VESSELS OF THE BRAIN IN AGING AND ALZHEIMER'S DISEASE

这个提议的目的是研究基本的细胞 衰老和痴呆的脑循环生物学， 确定大脑微循环的异常是否 与阿尔茨海默病的发病机制有关。 大脑是 一个需要大量不间断的 血液供应充足的氧气和代谢 基板，并处理不需要的产品。 还 脑毛细血管的内皮细胞位于界面处 在体循环和神经组织之间， 在维持神经元生长的稳定环境中的重要作用 功能和防止潜在的毒素进入 个脑袋 为了实现这一点，脑毛细血管内皮细胞是 具有独特的功能，如细胞间紧密的 连接点，重要水溶性分子的转运体， 如葡萄糖和酶系统，可以有效地防止 一些脂溶性毒素从血液进入大脑。 的 拟议的实验将采用免费的生物化学和 研究离体脑微血管的药理学技术 从受试者尸检中获得的人类大脑皮层组织 有或没有阿尔茨海默氏痴呆症，并从费舍尔-344大鼠的 三个年龄组。 实验将解决以下问题 主要研究方向：（1）人和大鼠的α和β肾上腺素受体 微血管 (2)利用哇巴因特异性结合的Na+，K+ ATP酶 方法. (3)葡萄糖转运蛋白在脑内的地位 受试者的微血管和局部脑膜 老年痴呆症 (4)对酶的研究 血脑屏障的“生化”方面。 (5)调查 对已知功能性蛋白质部分的影响，例如转铁蛋白 从血液输送到大脑。 更好地了解脑循环及其改变 功能可能是欣赏 循环的病理生理学。 拟议的研究可能 为进一步认识本病的发病机制提供科学依据 阿尔茨海默病和衰老中的神经功能障碍。

The goal of this proposal is to investigate the basic cellular biology of the brain circulation in aging and dementia and to determine whether abnormalities of the brain microcirculation are related to the pathogeneis in Alzheimer's Disease. The brain is a fastidious organ that requires a large volume of uninterrupted blood supply for adequate delivery of oxygen and metabolic substrates, and for disposal of unwanted products. Also, the endothelial cells of brain capillaries stand at the interface between the systemic circulation and nervous tissue and have a vital role in maintaining a stable environment for neuronal function and preventing the entry of potential toxins into the brain. To accomplish this, the brain capillary endothelium is endowed with unique features, such as tight intercellular junctions, transporters for essential water-soluble molecules such as glucose, and enzyme systems that can effectively prevent the entry of some lipid-soluble toxins from blood to brain. The proposed experiments will employ complimentary biochemical and pharmacological techniques to study isolated brain microvessels from human cerebral cortical tissue obtained autopsy from subjects with or without Alzheimer's dementia, and from Fischer-344 rats of three age groups. The experiments will address the following interests: (1) alpha and beta-adrenoceptors in human and rat microvessels. (2) Na+, K+ATPase using specific ouabain binding methods. (3) The status of the glucose transporter in brain microvessels and regional brain membranes of subjects with Alzheimer's dementia. (4) Studies of the enzymes that contribute to the "biochemical" aspects of the BBB. (5) Investigation of effects on known functional protein moieties, such as transferrin that are transported from blood to brain. Better understanding of the brain circulation and its altered functions may be a prerequisite for appreciating the pathophysiology of the circulation. The proposed research may provide scientific bases for understanding the pathogenesis of neurological dysfunction in Alzheimer's Disease and aging.