Formation of amyloid-beta oligomers in brain vascular smooth muscle cells transiently exposed to iron-induced oxidative stress

Vascular smooth muscle cells are involved in deposition of amyloid in brain blood vessels. Accumulation of amyloid-beta peptide (A beta) in cultured brain vascular smooth muscle cells that overexpress human amyloid-beta precursor protein (APP) Swedish, is strongly enhanced by exposure to iron ions. We studied cellular accumulation of A beta and APP processing in vascular smooth muscle cells during recovery after exposure to ferrous ions using cells cultured from Tg2576 mice. The treatment with ferrous ions for 24 and 48 h significantly increased the intracellular levels of ferric, but not ferrous iron. The treatment led to cellular accumulation of C-terminal fragments of APP and to a decreased secretion of APP, A beta 1-40, and A beta 1-42, all of which were quickly normalized in iron-free culture conditions. These effects of iron were neutralized by alpha-tocopherol, suggesting the role of oxygen reactive species in altered APP processing. Formation of abundant A beta oligomers, mainly A beta 1-40 tetramers and pentamers, were detected in iron-treated cells, particularly during subsequent culture in iron-free media for up to 72 h. The data suggest that transient increases in local availability of iron in brain blood vessel walls in vivo, e.g., after microhemorhages, may trigger A beta oligomerization.