Beta-amyloid fibrils activate the C1 complex of complement under physiological conditions: evidence for a binding site for A beta on the C1q globular regions.
Previous studies based on the use of serum as a source of C have shown that fibrils of beta-amyloid peptides that accumulate in the brain of patients with Alzheimer's disease have the ability to bind C1q and activate the classical C pathway. The objective of the present work was to test the ability of fibrils of peptide Abeta1-42 to trigger direct activation of the C1 complex and to carry out further investigations on the site(s) of C1q involved in the interaction with Abeta1-42. Using C1 reconstituted from purified C1q, C1r, and C1s, it was shown that Abeta1-42 fibrils trigger direct C1 activation both in the absence of C1 inhibitor and at C1 inhibitor:C1 ratios up to 8:0, i.e., under conditions consistent with the physiological context in serum. The truncated peptide Abeta12-42 and the double mutant (D7N, E11Q) of Abeta1-42 did not yield C1 activation, providing further evidence that the C1 binding site of beta-amyloid fibrils is located in the acidic N-terminal 1-11 region of the Abeta1-42 peptide. Binding studies performed using a solid phase assay provided strong evidence that C1q interacts with Abeta1-42 fibrils through its C-terminal globular regions. In contrast to previous studies based on a different experimental design, no significant involvement of the C1q collagen-like domain was detected. These findings were confirmed by additional experiments based on C1 activation and C4 consumption assays. These observations provide direct evidence of the ability of beta-amyloid fibrils to trigger activation of the classical C pathway and further support the hypothesis that C activation may be a component of the pathogenesis of Alzheimer's disease.
Tacnet-Delorme
P
P
Laboratoire d'Enzymologie Moléculaire, Institut de Biologie Structurale, Grenoble, France.
Chevallier
S
S
Arlaud
G J
GJ
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001216:Asparagine / Q000502:physiology; D001224:Aspartic Acid / Q000502:physiology; D001665:Binding Sites / Q000276:immunology; D003172:Complement C1 / Q000378:metabolism*; D015922:Complement C1q / Q000378:metabolism; D003171:Complement Pathway, Classical / Q000502:physiology*; D018698:Glutamic Acid / Q000502:physiology; D005973:Glutamine / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats
D016229:Amyloid beta-Peptides; D003172:Complement C1; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D005973:Glutamine; D001224:Aspartic Acid; D018698:Glutamic Acid; D001216:Asparagine; D015922:Complement C1q