The broad objectives of this proposal are: (l) to determine when the amyloid P component is incorporated into the intracellular and extracellular brain lesions of Alzheimer's disease. (2) to investigate the potential in vivo sequelae of microinjection of the amyloid P component, obtained from Alzheimer neural tissues into rodent brains at different ages. The first objective will be carried out by single- and double-antigen immunohistochemistry in brains from Alzheimer patients and neurologically intact aged controls. Each Alzheimer brain will be carefully staged by histopathological methods to determine the severity of degeneration both at the gross, regional and microscopic lesion levels. Thereafter, the immunolabeling of the amyloid P component will be compared by quantitative stereological methods to early and late markers of Alzheimer lesions. The integrity of the neural defense mechanisms (both intra- and extracellular) and the microenvironment surrounding the deposits of the amyloid P component will also be investigated. Results from the first objective will point out when the amyloid P component becomes incorporated during the temporal sequence of Alzheimer lesion formation and whether its presence in the brain correlates to changes in the integrity of brain defense mechanisms and microenvironment. The second objective of this study will be carried out by microinjection of amyloid P component in the rodent brain at different ages. The amyloid P component used in these experiments will be extracted and purified from Alzheimer brains. Control animals will receive either amyloid P component obtained from normal aged brains or the carrier solution which will be Tris-saline. Following selected survival periods of up to 6 months, the fate of the amyloid P component deposit and its effects on the surrounding brain cells and microenvironment will be determined by quantitative stereological methods. This portion of the study will focus on the potential brain clearance mechanisms of the amyloid P component deposits and the effects of age on the efficiency of these mechanisms. The proposed study will add to our understanding of the potential etiological role of the amyloid P component in the process of Alzheimer lesion formation. Systematic study of the role played by each component of Alzheimer lesions will allow for future therapeutic strategies.
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