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

Apolipoprotein E4 (apoE4) encoded by ε4 allele is a strong genetic risk factor for Alzheimer's disease (AD). ApoE4 carriers have accelerated amyloid β-protein (Aβ) deposition in their brains, which may account for their unusual susceptibility to AD. We hypothesized that the accelerated Aβ deposition in the brain of apoE4 carriers is mediated through cholesterol-enriched low-density membrane (LDM) domains. Thus, the concentrations of Aβ 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 β-amyloid precursor protein (APP) transgenic mice (Tg2576). The Aβ40 and Aβ42 concentrations and the Aβ42 proportions in LDM domains did not differ between apoE3 and apoE4 KI mice up to 18 months of age. The Aβ40 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 Aβ deposition remains unknown. These data show that the apoE isoform-specific effects on the Aβ concentration in LDM domains do not occur in KI mouse models.