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

Abstract

The reduced antioxidant defense in apolipoprotein E ɛ4/ɛ4 carriers may contribute to β-amyloidosis. Previously we found that Fe 2+-induced oxidative stress caused greater protein oxidation in ɛ4/ɛ4 than in ɛ3/ɛ3 human brain vascular smooth muscle cells. Moreover, Fe 2+ 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 Fe 2+ 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 ɛ4/ɛ4 than in ɛ3/ɛ3 cells. In organotypic cultures of brain vessels Fe 2+ 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 ɛ4 carriers to Fe 2+ ions may result in an increased risk of β-amyloidosis.