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