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

The reduced antioxidant defense in apolipoprotein E ε4/ε4 carriers may contribute to β-amyloidosis. Previously we found that Fe²⁺-induced oxidative stress caused greater protein oxidation in ε4/ε4 than in ε3/ε3 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 ε4/ε4 than in ε3/ε3 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 ε4 carriers to Fe²⁺ ions may result in an increased risk of β-amyloidosis.