增龄性脑血管相关改变对阿尔茨海默病模型小鼠SAMP8认知能力的影响

Age-related changes in cerebral blood vessels influencing cognitive ability in SAMP8 mouse models of AD

目的探讨脑血流量、血脑屏障（BBB）通透性、脑葡萄糖跨膜转运蛋白表达情况随年龄增大对阿尔茨海默病（AD）模型小鼠SAMP8认知能力的影响。方法选择SAMP8小鼠及正常同源抗快速老化小鼠RI（SAMR1）各10只进行观察。采用Moms水迷宫测定小鼠的学习记忆能力，激光多普勒仪测定脑血流量，荧光分光光度计法测定BBB通透性，Westernblotting测定葡萄糖转运蛋白（GLUT）I和3的表达。结果与SAMR1相比，SAMP8的认知能力早在4月龄时即已出现明显损伤，表现为思维僵化、学习过程减慢。随着年龄增大，SAMP8脑血流明显下降，BBB渗漏更为严重．皮层和海马的GLUT1和GLUT3表达也有不同程度地改变。脑血流、BBB完整性、GLUT1和GLUT3表达受年龄和品系影响明显，并与认知能力高度相关。结论衰老及缺血引起的血管损伤、能量供给不足是造成AD神经元功能异常及导致认知障碍的主要原因。

Objective To explore the influence of age-related changes in the cerebral blood vessels （cerebral blood flow, blood-brain barrier integrity, and level of glucose transporter GLUT]） in cognitive ability of SAMP8 mouse models of AD. Methods Ten SAMP8 mice and 10 homologous anti-senescence accelerated mice R1 （SAMR1） were chosen in our study; spatial learning and memory abilities of these mice were assessed using Morris water maze; cerebral blood flow was determined by laser Doppler flowmeter; blood-brain barrier （BBB） permeability was examined by fluorescence spectrophotometer; and expressions of GLUT1 and GLUT3 were determined using Western blotting. Results The cognitive abilities of SAMP8 mice damaged apparently even at 4 months of age as compared with those of SAMR1 mice, showing rigid thinking pattern and slow learning process in their Morris water maze test. With increasing of age, much obvious decrement in cerebral blood flow and severe BBB leakage was observed in SAMP8 mice; moreover, alterations in GLUT1 and GLUT3 expressions in the cortex and hippocampus of SAMP8 mice were observed. The cerebral blood flow, BBB integrity, and expressions of GLUT1 and GLUT3 were significantly affected by age and strain, and closely associated with cognitive abilities. Conclusion The alterations in cerebral blood flow and energy failure induced by aging and vascular insults are the reasons for neuron dysfunction and cognitive impairment in mice models of AD.