Grammas Paula, Samany Pezhman Ghatreh, Thirumangalakudi Lakshmi
Garrison Institute on Aging and Department of Neuropsychiatry and Behavioral Sciences, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA.
J Alzheimers Dis. 2006 Mar;9(1):51-8. doi: 10.3233/jad-2006-9105.
The notion that microvascular abnormalities contribute to deleterious changes in the Alzheimer's disease (AD) brain is supported by work from our laboratory and others demonstrating biochemical and functional alterations of the microcirculation in AD. The objective of this study is to determine whether levels of neurotoxic (thrombin) and inflammatory (interleukin 8 (IL-8), integrins alphaVbeta3 and alphaVbeta5) proteins are altered in microvessels isolated from AD patients compared to levels in vessels obtained from non-demented age-matched controls. We also evaluate in AD and control microvessels expression of the transcription factor hypoxia-inducible factor 1-alpha(HIF1-alpha), which regulates pro-inflammatory gene expression, and the regulation of HIF1-alpha expression by thrombin in cultured brain endothelial cells. Our results indicate that in AD there are high levels of expression of the neurotoxic protease thrombin and the inflammation-associated proteins IL-8 and alphaVbeta3 and alphaVbeta5 integrins. HIF1-alpha is higher in AD microvessels compared to control and thrombin treatment of cultured brain endothelial cells results in increased expression of HIF1-alpha. These data suggest that in AD the cerebral microcirculation is a source of neurotoxic and inflammatory mediators and as such contributory to pathologic processes ongoing in the AD brain.
微血管异常导致阿尔茨海默病（AD）大脑发生有害变化这一观点，得到了我们实验室及其他研究机构工作的支持，这些研究表明AD患者的微循环存在生化和功能改变。本研究的目的是确定与非痴呆的年龄匹配对照组的血管相比，从AD患者分离出的微血管中神经毒性蛋白（凝血酶）和炎症蛋白（白细胞介素8（IL-8）、整合素αVβ3和αVβ5）的水平是否发生改变。我们还评估了AD和对照微血管中转录因子缺氧诱导因子1-α（HIF1-α）的表达，HIF1-α可调节促炎基因的表达，以及凝血酶对培养的脑内皮细胞中HIF1-α表达的调节。我们的结果表明，在AD中，神经毒性蛋白酶凝血酶以及与炎症相关的蛋白IL-8、αVβ3和αVβ5整合素的表达水平较高。与对照组相比，AD微血管中的HIF1-α水平更高，并且凝血酶处理培养的脑内皮细胞会导致HIF1-α表达增加。这些数据表明，在AD中，脑微循环是神经毒性和炎症介质的来源，因此对AD大脑中正在进行的病理过程有促进作用。
