β-amyloid fibrils activate the C1 complex of complement under physiological conditions:: Evidence for a binding site for Aβ 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 Clq and activate the classical C pathway. The objective of the present work was to test the ability of fibrils of peptide A beta1-42 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 A beta1-42. Using C1 reconstituted from purified C1q, C1r, and Cls, it was shown that A beta1-42 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 A beta 12-42 and the double mutant (D7N, E11Q) of A beta1-42 did not yield C1 activation, providing further evidence that the C1 binding site of beta -amyloid fibrils is located in the acidic N-terminaI 1-11 region of the A beta1-42 peptide. Binding studies performed using a solid phase assay provided strong evidence that C1q interacts with A beta1-42 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.