Activation of complement and contact system in Alzheimer's disease

Abstract

β-Amyloid protein (βA) has been implicated in the pathogenesis of Alzheimer's disease (AD) because of its neurotoxicity and ability to trigger a local inflammatory response. Although assembly of βA in particular aggregates seems to be crucial event in AD pathogenesis, soluble, non-fibrillar βA may also be involved. Non-fibrillar βA1-42, and truncated peptide 1–28, induced dose-dependent activation of C4 sparing C3. The mechanism of C4 activation was not dependent on C1q, because non-fibrillar βA can still activate C4 in plasma genetically deficient in C1q. A C1q independent mechanism of complement classical pathway activation could be via the activation of contact/kinin system. The possible involvement of contact system in AD is suggested by the finding that this system is massively activated in CSF of AD patients. The mechanism of activation of contact system could be the result of an anionic interaction of residues within the region 1–11 of βA1-42 with factor XII, and of kallikrein generation. Concomitant incubation of a small cationic peptide (lysine 4) with βA abrogated its ability to trigger the cleavage of high molecular weight kininogen. In vivo, prevention of contact system activation beside the reduction of kallikrein generation, can also decrease the activation of complement system and the release of interleukin-6, both factors being considered to play an important role in the inflammatory reactions in AD brain.