Ma Lou-Yan, Lv Ya-Li, Huo Kang, Liu Jie, Shang Su-Hang, Fei Yu-Lang, Li Yan-Bo, Zhao Bei-Yu, Wei Meng, Deng Yong-Ning, Qu Qiu-Min
Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; The Second Department of Geriatrics, Xi'an Ninth Hospital, Xi'an, China.
The Second Department of Geriatrics, Xi'an Ninth Hospital, Xi'an, China.
Behav Brain Res. 2017 Mar 1;320:484-493. doi: 10.1016/j.bbr.2016.10.031. Epub 2016 Oct 20.
β-Amyloid (Aβ) deposition has a central role in the pathogenesis of Alzheimer disease (AD). Previous studies have indicated that as a risk factor for AD, diabetes mellitus (DM) could induce Aβ deposition in the brain, but the mechanism is not fully elucidated. Autophagy-lysosome is a cellular pathway involved in protein and organelle degradation. In the present study, we used streptozotocin (STZ)-induced diabetic rats to investigate whether autophagy-lysosome is related to Aβ clearance in DM. We found that DM rats had a longer escape latency and less frequent entry into the target zone than that of the control group (p<0.05) in the Morris water maze test. Meanwhile, hippocampal neuron damage and apoptosis (p<0.05) were found in the DM rats. The Aβ expression in the hippocampus significantly increased in the DM group compared with the control group (p<0.05). The markers of autophagy, beclin-1 and LC3 II, were increased (p<0.05), whereas LC3 I was decreased (p<0.05), and the ratio of LC3 II / I was increased as the time advanced (p<0.01). LAMP1 and LAMP2, which are the markers of lysosome function, were decreased in the hippocampus of DM rats (p<0.05). The Aβ deposition was correlated with beclin-1, LC3 II, and LC3 I positively (p<0.05), but with LAMP1 and LAMP2 negatively (p<0.05). These findings indicate that DM activated autophagy, but lysosome function was impaired. Autophagy-lysosome dysfunction may be involved in the Aβ deposition in diabetic cognitive impairment.
β-淀粉样蛋白（Aβ）沉积在阿尔茨海默病（AD）的发病机制中起核心作用。先前的研究表明，作为AD的一个危险因素，糖尿病（DM）可诱导大脑中的Aβ沉积，但其机制尚未完全阐明。自噬-溶酶体是一种参与蛋白质和细胞器降解的细胞途径。在本研究中，我们使用链脲佐菌素（STZ）诱导的糖尿病大鼠来研究自噬-溶酶体是否与DM中的Aβ清除有关。我们发现，在莫里斯水迷宫试验中，DM大鼠的逃避潜伏期比对照组更长，进入目标区域的频率更低（p<0.05）。同时，在DM大鼠中发现海马神经元损伤和凋亡（p<0.05）。与对照组相比，DM组海马中的Aβ表达显著增加（p<0.05）。自噬标志物beclin-1和LC3 II增加（p<0.05），而LC3 I减少（p<0.05），并且随着时间的推移，LC3 II / I的比率增加（p<0.01）。溶酶体功能标志物LAMP1和LAMP2在DM大鼠海马中减少（p<0.05）。Aβ沉积与beclin-1、LC3 II和LC3 I呈正相关（p<0.05），但与LAMP1和LAMP2呈负相关（p<0.05）。这些发现表明，DM激活了自噬，但溶酶体功能受损。自噬-溶酶体功能障碍可能参与糖尿病认知障碍中的Aβ沉积。
