Aggregation and cytotoxic properties towards cultured cerebrovascular cells of Dutch-mutated Aβ40 (DAβ 1-40) are modulated by sulfate moieties of heparin

Abstract

Glycosaminoglycans (GAGs), in particular as part of heparan sulfate proteoglycans, are associated with cerebral amyloid angiopathy (CAA). Similarly, GAGs are also associated with the severe CAA found in patients suffering from hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), where the amyloid β (Aβ) peptide contains the Dutch mutation (DAβ 1-40). This suggests a role for GAGs in vascular Aβ aggregation. It was the aim of this study to investigate the effect of different GAGs (heparin, chondroitin sulfate, heparan sulfate), the macromolecule dextran sulfate and, using desulfated heparins, the role of GAG sulfate moieties on the in vitro aggregation of CAA-associated DAβ 1-40 and on DAβ 1-40-induced toxicity of cultured cerebrovascular cells. We also aimed to study the in vivo distribution of various sulfated heparan sulfate GAG epitopes in CAA. Of all GAGs tested, heparin was the strongest inducer of aggregation of DAβ 1-40 in the different aggregation assays, with both heparin and heparan sulfate reducing Aβ-induced cellular toxicity. Furthermore, (partial) removal of the sulfate moieties of heparin partially abolished the effects of heparin on aggregation and cellular toxicity, suggesting an essential role for the sulfate moieties in heparin. Finally, we demonstrated the in vivo association of sulfated heparan sulfate (HS) GAGs with CAA. We conclude that sulfate moieties within GAGs, like heparin and HS, have an important role in Aβ aggregation in CAA and in Aβ-mediated toxicity of cerebrovascular cells.