Complement activation by the amyloid proteins Aβ peptide and β2-microglobulin

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Abstract
Complement activation (CA) has been reported to play a role in the pathogenesis of Alzheimer's disease (AD). To investigate whether CA may contribute to amyloidogenesis in general, the CA potential of different amyloid fibril proteins was tested CA induced by Aβpreparations containing soluble protein, protofilaments and some fibrils or only fibrils in a solid phase system (ELISA) was modest with a slow kinetics compared to the positive ΔIgG control. Soluble Aβ induced no detectable CA in a liquid phase system (complement consumption assay) while fibrillar Aβcaused CA at 200 mg/ml and higher concentrations. Soluble β2-microglobulin (β2M purified from peritoneal dialysates was found to be as potent a complement activator as Aβin both solid and liquid phase systems while β2 M purified from urine exhibited lower activity, a difference which may be explained by differences observed in SDS-resistant oligomers and isoforms. Soluble Amyloid A-protein caused no significant CA. Aβ and β2M activated complement via the classical pathway. The modifying influence by amyloid-associated molecules on A β-induced CA was also investigated, but neither serum amyloid P component nor heparan sulfare did significantly alter the A β-induced CA. The results indicate that not only fibrillar A β but also oligomers of, in particular, β2M from patients with dialysis-associated amyloidosis are capable of inducing CA at supra-physiological concentrations.