The effect of oxidative stress on accumulation of apolipoprotein E3 and E4 in a cell culture model of beta-amyloid angiopathy (CAA).
Apolipoprotein E (apoE) is a multifunctional molecule that is active during brain development, maintenance, and injury. Allele epsilon 4 of apoE is recognized as a risk factor for beta-amyloidosis, but the responsible mechanisms are not clear. Recently, we showed that vascular smooth muscle cells (SMCs) from epsilon 4/ epsilon 4 carriers are the most susceptible to oxidative protein damage that was associated with the appearance of apoE-Abeta-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-Abeta deposits and increased immobilization of iron in cultures treated with ferrous ions. The accumulation of apoE-Abeta 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 beta-amyloid angiopathy that is more frequent in epsilon 4/ epsilon 4 carriers.
Mazur-Kolecka
Bozena
B
Department of Pathological Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Rd., Staten Island, NY 10314, USA. bmko_jfra@msn.com
Kowal
Dagmar
D
Sukontasup
Tirasak
T
Dickson
Dennis
D
Frackowiak
Janusz
J
D000368:Aged; D016229:Amyloid beta-Peptides / Q000502:physiology*; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000378:metabolism*; D002449:Cell Aggregation / Q000187:drug effects; D002478:Cells, Cultured; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D007501:Iron / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D011233:Precipitin Tests
D016229:Amyloid beta-Peptides; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D007501:Iron