Complement activation by cross-linked truncated and chimeric full-length beta-amyloid.
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.
Cribbs
D H
DH
Institute for Brain Aging and Dementia, Department of Neurology, University of California Irvine, 92697-4540, USA.
Velazquez
P
P
Soreghan
B
B
Glabe
C G
CG
Tenner
A J
AJ
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D003167:Complement Activation / Q000187:drug effects*; D015922:Complement C1q / Q000187:drug effects / Q000378:metabolism; D003432:Cross-Linking Reagents; D005022:Ethyldimethylaminopropyl Carbodiimide; D006168:Guinea Pigs; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000494:pharmacology; D017384:Sequence Deletion
D016229:Amyloid beta-Peptides; D003432:Cross-Linking Reagents; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D015922:Complement C1q; D005022:Ethyldimethylaminopropyl Carbodiimide