The effect of oxidative stress on accumulation of apolipoprotein E3 and E4 in a cell culture model of β-amyloid angiopathy (CAA)

Apolipoprotein E (apoE) is a multifunctional molecule that is active during brain development, maintenance, and injury. Allele ε4 of apoE is recognized as a risk factor for β-amyloidosis, but the responsible mechanisms are not clear. Recently, we showed that vascular smooth muscle cells (SMCs) from ε4/ε4 carriers are the most susceptible to oxidative protein damage that was associated with the appearance of apoE-Aβ-immunoreactive granules in cells. Here, we demonstrate that apoE4 is more readily accumulated in SMCs treated with ferrous ions than is apoE3. ApoE accumulated in lysosomes in the form of monomers, dimers, apoE-containing complexes, and apoE fragments. ApoE4 and apoE4-containing complexes persisted in SMCs longer than apoE3 and its complexes. Both isoforms of apoE stimulated formation of apoE-Aβ deposits and increased immobilization of iron in cultures treated with ferrous ions. The accumulation of apoE-Aβ deposits in lysosomes was associated with the appearance of lipid peroxidation products such as malondialdehyde and 4-hydroxynonenal-2-nonenal. The higher cellular accumulation of apoE4 than apoE3 in SMCs exposed to oxidative stress may facilitate development of β-amyloid angiopathy that is more frequent in ε4/ε4 carriers.