Inhibiting the formation of classical C3-convertase on the Alzheimer's β-amyloid peptide

Abstract

Amyloid plaques are the pathological hallmark of Alzheimer Disease (AD) brains, being found primarily in the hippocampus and neocortex, where AD pathology is most evident. Complement activation is associated with amyloid plaques which are made from fibrils of aggregated amyloid peptides, 39–42 amino acids long. In vitro studies show that aggregated amyloid peptides activate complement via the classical pathway, implying that amyloid plaques themselves cause complement activation in AD brains. In order to test this hypothesis, we sought to determine if a major peptide component of amyloid plaques, Aβ1–42, supports the formation of the classical pathway C3 convertase. Using normal human serum depleted of C3, we are able to detect C3 convertase activity on aggregated Aβ1–42 in vitro. The convertase activity is associated with the binding of Clq and activation of C4 on the aggregated peptide. Inhibitors of C1 esterase and the cation chelator EGTA both block the formation of the convertase activity. Congo red, a histochemical stain for amyloid deposits and an inhibitor of amyloid aggregation, reduces C3 convertase activity on aggregated A β1–42, indicated by decreased C3a production. Our results provide further evidence that aggregated A β1–42 alone is sufficient to serve as a nidus for complement activation, and thus may be involved directly in initiating the inflammation seen in AD brains.