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J Biol Chem, Vol. 274, Issue 43, 30631-30635, October 22, 1999

Common Binding Sites for -Amyloid Fibrils and Fibroblast Growth Factor-2 in Heparan Sulfate from Human Cerebral Cortex

Birgitta Lindahl, Camilla Westling, Guillermo Giménez-Gallego^¶, Ulf Lindahl, and Markku Salmivirta

From the  Department of Medical Biochemistry and Microbiology, Uppsala University, S-75123 Uppsala, Sweden and the ^¶ Centro de Investigaciones Biológicas, E-28006 Madrid, Spain

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

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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