Induction of vascular amyloidosis-β by oxidative stress depends on APOE genotype

The reduced antioxidant defense in apolipoprotein E var epsilon4/var epsilon4 carriers may contribute to β-amyloidosis. Previously we found that Fe2+-induced oxidative stress caused greater protein oxidation in var epsilon4/var epsilon4 than in var epsilon3/var epsilon3 human brain vascular smooth muscle cells. Moreover, Fe2+ induced lysosomal accumulation of endogenous Aβ and APOE in cultured cells, and Aβ deposition in vascular tunica media in organotypic cultures of brain vessels. Here we demonstrated that Fe2+ enhanced an uptake of exogenous Aβ 1–40 and its deposition together with APOE in lysosomes in myocytes. Aβ deposits were associated with lipid-peroxidation and protein ubiquitination, and were more abundant and stable in var epsilon4/var epsilon4 than in var epsilon3/var epsilon3 cells. In organotypic cultures of brain vessels Fe2+ induced deposition of non-fibrillar and fibrillar Aβ 1–40 in vascular tunica media. We hypothesize that locally increased concentrations of iron induce accumulation of exogenous and endogenous Aβ in SMCs, triggering β-amyloid angiopathy. The greater susceptibility of var epsilon4 carriers to Fe2+ ions may result in an increased risk of β-amyloidosis.