Aβ(1–40) Prevents Heparanase-catalyzed Degradation of Heparan Sulfate Glycosaminoglycans and Proteoglycans in Vitro

• Published in: The Journal of biological chemistry 1997-07, Vol.272 (27), p.17005-17011
• Main Authors: Bame, Karen J., Danda, Joseph, Hassall, Alan, Tumova, Sarka
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.272.27.17005

Alzheimer's disease is characterized by senile plaques composed of polymeric fibrils of beta amyloid (Aβ), a 39–42-amino acid peptide formed after proteolytic processing of the amyloid precursor protein (βAPP). Heparan sulfate proteoglycans have been shown to colocalize with Aβ 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 Aβ-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 βAPP is processed to Aβ. Using partially purified heparanase activities from Chinese hamster ovary cells we examined whether Aβ(1–40) affects the catabolism of Chinese hamster ovary heparan sulfate glycosaminoglycans and proteoglycans in vitro. Aβ(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 Aβ(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 Aβ in the endosomal pathway are not sufficient to interfere with heparanase activity in vivo. However, once the level of Aβ-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 Aβ to the proteoglycan species will predominate.