Common binding sites for beta-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 (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.
Lindahl
B
B
Department of Medical Biochemistry, Uppsala University, S-75123 Uppsala, Sweden.
Westling
C
C
Giménez-Gallego
G
G
Lindahl
U
U
Salmivirta
M
M
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002540:Cerebral Cortex / Q000378:metabolism*; D004187:Disaccharides / Q000737:chemistry; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry / Q000378:metabolism*; D005944:Glucosamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D007067:Iduronic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D009844:Oligosaccharides / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D004187:Disaccharides; D016222:Fibroblast Growth Factor 2; D005944:Glucosamine; D006497:Heparan Sulfate; D007067:Iduronic Acid; D009844:Oligosaccharides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C067448:iduronate 2-sulfate; C046905:glucosamine 6-O-sulfate