The Neuropathology Core C, serves as a focal point to address the central question of this program project: What are the pathogenic cerebrovascular mechanisms in the aging brain that determine the relationships of cerebrovascular amyloidosis to age-dependent Chronic vascular activation and injury, and to the initiation of brain injury and/or stroke? The Core will prepare post-mortem human CNS tissues and accession non-human primate CNS tissues from the animal core . Four of the 4 projects will directly receive tissues from the Core. Brains with clinically and neuropathologically confirmed Alzheimer's disease (AD), will be compared to normal, young, and aged control brains, and those with other non-AD dementias. Parallel studies will be done on aged and adult squirrel and rhesus monkey brains as non-human primate models for vascular and parenchymal amyloid deposits respectively. The amyloid-related vasculopathy will be defined as to regional distribution, vessel sizes and type. Fresh brain tissues will serve as a source of endothelial and smooth muscle cells for cultures and for ApoE isotyping. Vasculopathy with amyloid burden assessed histochemically, and immunocytochemically for Abeta peptide type, will be correlated with distribution of receptors such as gp330/megalin, a member of the LDL receptor family that binds Abeta/APO-J complex; RAGE, for Abeta binding; macrophage markers )CD11b, CD68); cell surface adhesion molecules (PECAM-1 and PAF receptors), and hemostasis markers (CPA, thrombomodulin). Electron microscopy, including immunocytochemistry with the above antibodies will identify disease-related translocations of these receptors. Our database will track tissue distribution from each patient to every investigator. Results of studies with human tissues with human tissues will be compared among the projects including project 3, which examines a murine transgenic model of RAGE. These studies are complementary. and underlie functional relationships of Abeta and the four cellular components, endothelial, smooth muscle, pericytes and astrocytes, which participate in the blood-brain barrier.
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