COMPLEMENT INTERACTIONS WITH AMYLOID-BETA-1-42 - A NIDUS FOR INFLAMMATION IN AD BRAINS

Complement activation and its deposition on beta-amyloid plagues in Al zheimer's Disease (AD) brains correlates with the development of AD de mentia Results fr om immunocytochemical studies suggest that the appea rance of complement activation in AD brains results in part from a dir ect interaction with the beta-amyloid (A beta) peptide A beta 1-42, th e major peptide of beta-amyloid plagues. To study this possibility, we exposed aggregated AP of different lengths to complement present in n ormal human serum (NHS) in vitro. NHS contains two pathways for comple ment activation, the classical and alternative. Solubilization of boun d 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 bin ding of C3, unlike C1q and C4, requires complement activation. In NHS, C3 binding to aggregated A beta 1-42 occurs by both the alternative p athway 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 a nd the formation of the anaphylatoxin peptide, C3a. The labeling of A beta 1-42 by C3 and other complement proteins, and the formation of an aphylatoxins could be essential steps in initiating the inflammation s een in AD brains.