TAK-875改善APP/PS1双转基因AD模型小鼠认知功能的作用

TAK-875 improves cognitive function of mice model with APP/PS1 double transgenic Alzheimer’s disease

目的探讨TAK-875对APP/PS1双转基因阿尔兹海默症(AD)模型小鼠认知障碍的治疗作用。方法60只APP/PS1 AD模型小鼠均分为模型对照组、多奈哌齐(1 mg/kg)阳性对照组和高TAK-875(16 mg/kg)、中TAK-875(8 mg/kg)和低TAK-875(4 mg/kg)三个剂量药物处理组。另取同窝C57BL/6J背景小鼠作为对照组。行水迷宫实验和避暗实验评估小鼠学习记忆能力。ELISA法检测小鼠大脑皮层和海马组织中β-淀粉样蛋白1-42(Aβ1-42)和β-分泌酶1(BACE1)的表达;Western blot法检测小鼠大脑皮层和海马组织中磷酸化cAMP应答元件结合蛋白(p-CREB)和脑源性神经营养因子(BDNF)水平。结果与模型对照组比较,多奈哌齐组、TAK-875中剂量组和高剂量组水迷宫实验中目标象限停留时间及穿台次数均增加,避暗实验中错误次数减少,穿台次数增加(P<0.05或P<0.01),而TAK-875低剂量组上述指标与其比较无统计学性差异(P>0.05)。多奈哌齐组和TAK-875高剂量组小鼠大脑皮层和海马组织中Aβ1-42和BACE1水平低于模型对照组(P<0.05或P<0.01),而TAK-875低剂量组上述指标与模型对照组比较无统计学性差异(P>0.05)。多奈哌齐组、TAK-875中剂量组和高剂量组小鼠大脑皮层和海马中p-CREB和BDNF水平高于模型对照组(P<0.05或P<0.01),而TAK-875低剂量组上述指标与模型对照组比较差异无统计学意义(P>0.05)。结论中、高剂量TAK-875能降低大脑皮层和海马组织中Aβ1-42与BACE1的表达,增加p-CREB和BDNF的表达,改善小鼠的学习记忆能力。

Objective To investigate the therapeutic effect of TAK-875 on cognitive impairment in mice model with APP/PS1 double transgenic Alzheimer’s disease(AD).Methods Sixty APP/PS1 AD model mice were divided into five groups of A(model control),B(treated with donepezil 1 mg/kg),C(treated with TAK-87516 mg/kg),D(treated with TAK-8758 mg/kg)and E(treated with TAK-8754 mg/kg).The C57 BL/6 J mice served as blank controls.Water maze test and dark-avoidance test were used to test the learning and memory ability of mice.The expressions ofβ-amyloid amyloid 1-42(Aβ1-42)andβ-secretase 1(BACE1)in mouse cerebral cortex and hippocampus were detected by ELISA.Western blot analysis was performed to detect phosphorylated cAMP-response element binding protein(p-CREB)and brain derived neurotrophic factor(BDNF)levels in mouse cerebral cortex and hippocampus.Results Compared with group A,the target quadrant dwell time and the number of penetrating times in the water maze test were increased,the number of errors decreased and the latency increased in groups of B,C and D(P<0.05 or P<0.01),which in group E were not statistically different(P>0.05).The levels of Aβ1-42 and BACE1 in the cerebral cortex and hippocampus in groups of B and C were lower than those in group A(P<0.05 or P<0.01),which were not significantly different between groups of A and E(P>0.05).The levels of p-CREB and BDNF in the cerebral cortex and hippocampus in groups of B,C and D were higher than those in group A(P<0.05 or P<0.01),which were not significantly different between groups of A and E(P>0.05).Conclusion The TAK-875 in medium and high doses can decrease the expressions of Aβ1-42 and BACE1 and increase the expressions of p-CREB and BDNF in the cerebral cortex and hippocampus,significantly improve the learning and memory ability of AD model mice.