阿尔茨海默病合并2型糖尿病模型小鼠海马血管损伤与认知改变

Hippocampal vascular injury and cognitive impairment in a mixed mouse models of Alzheimer’s disease and type 2 diabetes mellitus

目的探讨2型糖尿病(T2DM)对阿尔茨海默病(AD)脑血管发育的影响,及其对AD病理发生的影响机制。方法 40只6月龄APP/PS1转基因小鼠及同窝野生型小鼠采用高糖高脂饲料喂养6个月后,即各组小鼠12月龄时,连续4 d腹腔注射1%链脲佐菌素溶液,建立AD合并T2DM模型小鼠及单纯T2DM模型小鼠。设立4个组别:正常对照组、AD组、T2DM组、AD合并T2DM组,每组小鼠各10只。通过小鼠跳台实验检测小鼠学习记忆能力,墨汁灌注观察小鼠海马区血管形态,油红O染色、免疫荧光实验检测小鼠海马区各病理指标变化。结果与正常对照组相比,AD合并T2DM模型小鼠学习与记忆能力明显下降(P<0.05),海马区血管变细、密度明显减低(P<0.05),脂质沉积增多并出现小血管渗漏,且其海马区β-淀粉样前体蛋白裂解酶1(BACE-1)、核因子(NF)-κB与基质金属蛋白酶(MMP)-9表达增多(P<0.05)。结论 T2DM对小鼠学习记忆功能起负作用,通过促进AD病理变化加速AD模型小鼠脑血管病变,MMP-9的异常表达也可能是引起AD血管病变的原因之一。

Objective To study the effect of type 2 diabetes mellitus( T2 DM) on the cerebral blood vessels in Alzheimer’s disease( AD),and to explore its mechanism of influence on the pathogenesis of Alzheimer ’s disease.Methods To generate a mouse model with AD complicated with long-term T2 DM,forty 6-month-old APP/PS1 transgenic mice were fed with high-sugar and high-fat diet for 6 months,that was,when mice at 12 months of age,they were intraperitoneally injected with 1% streptozotocin solution for 4 consecutive days. Then,mice were randomly divided into 4 groups: the normal control group,AD model group,T2 DM model group and AD complicated with T2 DM model group,10 mice were used in each group. The learning and memory ability of the mice were tested by the mouse step-down assay,and the vascular morphology of the mice’s hippocampal CA1 area was observed by ink perfusion. Then oil red O staining and immunofluorescent staining were applied to test the pathological indices of the hippocampal area in the model. Results Compared with the control group,AD combined with T2 DM mice showed decreasing significantly abilities in the learning and memory( P < 0. 05),and the blood vessels in the hippocampus became thinner and the vascular density decreased.Moreover,T2 DM promoted lipid deposits and vascular leak in the hippocampus of the model. Additionally,the expression of β-site amyloid precursor protein cleaving enzyme-1( BACE-1),nuclear factor( NF)-κB and matrix metalloproteinase( MMP)-9 were increased compared with the controls in the hippocampal CA1 region. Conclusion T2 DM plays a negative regulatory role on learning and memory functions of mice,accelerates the onset of AD and result in cerebrovascular lesions.In addition,the abnormal expression of MMP-9 may also be one of the causes of AD vascular lesions.