糖尿病加速脑老化的成体干细胞机制

项目名称： 糖尿病加速脑老化的成体干细胞机制

项目编号： No.30872731

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 景玉宏

作者单位： 兰州大学

项目金额： 30万元

中文摘要： 糖尿病是胰岛素相对或绝对不足为主要原因，导致的糖脂代谢障碍为主要病理变化的代谢综合征，可以波及多个脏器。近年来也发现糖尿病可以导致中枢神经系统的损伤。研究项目基于1型和2型糖尿病动物模型，系统评价了糖尿病脑损伤的主要病理变化。着重研究了糖尿病状态对脑内成体干细胞状态的影响及分子机制，同时也研究了脑内胰岛素信号变化对下丘脑神经细胞的影响及其与自噬的关系。研究结果表明糖尿病可以导致中枢胰岛素信号下降，出现皮层、下丘脑及海马区广泛的神经细胞变性，在糖尿病4个月时出现海马萎缩，海马区Aβ34920;达增加，前额皮层锥体细胞及海马区锥体细胞树突棘数量减少，突触相关蛋白SYN表达减少。通过水迷宫和穿梭箱两种方法评价其学习记忆能力，发现4个月糖尿病鼠出现认知功能减退。对SVZ区和SGZ区成体干细胞的研究发现，糖尿病2个月动物表现为前体细胞增殖能力下降，BrdU和Ki67标记的阳性细胞数均减少，对新生细胞类型进行鉴定发现表达DCX的成神经细胞减少尤为明显。这种变化的机制因为脑内胰岛素信号水平下降，导致GSK3β30967;酸化水平下降，βatenin减少，抑制了细胞增殖所致。上述结果表明糖尿病可以抑制脑内成体干细胞。

中文关键词： 糖尿病;神经干细胞;脑老化;GSK3/catenin;自噬

英文摘要： Diabetes mellitus is characterized by insulin deficit, which lead to the glyco-lipoidosis involving to mutiple organs. Recently, many evidence indicate that brain was damaged within diabetes mellitus in clinical study and experiental study. Diabetic encephalopathology was systematicaly evaluated based on the type 1 and type 2 diabetic animal model.Our study focused on exploring the status of adult neural stem cells and underlying regulated mechanisms within suffering from diabetes mellitus. In addition, the alteration of insulin signals and autophagic signal in hypothalamus were studied under aberrant metabolic condition. The results show dabetes mellitus caused decline of brain insulin signalling accompanied with the neurodegeneration in cortex, hypothalamus and hippocampus. There are age-related pathologies including hippocampal atrophy, beta amyloid deposition, decreased dendritical spine, low level of synaptophasin in hippocampus and cortex. Ability of learning and memory was evaluated by Morris water maze and shuttle box, which indicates the cognition was impaired in diabetic rats. Ki67 positive cells in SVZ or SGZ significantly decrease in diabetic rats compared to the age-matched control group, Brdu positive cells in SVZ or SGZ are less in diabetic rats than that of the age-matched rats.Type A cells (GFAP labeling) in SVZ or SGZ significantly decrease in diabetic rats compared to the age-matched control group; Type B cells (DCX labeling) in SVZ or SGZ also decrease in diabetic rats compared to the age-matched control group.The precursor cells in SVZ or SGZ differentiated into less numbers of DCX +/ Brdu+ positive cells in diabetic rats than that of age-matched control rats. And the GFAP+ / Brdu+ positive cells in SVZ or SGZ also decrease in diabetic rats compared to the age-matched control group.The expression of P-GSK-3βIR-βnd βatenin were decreased in cortex and hippocampus of diabetic rats compared to the age-matched control group.These results indicate sustained high glucose causes desensitivity of insulin signaling, and inhibits the activity of GSK3-βfurther increase the degradation of βatenin in cortex, which may contribute to the decline of proliferation of precursor cells in SVZ and SGZ. In type 2 diabetic rats, aberrant metabolism lead to the hypothalamu injury associated with decline of autophagic signalling.

英文关键词： diabetes mellitus; neural stem cell; brain aging; GSK3/catenin; autophagy