Alzheimer's beta-amyloid peptides can activate the early components of complement classical pathway in a C1q-independent manner.
beta-Amyloid (beta-A) accumulates in the brain of patients with Alzheimer's disease (AD) and is presumably involved in the pathogenesis of this disease, on account of its neurotoxicity and complement-activating ability. Although assembly of beta-A in particular aggregates seems to be crucial, soluble non-fibrillar beta-A may also be involved. Non-fibrillar beta-A does not bind C1q, so we investigated alternative mechanisms of beta-A-dependent complement activation in vitro. On incubation with normal human plasma, non-fibrillar beta-A 1-42, and truncated peptide 1-28, induced dose-dependent activation of C1s and C4, sparing C3, as assessed by densitometric analysis of immunostained membrane after SDS-PAGE and Western blotting. The mechanism of C4 activation was not dependent on C1q, because non-fibrillar beta-A can still activate C1s and C4 in plasma genetically deficient in C1q (C1qd). In Factor XII-deficient plasma (F.XIId) the amount of cleaved C4 was about 5-10% less that in C1qd and in normal EDTA plasma; the reconstitution of F.XIId plasma with physiologic concentrations of F.XII resulted in an increased (8-15%) beta-A-dependent cleavage of C4. Thus our results indicate that the C1q-independent activation of C1 and C4 can be partially mediated by the activation products of contact system. Since the activation of contact system and of C4 leads to generation of several humoral inflammatory peptides, non-fibrillar beta-A might play a role in initiating the early inflammatory reactions leading to a multistep cascade contributing to neuronal and clinical dysfunction of AD brain.
Bergamaschini
L
L
Department of Internal Medicine, Maggiore Hospital, IRCCS, Milan, Italy. Luigi.Bergamaschini@unimi.it
Canziani
S
S
Bottasso
B
B
Cugno
M
M
Braidotti
P
P
Agostoni
A
A
D000544:Alzheimer Disease / Q000097:blood / Q000209:etiology / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000276:immunology* / Q000648:ultrastructure; D015922:Complement C1q / Q000378:metabolism*; D003173:Complement C1s / Q000378:metabolism; D003171:Complement Pathway, Classical; D005175:Factor XII Deficiency / Q000276:immunology; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005342:Fibrinolysis; D006801:Humans; D066298:In Vitro Techniques; D008854:Microscopy, Electron; D010446:Peptide Fragments / Q000276:immunology / Q000648:ultrastructure
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C084358:amyloid beta-protein (1-28); C075222:amyloid beta-protein (1-42); D015922:Complement C1q; D003173:Complement C1s; D005341:Fibrinolysin