Recent evidence shows that the amyloid beta protein precursor (ABPP) is secreted from cells and can be incorporated into extracellular matrix (ECM). ECM is a major component of the developing nervous system and it is also juxtapositioned between the pre and post synaptic cells of CNS synapses. It is possible that Alzheimer's plaques and associated cognitive losses arise from the aberrant metabolism of ABPP in ECM. Alternatively, altered expression of ABPP in Alzheimer's patients may change the synthesis and breakdown of other ECM components. To test these alternatives, we propose to examine the effect of ABPP on the metabolism of extracellular matrix deposited by clonal nerve cell lines as well as the effect of proteases secreted by CNS cells on the breakdown of ABPP in ECM. These studies will use rodent nerve cell lines which synthesize ABPP as well as a rat cell , which makes no ABPP of its own, and a derivative of this line transfected with human ABPP. Specifically, the breakdown of metabolically labeled ECM deposited by neuronal cell lines will be induced by proteases, and the effect of the forms of ABPP with and without protease inhibitor on this process examined. In addition, the effects of ABPP on its own breakdown within the ECM will be examined. These experiments should either support or rule out the possibility that ABPP is involved in the metabolism of CNS matrix, and shed some light upon a role of this process in Alzheimer's disease. In addition, experiments are proposed which will examine the cell-cell and cell-substratum adhesion inducing properties of ABPP. These adhesive interactions will be studied in the context of their role in cell division, neurite outgrowth, and neurotrophic effects.
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