MULTIVALENT BINDING OF COMPLEMENT PROTEIN C1Q TO THE AMYLOID BETA-PEPTIDE (A-BETA) PROMOTES THE NUCLEATION PHASE OF A-BETA AGGREGATION

Activation of the classical complement pathway has been proposed as a mechanism of neurodegeneration in Alzheimer's disease. This activation is a result of the binding of Clq to amyloid beta-peptide (A beta). R ecent work has shown that A beta/C1q binding has an additional consequ ence: enhanced formation of the neurotoxic, fibrillar, cross beta-plea ted A beta configuration. Here we show that Clq enhances A beta aggreg ation at physiologically relevant, nanomolar concentrations of the pep tides, and demonstrate that the kinetics of this enhancement are consi stent with a nucleating interaction. We also show that the intact, mul timeric structure of Clq, which offers multiple A beta binding sites s paced at 2-3 nm intervals, is required. (C) 1995 Academic Press, Inc.