Alzheimer's β-amyloid peptides can activate the early components of complement classical pathway in a C1q-independent manner

Abstract

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.

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“…These findings are in agreement with in vitro studies indicating that Aβ and tau protein, the major components in SPs and NFTs, can fully activate human complement [42,68-71]. Although the above studies suggested that complement is activated principally by the aggregated forms of Aβ and tau, soluble, non-fibrillar Aβ may also be capable of activating complement [72]. In contrast to the robust staining of complement proteins in mature plaques, immunoreactivity to these proteins in diffuse plaques has generally been below the level of detection, though it has been reported in some studies [36,73,74].…”

Distinct Pathways of Mannan-Binding Lectin (MBL)- and C1-Complex Autoactivation Revealed by Reconstitution of MBL with Recombinant MBL-Associated Serine Protease-2

“…It has been reported that C1 activation can occur through interaction with proteases of the blood-clotting cascade (35,36). Although the physiological significance of this mechanism is unclear, it may be speculated also to contribute to the observed difference in the activation of rMASP-2 and natural MASP-2 presented in the form of MBL-deficient serum.…”

Histological and Direct Evidence for the Role of Complement in the Neuroinflammation of AD

“…Together with the high levels of cleaved high molecular weight kininogen (HMWK) found in AD CSF samples, this suggests that A may serve as an initiating factor for contact activation in AD brains [221]. The Ainduced FXII activation can subsequently lead to activation of HMWK, and to activation of C1s and C4, independent of C1q, as it was shown also to occur in C1q deficient plasma in vitro [222]. A study with baboons that were treated with a monoclonal antibody that inhibits F XII activation, indicated that Factor XII -dependent activation of CP can also occur in vivo [223].…”