Differential effects of apolipoprotein E isoforms on metal-induced aggregation of A beta using physiological concentrations

The epsilon 4 allele of apolipoprotein E (APOE) has been found to be a risk factor for late-onset Alzheimer's disease (AD). While the pathogenic mecha nism of APOE in AD is not yet clear, APOE isoforms appear to differentially influence the aggregation of A beta, the principal component of Alzheimer- associated beta-amyloid deposits. To date, no data are available for the pr opensity of A beta to aggregate in the presence of APOE under conditions wh ere these components are at physiological concentrations (in cerebrospinal fluid, APOE and A beta are approximate to 100 nM and approximate to 5 nM, r espectively). We employed a novel in vitro filtration assay for detecting z inc(II)- and copper(II)-induced aggregation of A beta in solutions containi ng concentrations of the peptide that are similar to those reported for hum an cerebrospinal fluid. The potential for resolubilization with EDTA and th e relative densities of zinc- and copper-induced A beta aggregates were als o compared. Zinc-induced A beta aggregates were found to be denser and less easily resolubilized than copper-induced precipitates. Metal-induced aggre gation of A beta was studied in the presence of purified apolipoprotein E2, apolipoprotein E3, and apolipoprotein E4 under conditions that approximate the physiological concentrations and ratios of these proteins. In the pres ence of all three APOE isoforms, zinc-induced aggregation of A beta was att enuated, while precipitation with copper was enhanced. Consistent with the increased risk for AD associated with the epsilon 4 allele of APOE, metal-i nduced aggregation of A beta was highest for both zinc and copper in the pr esence of apolipoprotein E4. Our data are consistent with a role for APOE a s an in vivo molecular chaperone for A beta.