Heparin-binding properties of the amyloidogenic peptides Aβ and amylin: Dependence on aggregation state and inhibition by Congo red
- Author(s): Watson, DJ
- Lander, AD
- Selkoe, DJ
- et al.
Published Web Locationhttps://doi.org/10.1074/jbc.272.50.31617
Aggregation and deposition of the 40-42-residue amyloid β-protein (Aβ) are early and necessary neuropathological events in Alzheimer's disease. An understanding of the molecular interactions that trigger these events is important for therapeutic strategies aimed at blocking Aβ plaque formation at the earliest stages. Heparan sulfate proteoglycans may play a fundamental role since they are invariably associated with Aβ and other amyloid deposits at all stages. However, the nature of the Aβ-heparan sulfate proteoglycan binding has been difficult to elucidate because of the strong tendency of Aβ to self-aggregate. Affinity co-electrophoresis can measure the binding of proteoglycans or glycosaminoglycans to proteins without altering the physical state of the protein during the assay. We used affinity co-electrophoresis to study the interaction between Aβ and the glycosaminoglycan heparin and found that the aggregation state of Aβ governs its heparin-binding properties: heparin binds to fibrillar but not nonfibrillar Aβ. The amyloid binding dye, Congo red, inhibited the interaction in a specific and dose-dependent manner. The 'Dutch' mutant Aβ(E22Q) peptide formed fibrils more readily than wild type Aβ and it also attained a heparin-binding state more readily, but, once formed, mutant and wild type fibrils bound heparin with similar affinities. The heparin-binding ability of aggregated Aβ(E22Q) was reversible with incubation in a solvent that promotes α-helical conformation, further suggesting that conformation of the peptide is important. Studies with another human amyloidogenic protein, amylin, suggested that its heparin- binding properties were also dependent on aggregation state. These results demonstrate the dependence of the Aβ-heparin interaction on the conformation and aggregation state of Aβ rather than primary sequence alone, and suggest methods of interfering with this association.
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