Garrison Institute on Aging and Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
Cleve Clin J Med. 2011 Aug;78 Suppl 1:S50-3. doi: 10.3949/ccjm.78.s1.09.
Our laboratory has documented that brain microvessels derived from patients with Alzheimer disease (AD) express or release a myriad of factors that have been implicated in vascular activation and angiogenesis. In addition, we have documented that signaling cascades associated with vascular activation and angiogenesis are upregulated in AD-derived brain microvessels. These results are consistent with emerging data suggesting that factors and processes characteristic of vascular activation and angiogenesis are found in the AD brain. Despite increases in proangiogenic factors and signals in the AD brain, however, evidence for increased vascularity in AD is lacking. Cerebral hypoperfusion/hypoxia, a potent stimulus for vascular activation and angiogenesis, triggers hypometabolic, cognitive, and degenerative changes in the brain. In our working model, hypoxia stimulates the angiogenic process; yet, there is no new vessel growth. Therefore, there are no feedback signals to shut off vascular activation, and endothelial cells become irreversibly activated. This activation results in release of a large number of proteases, inflammatory proteins, and other gene products with biologic activity that can injure or kill neurons. Pathologic activation of brain vasculature may contribute noxious mediators that lead to neuronal injury and disease processes in AD brains. This concept is supported by preliminary experiments in our laboratory, which show that pharmacologic blockade of vascular activation improves cognitive function in an animal model of AD. Thus, "vascular activation" could be a novel, unexplored therapeutic target in AD.
我们的实验室已经证明，源自阿尔茨海默病（AD）患者的脑微血管表达或释放了许多因子，这些因子与血管激活和血管生成有关。此外，我们还记录到与血管激活和血管生成相关的信号级联在 AD 衍生的脑微血管中上调。这些结果与新出现的数据一致，即血管激活和血管生成的特征因子和过程存在于 AD 大脑中。然而，尽管 AD 大脑中的促血管生成因子和信号增加，但缺乏 AD 中血管增多的证据。脑灌注/缺氧是血管激活和血管生成的有力刺激因素，会引发脑代谢、认知和退行性变化。在我们的工作模型中，缺氧刺激血管生成过程；然而，没有新的血管生长。因此，没有反馈信号来关闭血管激活，内皮细胞变得不可逆地激活。这种激活导致大量具有生物活性的蛋白酶、炎症蛋白和其他基因产物的释放，这些产物可能会损伤或杀死神经元。脑血管的病理性激活可能会产生有害的介质，导致 AD 大脑中的神经元损伤和疾病过程。我们实验室的初步实验支持这一概念，该实验表明，血管激活的药理学阻断可改善 AD 动物模型的认知功能。因此，“血管激活”可能是 AD 中一个新颖的、尚未探索的治疗靶点。
