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

Heparan sulfate found in the cerebral plaques of Alzheimer's disease binds to beta-amyloid (A beta) fibrils. This interaction has been proposed to enhance fibril deposition and mediate A beta-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 A beta. We defined structures in heparan sulfate from human cerebral cortex that bind A beta 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 A beta monomers requires, in addition, 6-O-sulfate groups on glucosamine residues. The binding specificity of fibrillar A beta is shared by FGF-2, and we here show that cerebral heparan sulfate domains selected for binding to A beta-(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.