摘要
目的探讨矢车菊素-3-葡萄糖苷(Cy3G)对阿尔茨海默病(AD)模型小鼠糖脂代谢的影响。方法将7月龄APP^(swe)/PS1^(ΔE9)(PAP)的AD模型小鼠随机分为AD模型组(PAP)、Cy3G治疗组(PAPCy,5mg/kg/d)及同窝阴性对照组(n PAP);另外选择相同月龄的正常野生型C57BL/6J小鼠分别作为空白对照组(WT)和Cy3G干预组(WTCy,5mg/kg/d);每组12只,雌雄各半。Cy3G灌胃8周后,用MicroPET/CT检测脑葡萄糖代谢率;血生化方法检测小鼠肝肾功能及脂代谢相关指标;取全脑称重并计算脏器系数,HE染色进行组织病理学检查;透射电镜观察海马中老年斑沉积情况;Western-blot分析Jun氨基末端激酶(JNK)和蛋白激酶B(AKT)的表达情况。结果MicroPET/CT结果显示,与WT组相比,PAP组小鼠脑^(18)F-FDG的摄取率显著降低(P<0.05),尤其在额叶和海马区降低尤为明显;与PAP组相比,PAPCy组小鼠额叶和海马区的^(18)F-FDG的摄取率显著升高(P<0.05)。血生化结果显示,与WT组相比,PAP组小鼠血清中天冬氨酸转氨酶(AST)和乳酸脱氢酶(LDH)水平显著升高(P<0.05),脂代谢指标相对正常;与PAP组相比,PAPCy组血清LDH水平显著降低(P<0.05)。脑组织HE染色未发现异常,但是在脑系数比较中,与WT组相比,PAP组小鼠脑系数显著降低(P<0.05);与PAP组相比,PAPCy组小鼠大脑的脑系数显著升高(P<0.05)。透射电镜下观察发现,WT组、WTCy组及nPAP组海马中未见有老年斑沉积,PAP组小鼠海马可观察到有老年斑沉积,而PAPCy组小鼠海马中老年斑沉积有所减少。Western blot结果显示,与WT组相比,PAP组JNK蛋白水平显著降低(P<0.05)、AKT蛋白水平显著升高(P<0.05);与PAP组相比,PAPCy组JNK蛋白水平显著升高(P<0.05),而AKT蛋白水平显著降低(P<0.05)。结论 Cy3G可以有效改善AD模型小鼠脑葡萄糖代谢障碍,但对脂代谢调节并不显著,同时还能抑制大脑海马中老年斑的沉积。提示,Cy3G可能是通过JNK/AKT通路调节胰岛素抵抗和炎症反应。
Objective To investigate the effect of cyaniding-3-glucoside （Cy3G） on glucose and lipid metabolism in the Appsw/PS1 At9 mouse model of Alzheimer＇ s disease （AD）. Methods Seven-month-old Appsw/PS1 AE9 （PAP） mice were randomly divided into model group （PAP） , Cy3G treatment group （PAPCy, 5 mg/kg/d） and negative-control group （nPAP）. In addition, age-matched and normal wild-type of C57BL/6J mice were selected and divided into vehicle group （WT） , Cy3G intervention group （WTCy, 5 mg/kg/d）. Each group containing 12 mice, with equal number of male and female mice. After 8-week Cy3G supplementation, microPET/CT was used to measure cerebral glucose metabolism rate of mice in each group. Biochemical methods were used to detect the liver / kidney function as well as indicators associated with lipid metabolism. After weighting brain tissue, the brain coefficient was tested and pathological examination was used to observe tissues changes. Transmission electron microscope was used to observe neuropathological amyloid plaques deposition. Western- blot was used to determine protein levels of AKT and JNK. Results Compared with the WT group, PAP mice had low levels of IS F-FDG uptake rates, especially in the regions of the frontal lobe and hippocampus accompanied by the decreased brain coefficient and amyloid plaques deposition in hippocampus. And levels of aspartate transaminase （AST） and lactic dehydrogenase （LDH） were also increased in PAP mice, but lipid metabolism index was relatively normal. In addition, the expression of JNK was decreased and AKT was increased in mice of PAP. However, in the PAPCy group, ISF-FDG uptake rates were obviously increased in the regions of the frontal lobe and hippocampus compared with those in the PAP mice. And the reduction of brain atrophy and amyloid plaques deposition, normal lipid metabolism and no obvious liver/kidney toxicity were also observed. Cy3G also could reverse the changes of JNK and AKT protein. Conclusions Cy3G can improve glucose metabolism disorders instead of lipid metabolism, inhibit the senile plaques deposition in hippocampus and regulate insulin resistance and inflammatory reaction associated with JNK/AKT pathway. Thus, Cy3G has a good safety profile and may be used as an ideal alternative to traditional disease-modifying treatments against AD.
出处
《中国比较医学杂志》
CAS
北大核心
2016年第7期15-23,共9页
Chinese Journal of Comparative Medicine
基金
国家自然基金(81500938)
协和青年基金(3332015151)
