Moir Robert D, Atwood Craig S, Romano Donna M, Laurans Maxwell H, Huang Xudong, Bush Ashley I, Smith Jonathan D, Tanzi Rudolph E. Differential Effects of Apolipoprotein E Isoforms on Metal-Induced Aggregation of A Using Physiological Concentrations, Biochemistry 38(14) :4595 -4603, 1999.

Abstract

The 4 allele of apolipoprotein E (APOE) has been found to be a risk factor for late-onset Alzheimer's disease (AD). While the pathogenic mechanism of APOE in AD is not yet clear, APOE isoforms appear to differentially influence the aggregation of A, the principal component of Alzheimer-associated -amyloid deposits. To date, no data are available for the propensity of A to aggregate in the presence of APOE under conditions where these components are at physiological concentrations (in cerebrospinal fluid, APOE and A are 100 nM and 5 nM, respectively). We employed a novel in vitro filtration assay for detecting zinc(II)- and copper(II)-induced aggregation of A in solutions containing concentrations of the peptide that are similar to those reported for human cerebrospinal fluid. The potential for resolubilization with EDTA and the relative densities of zinc- and copper-induced A aggregates were also compared. Zinc-induced A aggregates were found to be denser and less easily resolubilized than copper-induced precipitates. Metal-induced aggregation of A 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 presence of all three APOE isoforms, zinc-induced aggregation of A was attenuated, while precipitation with copper was enhanced. Consistent with the increased risk for AD associated with the 4 allele of APOE, metal-induced aggregation of A was highest for both zinc and copper in the presence of apolipoprotein E4. Our data are consistent with a role for APOE as an in vivo molecular chaperone for A.


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