title: Aggregation and cytotoxic properties towards cultured cerebrovascular cells of Dutch-mutated Abeta40 (DAbeta(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 beta (Abeta) peptide contains the Dutch mutation (DAbeta(1-40)). This suggests a role for GAGs in vascular Abeta 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 DAbeta(1-40) and on DAbeta(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 DAbeta(1-40) in the different aggregation assays, with both heparin and heparan sulfate reducing Abeta-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 Abeta aggregation in CAA and in Abeta-mediated toxicity of cerebrovascular cells.
authors.affiliation: Radboud University Nijmegen Medical Centre, Department of Neurology, Department of Laboratory Medicine, Donders Centre for Brain, Cognition and Behavior, Alzheimer Centre Nijmegen, Nijmegen, The Netherlands. n.timmer@cukz.umcn.nl
authors.forename: Nienke M
authors.initials: NM
authors.lastname: Timmer
authors.forename: Tom J J
authors.initials: TJ
authors.lastname: Schirris
authors.forename: Ilona B
authors.initials: IB
authors.lastname: Bruinsma
authors.forename: Irene
authors.initials: I
authors.lastname: Otte-Höller
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.forename: Robert M W
authors.initials: RM
authors.lastname: de Waal
authors.forename: Marcel M
authors.initials: MM
authors.lastname: Verbeek
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D016657:Cerebral Amyloid Angiopathy / Q000473:pathology*; D002809:Chondroitin Sulfates / Q000502:physiology; D005260:Female; D006493:Heparin / Q000502:physiology*; D006497:Heparan Sulfate / Q000502:physiology; D006801:Humans; D009154:Mutation; D009778:Occipital Lobe / Q000098:blood supply / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D020286:Pericytes / Q000187:drug effects / Q000473:pathology*
chemical_list: D016229:Amyloid beta-Peptides; D002809:Chondroitin Sulfates; D006493:Heparin; D006497:Heparan Sulfate; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)