Influence of Proteoglycans/GAGs On APP Metabolism

          Proteoglycans and glycosaminoglycans are a specific class of carbohydrates that have been identified and localized to the protein deposits (ie. arnyloid) in the brains of patients with Alzheimer’s disease. Our studies have now identified two specific classes of proteoglycans, (a heparan sulfate proteoglycan and a dermatan sulfate proteoglycan), which may be primarily involved. The major reason why these two specific classes of proteoglycans may be localized to tissue sites containing the betaarnyloid protein (the major protein component of arnyloid deposits in Alzheimer brain), may be due to their affinities for the beta-arnyloid protein itself. Studies by our lab have now shown that a particular fragment of the beta-arnyloid protein binds with high affinity to a heparan sulfate proteoglycan, and with low affinity to two dermatan sulfate proteoglycans. In addition, specific glycosarninoglycans have been demonstrated to regulate the expression of the precursor protei n to the beta-arnyloid protein (ie. the beta-arnyloid precursor protein ) . These studies suggest that specific proteoglycans/glycosarninoglycans may regulate the processi ng of the beta-arnyloid precursor protein, leading to the eventual deposition of the beta-amyloid protein in amyloid deposits .        In the current proposal, we will use a cell culture system to define and determine the relationship between neuronal proteoglycans/ glycosarninoglycans and their influence and possible regulatory affects on the metabolism of the beta-arnyloid precursor protein. In the first specific aim of our proposal, we will determine the relationship between the synthesis and expression of proteoglycans and beta-amyloid precursor protein in this neuronal cell culture model. In the second specific aim, we wi ll determine the consequences of alterations in proteoglycan metabolism, on the synthesis and expression of the beta-amyloid precursor protein. In the third specific aim, we will determine whether specific proteoglycans/glycosarninoglycans bind to particular regions on the beta-amyloid precursor protein, and determine if this binding therefore prevents the normal breakdown of the beta-arnyloid precursor protein or alters its normal degradative pathway . These studies are important in Alzheimer’s disease research since factors which regulate the metabolism of the betaarnyloid precursor protein may enable us a closer understanding of the mechanisms involved in the deposition and accumulation of the beta-amyloid protein, a principal component of the amyloid lesions in the brains of Alzheimer’s patients.