的变化。结果：1.与对照组相比，糖尿病组小鼠的空间记忆和条件性恐惧记忆能力明显降低(P均<0.05)，抑郁倾向明显增加(P<0.05)。2.MRI显示老年糖尿病小鼠多数伴有多发性脑小血管病变。有些人甚至出现了海马区萎缩、脑室扩张和脑白质疏松。3.FDG-PET-CT发现杏仁核和海马区的糖代谢明显低于正常老龄小鼠(P<；0.05)。4.电子显微镜观察发现，虽然自噬小体分布不广，两组间无显著差异，但与正常老年小鼠相比，老年糖尿病小鼠脑内存在明显的细胞水肿、髓鞘减少和细胞内脂褐素升高。5.与正常老年小鼠相比，STZ诱导的糖尿病小鼠海马区和纹状体中p62蛋白表达水平升高，而Beclin1蛋白表达水平显著降低(P<；0.05)。结论：与正常老年小鼠相比，糖尿病老年小鼠更易发生脑小血管病变，并伴有认知和情感障碍，这可能与糖尿病老年小鼠海马区和杏仁核糖代谢显著降低有关。Beclin1介导的海马区自噬可能在STZ诱导的老年糖尿病小鼠认知和情感障碍中起重要作用。
Background:Diabetes is the most common metabolic disease with many chronic complications, and cognitive disorders are one of the common complications in patients with diabetes. Previous studies have showed that autophagy played important roles in the progression of metabolic syndrome, diabetes and other diseases. So we investigated whether aged diabetic mice are prone to be associated with the cognitive and affective disorders and whether Beclin-1-mediated autophagy might be involved in thepahological process.Methods:High-fat diet/streptozotocin (STZ) injection-induced diabetic C57 mice were adopted in this study. Cognitive disorders were detected by Morris water maze and fear conditional test. Affective disorders were detected by tail suspension test and forced swimming test. Magnetic resonance imaging was applied to observe changes of morphology and metabolism in the brain. The 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) was used to assess metabolism changes in the brain of aged diabetic mice. Autophagy were evaluated by Beclin- 1, LC3II/I and P62, which were detected by western blot analysis and observed by electron microscopy.Results:1. Compared with control group, diabetes mice showed significantly decreasing abilities in spatial memory and conditioned fear memory (allP< 0.05), and increasing tendency of depression (P< 0.05). 2. MRI showed that the majority of elderly diabetic mice were associated with multiple cerebral small vessel disease. Some even showed hippocampal atrophy, ventricular dilatation and leukoaraiosis. 3. FDG-PET-CT discovered that the glucose metabolism in the amygdala and hippocampus was significantly decreased compared with normal aged mice (P< 0.05). 4. Electron microscopy found that, although autophagy bodies was not widespread, and there was no significant difference between the two groups, yet compared with normal aged mice, apparent cell edema, myelinated tow reduction and intracellular lipofuscin augmentation existed in elderly diabetic mice brain. 5. The level of p62 was increased in the STZ-induced diabetic mice hippocampus and striatum, and beclin1 protein expression were significantly decreased in diabetic mice hippocampus compared with normal aged mice (P< 0.05). There was a upward trend of the ratio of LC3II/I in hippocampus, cortex and striatum, but no statistically difference between the two groups.Conclusion:Compared with normal aged mice, diabetic aged mice were apt to cerebral small vessel disease and associated with cognitive and affective disorders, which may be related to the significantly reduced glucose metabolism in hippocampus and amygdala. Beclin1 mediated autophagy in hippocampus probably played an important role in cognitive and affective disorders of STZ-induced aged diabetic mice.