This proposal describes experiments to study expression of the Alzheimer's disease (AD) associated beta/A4 amyloid precursor protein (APP) in brain injury induced by ischemia. Brain tissue from rats subjected to focal or global cerebral ischemia will be analyzed immunochemically to evaluate the changes in distribution and time course of APP expression resulting from the insults. Further analyses by immunocytochemistry will entail identifying types of brain cells involved in altered APP expression after ischemic injury. For comparison, a small sample of brain tissues obtained at autopsy from humans who died with stroke episodes will be examined. Preliminary evidence from our laboratory suggests that APP immunoreactivity, detected by various antibodies to fragments of APP, is increased in perifocal regions and brain white matter of rats with permanent and reversible occlusions of the middle cerebral artery. These studies are based on the hypothesis that localized ischemic insults or cerebrovascular insufficiency leads to increased expression of APP in surviving brain cells. The project has direct relevance to AD in that chronic hypoperfusion or cerebrovascular insufficiency indicated by reduced cerebral blood flow may cause increased expression of APP which may in turn lead to deposition of the insoluble beta amyloid. It is expected that these studies will provide a basis for further intensive studies and open up therapeutic possibilities to impede the overexpression of APP or the aggregation of beta amyloid.
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