Common binding sites for beta-amyloid fibrils and fibroblast growth factor-2 in heparan sulfate from human cerebral cortex

6 p.-4 fig.-1 tab.Heparan sulfate found in the cerebral plaques of Alzheimer's disease binds to beta-amyloid (Abeta) fibrils. This interaction has been proposed to enhance fibril deposition and mediate Abeta-induced glia activation and neurotoxicity. On the other hand, heparan sulfate augments signaling of fibroblast growth factor-2 (FGF-2), a neuroprotective factor that antagonizes the neurotoxic effects of Abeta. We defined structures in heparan sulfate from human cerebral cortex that bind Abeta fibrils. The minimal binding site is found in N-sulfated hexasaccharide domains and contains critical 2-O-sulfated iduronic acid residues. By contrast, binding of Abeta monomers requires, in addition, 6-O-sulfate groups on glucosamine residues. The binding specificity of fibrillar Abeta is shared by FGF-2, and we here show that cerebral heparan sulfate domains selected for binding to Abeta-(1-40) fibrils bind also to FGF-2. These data suggest that neurotoxic and neuroprotective signals may converge by competing for the same binding sites on the heparan sulfate chain.This work was supported by grants from the Swedish Medical Research Council (Grants K96–03P, 013004, and 2309), the Alzheimer Foundation, Sweden, Stiftelsen för Gamla Tjänarinnor, Thuréus Foundation, Svenska Lundbeckstiftelsen, Torsten och Ragnar Söderbergs Stiftelser, The Medical Faculty of Uppsala University, Polysackaridforskning AB (Uppsala, Sweden), and the program “Glycoconjugates in Biological Systems” sponsored by The Swedish Foundation for Strategic Research.Peer reviewe