The effect of oxidative stress on amyloid precursor protein processing in cells engaged in β-amyloidosis is related to apolipoprotein E genotype

The reduced antioxidative defense in allele ε4 carriers is suggested to contribute to β-amyloidosis in Alzheimer’s disease and Down’s syndrome. We studied the effect of oxidative stress on accumulation of amyloid-β peptide (Aβ) in vascular smooth muscle cells (SMCs) that are engaged in production of amyloid-β in vivo. Previously, we found that oxidative stress caused by ferrous ions induced accumulation of Aβ-apolipoprotein E deposits in lysosomes and was associated with a greater oxidative protein damage in ε4 carriers. Here, we demonstrate that ferrous ions induce formation of Aβ deposits also in vascular tunica media in organotypic cultures of whole brain vessels, suggesting the role of oxidative stress in development of vascular β-amyloidosis. Cellular accumulation of Aβ in SMCs treated with ferrous ions was associated with a greater accumulation of C-terminal amyloid precursor protein (APP) fragments in ε4/ε4 than in ε3/ε3 myocytes and reduced the amount of soluble APPα in ε3/ε3, but not ε4/ε4, cultures. Antioxidant vitamin E prevented these effects, and, when applied alone, diminished the amount of APP C-terminal fragments and increased the amount of secreted APP in ε3/ε3, but not ε4/ε4, cells. C-terminal APP-immunoreactive material was accumulated in lysosomes partly with Aβ- and N-terminal APP immunoreactivities. These results suggest that the increased accumulation of APP and its fragments in lysosomes may yield additional amounts of cellular Aβ, particularly in ε4 carriers. We hypothesize that the altered processing of APP in SMCs locally exposed to oxidative stress facilitates cellular deposition of Aβ and contribute to the increased risk of development of β-amyloidosis in ε4/ε4 carriers.