Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid- from the mouse brain
Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid- from the mouse brain
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DOI：
10.1111/acel.12045
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发表时间：
2013-04-01
期刊：
影响因子：
7.8
通讯作者：
Carare, Roxana O.
中科院分区：
文献类型：
--
作者：
Hawkes, Cheryl A.;Gatherer, Maureen;Carare, Roxana O.
脑淀粉样血管病（CAA）和阿尔茨海默病（AD）的发生与淀粉样蛋白（A）不能沿沿着血管周围基底膜从脑中消除有关，血管周围基底膜形成从脑中排出间质液和溶质的途径。在AD的转基因APP小鼠模型中，大脑淀粉样蛋白血管病的严重程度在大脑皮层和海马体中较大，在丘脑中居中，并且在纹状体中最小。在这项研究中，我们测试的假设，年龄相关的区域变化（1）血管基底膜和（2）血管周围引流的A有助于不同的区域模式的CAA在小鼠大脑。对2个月、7个月和23个月大的小鼠进行的定量电子显微镜检查显示，大脑皮层、海马和丘脑中的毛细血管基底膜出现显著的年龄相关性增厚，但纹状体中没有。从蛋白质印迹和免疫细胞化学实验的结果显示，随着年龄的增长，皮质和海马中的胶原IV显着减少，皮质和纹状体中的层粘连蛋白和巢蛋白2减少。将可溶性A注射到海马或丘脑中显示出与年龄相关的海马而不是丘脑的血管周围引流减少。研究结果表明，血管基底膜和血管周围引流随年龄的变化在小鼠脑区之间存在差异，这种变化可能有助于解释AD中A在脑中的差异沉积，并可能有助于开发改进的治疗策略以从AD中的脑中去除A。
Development of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) is associated with failure of elimination of amyloid- (A) from the brain along perivascular basement membranes that form the pathways for drainage of interstitial fluid and solutes from the brain. In transgenic APP mouse models of AD, the severity of cerebral amyloid angiopathy is greater in the cerebral cortex and hippocampus, intermediate in the thalamus, and least in the striatum. In this study we test the hypothesis that age-related regional variation in (1) vascular basement membranes and (2) perivascular drainage of A contribute to the different regional patterns of CAA in the mouse brain. Quantitative electron microscopy of the brains of 2-, 7-, and 23-month-old mice revealed significant age-related thickening of capillary basement membranes in cerebral cortex, hippocampus, and thalamus, but not in the striatum. Results from Western blotting and immunocytochemistry experiments showed a significant reduction in collagen IV in the cortex and hippocampus with age and a reduction in laminin and nidogen 2 in the cortex and striatum. Injection of soluble A into the hippocampus or thalamus showed an age-related reduction in perivascular drainage from the hippocampus but not from the thalamus. The results of the study suggest that changes in vascular basement membranes and perivascular drainage with age differ between brain regions, in the mouse, in a manner that may help to explain the differential deposition of A in the brain in AD and may facilitate development of improved therapeutic strategies to remove A from the brain in AD.