The
amyloid plaque is the hallmark of
Alzheimer's disease (AD). The transmembrane domain and a portion of the C-terminus (A beta) of the
amyloid precursor
protein, are known to form the nucleus of the
amyloid plaque. It has been demonstrated recently, using in vitro assays, that the A beta
peptide can activate both the classical (antibody-independent) and alternate pathways of complement activation. The proposed complement activation is due to the binding of A beta to the
complement components C1q and C3, respectively, which initiate formation of the proinflammatory C5a and
C5b-9 membrane attack complex. In this report, we have investigated the in vitro findings for the likely
complement-dependent proinflammatory properties of the
Alzheimer's disease A beta
peptide. We have performed experiments using congenic C5-deficient and C5-sufficient mice injected with synthetic A beta and recombinant
polypeptide (C-100) containing A beta. Injection of C-100 into C5-sufficient mice induced a clear increase in the number of polymorphonuclear cells (neutrophils) at the site of injection due to complement activation and the subsequent release of proinflammatory chemtoactic factors. In sharp contrast, the C5-deficient mice did not show any increase in cellular influx. The
vaccinia virus complement control protein, an inhibitor of both the classical and alternate pathway can down-regulate the biologically significant activation of
complement by A beta, as demonstrated by an in vitro immunassay. The therapeutic down-regulation of A beta-caused complement activation could greatly alleviate the progression of some of the chronic neurodegeneration characteristic of
Alzheimer's disease.