Vascular basement membrane alterations and β-amyloid accumulations in an animal model of cerebral small vessel disease
Vascular basement membrane alterations and β-amyloid accumulations in an animal model of cerebral small vessel disease
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DOI：
10.1042/cs20170004
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发表时间：
2017-05-01
期刊：
影响因子：
6
通讯作者：
Schreiber, Stefanie
中科院分区：
文献类型：
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作者：
Held, Friederike;Morris, Alan W. J.;Schreiber, Stefanie
非淀粉样脑小血管病（Non-amyloid cerebral small vessel disease，CSVD）和淀粉样脑血管病（cerebral amyloid angiopathy，CAA）可能通过小血管基底膜（basement membrane，BM）损伤和细胞外基质（extracellular matrix，ECM）改变，导致β-淀粉样蛋白（beta-amyloid，A β）转运和降解障碍而相互关联。我们分析了自发性高血压卒中易感大鼠（SHRSP）（一种非转基因CSVD模型）的BM变化和血管壁A β沉积模式。在45只SHRSP和38只18 - 32周龄Wistar大鼠中：（i）定量血管IV型胶原和层粘连蛋白免疫染色的面积百分比;（ii）使用透射电子显微镜（TEM）分析毛细血管BM厚度以及内皮和周细胞病理变化;（iii）评估血管A β的存在。与对照组相比，SHRSP在纹状体和丘脑中表现出显著更高的IV型胶原免疫染色面积百分比。SHRSP还显示了年龄依赖性增加毛细血管BM厚度和内皮细胞空泡（小窝）内皮质下区域。在皮质（在额顶叶区域内发现的发生率最高）、纹状体、丘脑和海马中观察到小血管壁中的内源性A β沉积。在小血管壁损伤部位经常检测到血管β-淀粉样蛋白积聚。我们的数据表明，在SHRSP的小血管中的胶原IV的表达和BM的超微结构的变化。改变伴随着内源性A β的血管沉积。β-淀粉样蛋白清除沿着血管周围和内皮途径受损以及细胞外A β降解失败可能是连接非淀粉样蛋白CSVD和CAA的关键机制。
Non-amyloid cerebral small vessel disease (CSVD) and cerebral amyloid angiopathy (CAA) may be interrelated through the damaged basement membranes (BMs) and extracellular matrix changes of small vessels, resulting in a failure of beta-amyloid (A beta) transport and degradation. We analyzed BM changes and the pattern of deposition of A beta in the walls of blood vessels in spontaneously hypertensive stroke-prone rats (SHRSP), a non-transgenic CSVD model. In 45 SHRSP and 38 Wistar rats aged 18 to 32 weeks: (i) the percentage area immun-ostained for vascular collagen IV and laminin was quantified; (ii) the capillary BM thickness as well as endothelial and pericyte pathological changes were analysed using transmission electron microscopy (TEM); and (iii) the presence of vascular A beta was assessed. Compared with controls, SHRSP exhibited a significantly higher percentage area immunostained with collagen IV in the striatum and thalamus. SHRSP also revealed an age-dependent increase of the capillary BM thickness and of endothelial vacuoles (caveolae) within subcortical regions. Endogenous A beta deposits in the walls of small blood vessels were observed in the cortex (with the highest incidence found within fronto-parietal areas), striatum, thalamus and hippocampus. Vascular beta-amyloid accumulations were frequently detected at sites of small vessel wall damage. Our data demonstrate changes in the expression of collagen IV and of the ultrastructure of BMs in the small vessels of SHRSP. Alterations are accompanied by vascular deposits of endogenous A beta. Impaired beta-amyloid clearance along perivascular and endothelial pathways and failure of extracellular A beta degradation may be the key mechanisms connecting non-amyloid CSVD and CAA.