Effects of human apolipoprotein E isoforms on the amyloid [beta]-protein concentration and lipid composition in brain low-density membrane domains

Apolipoprotein E4 (apoE4) encoded by Epsilon4 allele is a strong genetic risk factor for Alzheimer's disease (AD). ApoE4 carriers have accelerated amyloid Beta-protein (ABeta) deposition in their brains, which may account for their unusual susceptibility to AD. We hypothesized that the accelerated ABeta deposition in the brain of apoE4 carriers is mediated through cholesterol-enriched low-density membrane (LDM) domains. Thus, the concentrations of ABeta and various lipids in LDM domains were quantified in the brains of homozygous apoE3 and apoE4 knock-in (KI) mice, and in the brains of those mice bred with Beta-amyloid precursor protein (APP) transgenic mice (Tg2576). The ABeta40 and ABeta42 concentrations and the ABeta42 proportions in LDM domains did not differ between apoE3 and apoE4 KI mice up to 18 months of age. The ABeta40 concentration in the LDM domains was slightly, but significantly higher in apoE3/APP mice than in apoE4/APP mice. The lipid composition of LDM domains was modulated in an apoE isoform-specific manner, but its significance for ABeta deposition remains unknown. These data show that the apoE isoform-specific effects on the ABeta concentration in LDM domains do not occur in KI mouse models. [PUBLICATION ABSTRACT]