Alzheimer's disease is characterized by senile plaques composed of polymeric fibrils of beta amyloid (A␤), a 39 -42-amino acid peptide formed after proteolytic processing of the amyloid precursor protein (␤APP). Heparan sulfate proteoglycans have been shown to colocalize with A␤ in Alzheimer's disease brain, and experimental evidence indicates that the interactions between the proteoglycan and the peptide are important for the promotion, deposition, and/or persistence of the senile plaques. Studies in rat brain indicated that both the core protein and the heparan sulfate glycosaminoglycan chains are required for amyloid fiber formation and deposition in vivo (Snow, A. D., Sekiguchi, R., Nochlin, D., Fraser, P., Kimata, K., Mizutani, A., Arai, M., Schreier, W. A., and Morgan, D. G. (1994) Neuron 12, 219 -234), suggesting that one mechanism to prevent the formation of A␤-heparan sulfate proteoglycan complexes that lead to deposition of amyloid would be to degrade the proteoglycan. Normally, heparan sulfate proteoglycans are internalized and degraded to short glycosaminoglycans by intracellular heparanases. These reactions occur in the endosomal-lysosomal pathway, which is the same intracellular location where ␤APP is processed to A␤. Using partially purified heparanase activities from Chinese hamster ovary cells we examined whether A␤(1-40) affects the catabolism of Chinese hamster ovary heparan sulfate glycosaminoglycans and proteoglycans in vitro. A␤(1-40) binds to both the long heparan sulfate glycosaminoglycans attached to core proteins and the short, heparanase-derived chains in a concentration-dependent and pH-dependent manner. When A␤(1-40) is added to heparanase assays, it prevents the partially purified activities from releasing heparan sulfate chains from core proteins and degrading them to short glycosaminoglycans; however, a large molar excess of the peptide to heparan sulfate is required to see the effect. Our results suggest that normally the levels of A␤ in the endosomal pathway are not sufficient to interfere with heparanase activity in vivo. However, once the level of A␤-peptides are elevated, as they are in Alzheimer's disease, they could interact with heparan sulfate proteoglycans and prevent their catabolism. This could promote the formation and deposition of amyloid, since the binding of A␤ to the proteoglycan species will predominate.Histochemical and immunocytochemical studies have shown that heparan sulfate (HS) 1 proteoglycans (HSPGs) and glycosaminoglycans colocalize with ␤-amyloid protein (A␤) in the senile plaques characteristic of Alzheimer's disease (1). Although the precise role of the proteoglycans in the process of amyloidosis is not known, experimental evidence suggests that they may promote amyloid formation, deposition, and/or persistence (1) by binding to A␤ (2-5). HSPGs are anionic molecules consisting of one or more HS glycosaminoglycan chains covalently attached to a core protein (6). A␤ binds to HSPGs with high affinity, and interestingly, it interacts with both the core pr...