van Helmond Z K, Miners J S, Bednall E, Chalmers K A, Zhang Y, Wilcock G K, Love S, Kehoe P G
Dementia Research Group, Institute of Clinical Neurosciences, Clinical Science at North Bristol, University of Bristol, Frenchay Hospital, Bristol, UK.
Neuropathol Appl Neurobiol. 2007 Jun;33(3):317-27. doi: 10.1111/j.1365-2990.2006.00815.x.
Cerebral amyloid angiopathy (CAA) affects over 90% of patients with Alzheimer's disease (AD) and increases the risk of cerebral haemorrhage and infarction. Caveolae--cholesterol-enriched plasmalemmal microinvaginations--are implicated in the production of amyloid beta peptide (Abeta). Caveolin-1 (CAV-1) is essential for the formation of caveolae. Caveolin-2 (CAV-2) is expressed at the plasma membrane only when in a stable hetero-oligomeric complex with CAV-1. CAV-1 and CAV-2 are highly co-expressed by endothelium and smooth muscle. Recent studies suggest that down-regulation of CAV-1 causes a reduction in alpha-secretase activity and consequent accumulation of Abeta. We have used quantitative immunohistochemical techniques to assess the relationship between CAV-1 and CAV-2 with respect to Abeta accumulation in the cerebral vasculature in a series of post mortem brains. CAV-1 and CAV-2 were co-expressed within the tunica media and endothelium of cerebral blood vessels. There were regional differences in CAV-1 immunolabelling, which was significantly greater in the frontal cortex and white matter than in the parietal lobe (in both control and AD cases) or the temporal lobe (in AD alone). However, CAV-1 labelling in AD did not differ from that in controls in any of the three lobes examined. Assessment of CAV-1 labelling in relation to the severity of CAA showed CAV-1 to be significantly increased in the frontal white matter in a subgroup of AD cases with absent/mild CAA compared with controls with absent/mild CAA and to AD cases with moderate/severe CAA, but the latter groups did not show significant differences from one another. CAV-1 labelling did not vary with age, gender, APOE genotype, post mortem delay or brain weight. Only segments of blood vessels with particularly abundant Abeta and extensive loss of smooth muscle actin showed loss of CAV-1 and CAV-2 from the tunica media. Within these vessels endothelial CAV-1 was preserved and discontinuous CAV-2 labelling was noted along the outer aspect of the vessel wall. Our findings suggest that alterations in the expression of vascular CAV-1 and CAV-2 are unlikely to play a role in the development of CAA in AD.
脑淀粉样血管病（CAA）影响超过90%的阿尔茨海默病（AD）患者，并增加脑出血和梗死的风险。小窝——富含胆固醇的质膜微内陷——与β淀粉样肽（Aβ）的产生有关。小窝蛋白-1（CAV-1）对小窝的形成至关重要。小窝蛋白-2（CAV-2）仅在与CAV-1形成稳定的异源寡聚复合物时才在质膜上表达。CAV-1和CAV-2在内皮和平滑肌中高度共表达。最近的研究表明，CAV-1的下调会导致α-分泌酶活性降低，从而导致Aβ积累。我们使用定量免疫组织化学技术评估了一系列死后大脑中CAV-1和CAV-2与脑脉管系统中Aβ积累之间的关系。CAV-1和CAV-2在脑血容器的中膜和内皮中共表达。CAV-1免疫标记存在区域差异，在额叶皮质和白质中显著高于顶叶（在对照和AD病例中）或颞叶（仅在AD中）。然而，在所检查的三个叶中，AD中的CAV-1标记与对照中的没有差异。与CAA严重程度相关的CAV-1标记评估显示，与无/轻度CAA的对照和中度/重度CAA的AD病例相比，在无/轻度CAA的AD病例亚组中，额叶白质中的CAV-1显著增加，但后两组之间没有显著差异。CAV-1标记不随年龄、性别、APOE基因型、死后延迟或脑重量而变化。只有Aβ特别丰富且平滑肌肌动蛋白大量丢失的血管段显示中膜中CAV-1和CAV-2丢失。在这些血管内，内皮CAV-1得以保留，并且在血管壁外侧观察到不连续的CAV-2标记。我们的研究结果表明，血管CAV-1和CAV-2表达的改变不太可能在AD中CAA的发展中起作用。
