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.
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