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Complement activation by cross-linked truncated and chimeric full-length beta-amyloid.

D H Cribbs·P Velazquez·B Soreghan·C G Glabe·A J Tenner
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Abstract

The activation of complement by beta-amyloid (A beta) has been implicated in the local inflammatory response in Alzheimer's disease. To assess the structural parameters required for this activation, beta-sheet-containing fibrils of A beta1-28 were induced by low pH and then chemically cross-linked to constrain the beta-sheet conformation. Chimeric A beta peptides with a substituted C-terminal sequence derived from two different transmembrane proteins were also assessed for the ability to form fibrils rich in beta-sheet structure and to activate complement. Both the cross-linked A beta1-28 and the chimeric A beta peptides were strong activators of the classical complement pathway. These results suggest that the C-terminal residues (29-42) of A beta facilitate fibril assembly required for complement activation but do not contain the interaction sites required for complement activation, further supporting the hypothesis that C1q binds to the N-terminal hydrophilic domain of A beta, and that a fibrillar beta-sheet-rich conformation is required for effective binding and activation of C1.

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Amino Acid SequenceAmyloid beta-PeptidesAnimalsBinding SitesComplement ActivationComplement C1qCross-Linking ReagentsEthyldimethylaminopropyl CarbodiimideGuinea PigsHumansMolecular Sequence DataPeptide FragmentsProtein ConformationProtein Structure, SecondaryRecombinant Fusion ProteinsSequence DeletionComparative StudyJournal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.

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D H Cribbs, P Velazquez, B Soreghan, C G Glabe, A J Tenner. 1997-11-10. Complement activation by cross-linked truncated and chimeric full-length beta-amyloid.. https://doi.org/10.1097/00001756-199711100-00009

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