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 pathway via a specific interaction with a site within the collagen-like domain of C1q (C1q-CLF). Synthetic analogues of beta-amyloid peptides, beta 1-42 and beta 1-40, bound to C1q and were strong activators of C as assessed by both total C consumption and C4 consumption. beta 1-42 was significantly more effective than beta 1-40 in binding to C1q and triggering C activation, whereas beta 1-28 demonstrated little or no binding or C activation. This C-activating capacity seems to be largely correlated with the assembly of the beta 1-42 into low speed sedimentable aggregates and/or macromolecular fibrils. Radiolabeled C1q and C1q-CLF bind specifically to these aggregates or amyloid fibrils. In addition, 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 chain collagen-like residues 14-26, a region previously described as a novel 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 unrecognized mechanism of C activation (via binding to the C1q-CLF) may have crucial physiologic consequences. Finally, these observations provide further support for the hypothesis that C activation and inflammation may be a component in the pathogenesis of AD and suggest possibilities for modulating the progression of AD.
Jiang
H
H
Department of Molecular Biology and Biochemistry, University of California, Irvine 92717.
Burdick
D
D
Glabe
C G
CG
Cotman
C W
CW
Tenner
A J
AJ
D000544:Alzheimer Disease / Q000209:etiology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D001665:Binding Sites; D003094:Collagen / Q000378:metabolism*; D003167:Complement Activation / Q000187:drug effects*; D015922:Complement C1q / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data
D016229:Amyloid beta-Peptides; D015922:Complement C1q; D003094:Collagen