Apolipoprotein E lipoprotein particles inhibit amyloid-β uptake through cell surface heparan sulphate proteoglycan

Background: The accumulation, aggregation and deposition of amyloid-beta (A beta) peptides in the brain are central to the pathogenesis of Alzheimer's disease (AD). Alzheimer's disease risk increases significantly in individuals carrying one or two copies of APOE epsilon 4 allele compared to individuals with an epsilon 3/epsilon 3 genotype. Growing evidence has demonstrated that apolipoprotein E (apoE) strongly influences AD pathogenesis by controlling A beta aggregation and metabolism. Heparan sulphate proteoglycans (HSPGs) are abundant cell surface molecules that bind to both apoE and A beta. HSPGs have been associated with A beta aggregation and deposition. Although several lines of research have shown that apoE influences A beta clearance in the brain, it is not clear how apoE influences HSPG-mediated cellular uptake of A beta. Results: In this study, we show that apoE lipoprotein particles from conditioned media of immortalized astrocytes isolated from human APOE-targeted replacement (TR) mice significantly suppress cellular A beta 42 and A beta 40 uptake through cell surface HSPG. ApoE3 and apoE4 particles have similar binding affinity to heparin, while apoE4 particles are likely hypolipidated compared to apoE particles. We also found that the apoE particles antagonize A beta binding to cell surface, and inhibited A beta uptake in a concentration-dependent manner in Chinese hamster ovary (CHO) cells. While the effect was not apoE isoform-dependent, the suppressive effect of apoE particles on A beta uptake was not observed in HSPG-deficient CHO cells. We further demonstrated that apoE particles reduced the internalization of A beta in mouse primary neurons, an effect that is eliminated by the presence of heparin. Conclusions: Taken together, our findings indicate that apoE particles irrespective of isoform inhibit HSPG-dependent cellular A beta uptake. Modulating the ability of apoE particles to affect A beta cellular uptake may hold promises for developing new strategies for AD therapy.