CLUSTERIN (APOJ) ALTERS THE AGGREGATION OF AMYLOID BETA-PEPTIDE (A-BETA(1-42)) AND FORMS SLOWLY SEDIMENTING A-BETA COMPLEXES THAT CAUSE OXIDATIVE STRESS

Clusterin (apoJ), a multifunctional apolipoprotein made by cells in th e brain and many other locations, is associated with aggregated amyloi d beta-peptide (A beta) in senile and diffuse plaques of Alzheimer's d isease (AD). We observed that purified human serum clusterin partially blocked the aggregation of synthetic A beta(1-42), as shown by centri fugal assays (14,000g x 10 min) and by atomic force (scanning probe) m icroscopy. Slowly sedimenting A beta complexes were formed in the pres ence of clusterin, which included aggregates >200 kDa that resist diss ociation by low concentrations of SDS. Clusterin enhanced the oxidativ e stress caused by A beta, as assayed by oxidative stress in PC12 cell s with MTT, which is widely used to estimate neurotoxicity. These indi cations of enhanced neurotoxicity by the MTT assay were observed in th e highly aggregated rapidly sedimenting fraction, but also in more slo wly sedimenting ''soluble'' forms. This novel activity of slowly sedim enting A beta may enhance the neurotoxicity of A beta deposits in AD b rains, because soluble complexes have a potential for diffusing to dam age distal neurons. (C) 1995 Academic Press, Inc.