BETA-AMYLOID ACTIVATES COMPLEMENT BY BINDING TO A SPECIFIC REGION OF THE COLLAGEN-LIKE DOMAIN OF THE C1Q A-CHAIN

beta-amyloid peptides that accumulate within the brain of individuals with Alzheimer's disease bind to C1q and activate the classical C path way via a specific interaction with a site within the collagen-like do main of C1q (C1q-CLF). Synthetic analogues of beta-amyloid peptides, b eta 1-42 and beta 1-40, bound to C1q and were strong activators of C a s assessed by both total C consumption and C4 consumption. beta 1-42 w as significantly more effective than beta 1-40 in binding to C1q and t riggering C activation, whereas beta 1-28 demonstrated little or no bi nding or C activation. This C-activating capacity seems to be largely correlated with the assembly of the beta 1-42 into low speed sedimenta ble aggregates and/or macromolecular fibrils. Radiolabeled C1q and C1q -CLF bind specifically to these aggregates or amyloid fibrils. In addi tion, using synthetic C1q peptides in a solid phase binding assay, the major binding site of beta 1-42 to C1q was localized to the C1q A cha in collagen-like residues 14-26, a region previously described as a no vel interaction site for Ab-independent activators of C1. C1q A chain peptide 14-26 blocked the ability of beta-amyloid peptides to activate the classical C pathway, providing evidence that this relatively unre cognized mechanism of C activation (via binding to the C1q-CLF) may ha ve crucial physiologic consequences. Finally, these observations provi de further support for the hypothesis that C activation and inflammati on may be a component in the pathogenesis of AD and suggest possibilit ies for modulating the progression of AD.