The major component of the neuritic plaque cores and cerebrovascular amyloid of the Alzheimer's disease (AD) exists as a component of at least three distinct precursor proteins, referred to as APP695, APP751, APP770. APP is normally metabolized by at least two pathways: one pathway involves cleavage within the AbetaP sequence, thus preventing formation of the amyloid peptide. The second """"""""amyloidogenic"""""""" pathway results in the production of the amyloid peptide. Recent genetic studies showed that certain mutations in the APP gene that result in amino acid substitutions may cause Familial AD. However, it is still not clear whether these mutations cause AD by increasing production of the amyloid peptide or by altering the biological function of the APP protein. Since the structural elements of a biomolecule define both its biological function and its metabolic pathway, determination of the structural characteristics of the APP is important for the elucidation of its role in the development of AD. Research in our laboratory showed that APP exists as the core protein of a chondroitin sulfate proteoglycan (CSPG), ranging in apparent molecular size from 140 to 250 kDa, secreted by a glial cell line. Most of the secreted nexin II form oa APP occurs in the proteoglycan form. We also obtained evidence that the APP proteoglycan is present in human brain and neuroblastoma cells. Proteoglycans are molecules with important biological functions including cell adhesion and migration, cell-cell communication, modulation of growth factor activities and neural patterning. Dysfunction of the CSPG form of APP may contribute to the neuronal degeneration observed in AD. We find two potential chondroitin sulfate glycosaminoglycan (CSG) attachment sites in close proximity to both the N- terminus of the AbetaP sequence of APP and the secretase cleavage site, suggesting that the CSG chains may affect the proteolysis of APP and production of AbetaP. Here we propose to determine the attachment sites and length of the CSG chains, the structure of the carbohydrate residues attached to APP and the role of the APP CSPG in cell adhesion. In addition we will examine the expression of this novel APP form in normal and AD brains and its developmental regulation in rat brain.
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