【摘要】 目的:观察PS1M146V/APPswe/tau P301L三转基因阿尔茨海默病(AD)(3xTg-AD)模型小鼠的步态改变以及探究scFv17对其的改善作用。方法:本实验首先选用6月龄3xTg-AD小鼠(n=18)和C57BL/6野生型(WT)小鼠(n=24),观察记录它们的步态行为,在12月龄时发现3xTg-AD小鼠的步态严重受损后,将上述两种小鼠随机分为野生型对照组(WT+PBS)(n=12)、野生型给药组(WT+scFv17)(n=12)、3xTg-AD对照组(3xTg-AD+PBS)(n=9)以及3xTg-AD小鼠给药组(3xTg-AD+scFv17)(n=9)四组。采用鼻饲方法,每次给予每只小鼠20μl的scFv17(1.5 mg/kg)或者等体积的PBS(0.01 mol/L),每周两次,连续给药12周后进行步态行为测试及小脑病理学检测。结果:与同月龄野生型小鼠比较,12月龄3xTg-AD小鼠后爪步幅宽度增大(P<0.01),摇摆时间百分比减小(P<0.01),站立时间百分比增大(P<0.01),运动协调和平衡能力严重受损; scFv17可改善12月龄3xTg-AD小鼠运动协调和平衡能力(P<0.01),改善3xTg-AD小鼠小脑浦肯野细胞的形态结构,增多3xTg-AD小鼠小脑浦肯野细胞的尼氏小体(P<0.01),减少3xTg-AD小鼠小脑皮层内淀粉样β蛋白(Aβ)斑块和浦肯野细胞胞内神经原纤维缠结(NFT)(P<0.01)。结论:3xTg-AD小鼠在12月龄时的运动协调和平衡能力明显受损,给予scFv17可明显改善12月龄3xTg-AD小鼠的步态紊乱,其作用机制可能与改善小脑浦肯野细胞结构与蛋白功能,减少Aβ斑块和NFT有关。更多还原

【Abstract】 Objective: To observe the gait changes of Alzheimer’s disease PS1 M146 V/APPswe/tau P301 L triple-transgenic( 3xTg-AD) mice and to investigate the improvement effect of single chain variable domain antibody fragment 17( scFv17) on the gait.Methods: In the present study,a selection of 6-month-old 3xTg-AD mice( n = 18) and C57 BL/6 wild-type mice( n = 24) was performed. First,we observed their gait changes and found that the gait of 12-month-old 3xTg-AD mice was severely damaged. Then,the two groups of mice were randomly divided into four groups: WT + PBS( n = 12),WT + scFv17( n = 12),3xTg-AD + PBS( n = 9) and3xTg-AD+scFv17( n = 9). The gait behavior test and pathological test were performed after 12 weeks’ continuous administration of scFv17( 1.5 mg/kg) or an equal volume of PBS( 0.01 mol/L) by nasal gavage twice a week. Results: Compared with the same month old wild type mice,the rear track width of 12 month old 3xTg-AD mice was increased( P<0.01),swing time percent was decreased( P<0.01),stance time percent was increased( P < 0. 01),so the ability of movement coordination and balance was seriously damaged.Sc Fv17 could improve the coordination and balance ability of 12 month old 3xTg-AD mice( P < 0.01). The morphological structure of3xTg-AD mice cerebellar Purkinje cells was improved. The treatment of scFv17 increased the Nissl body number of the cerebellar Purkinje cells of 3xTg-AD mice( P<0.01). scFv17 reduced the amyloid β protein( Aβ) plaques in the cerebellar cortex of 3xTg-AD mice( P<0.01),and scFv17 reduced the intracellular neurofibrillary tangles( NFT) of the cerebellar Purkinje cells of the 3xTg-AD mice( P<0.01). Conclusion: The coordination and balance ability of 3xTg-AD mice was significantly impaired. Sc Fv17 can improve gait behaviour in the 3xTg-AD significantly.The mechanism may be related to the improvement of the structure and protein function of cerebellar Purkinje cells,and the eliminating of the Aβ plaques and the neurofibrillary tangles.更多还原