Complement interactions with amyloid-beta 1-42: a nidus for inflammation in AD brains

Complement activation and its deposition on beta-amyloid plagues in Alzheimer's Disease (AD) brains correlates with the development of AD dementia Results fr om immunocytochemical studies suggest that the appearance of complement activation in AD brains results in part from a direct interaction with the beta-amyloid (A beta) peptide A beta 1-42, the major peptide of beta-amyloid plagues. To study this possibility, we exposed aggregated AP of different lengths to complement present in normal human serum (NHS) in vitro. NHS contains two pathways for complement activation, the classical and alternative. Solubilization of bound complement proteins and immunoblotting reveal that aggregated A beta 1-42 binds larger amounts of complement proteins C1q, C4, C3, C5 and C6, than aggregated A beta 1-40, A beta 1-28 and A beta 17-43. The binding of C3, unlike C1q and C4, requires complement activation. In NHS, C3 binding to aggregated A beta 1-42 occurs by both the alternative pathway and, to a lesser extent, the classical pathway. The activation of C3 by both pathways leads to the covalent labeling of A beta 1-42 and the formation of the anaphylatoxin peptide, C3a. The labeling of A beta 1-42 by C3 and other complement proteins, and the formation of anaphylatoxins could be essential steps in initiating the inflammation seen in AD brains.