Complement interactions with amyloid β1–42: A nidus for inflammation in AD brains

Abstract

Complement activation and its deposition on β-amyloid plaques in Alzheimer's Disease (AD) brains correlates with the development of AD dementia. Results from immunocytochemical studies suggest that the appearance of complement activation in AD brains results in part from a direct interaction with the β-amyloid (Aβ) peptide Aβ–42, the major peptide of β-amyloid plaques. To study this possibility, we exposed aggregated Aβ 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 Aβ1–42 binds larger amounts of complement proteins C1q, C4, C3, C5 and C6, than aggregated Aβ1–40, Aβ1–28 and Aβ 17–43. The binding of C3, unlike CIq and C4, requires complement activation. In NHS, C3 binding to aggregated Aβ1–42 occurs by both the alternative path-way and, to a lesser extent, the classical pathway. The activation of C3 by both pathways leads to the covalent labeling of Aβ1–42 and the formation of the anaphylatoxin peptide, C3a. The labeling of Aβ1–42 by C3 and other complement proteins, and the formation of anaphylatoxins could be essential steps in initiating the inflammation seen in AD brains.