Induction of vascular amyloidosis-beta by oxidative stress depends on APOE genotype.
The reduced antioxidant defense in apolipoprotein E epsilon4/epsilon4 carriers may contribute to beta-amyloidosis. Previously we found that Fe(2+)-induced oxidative stress caused greater protein oxidation in epsilon4/epsilon4 than in epsilon3/epsilon3 human brain vascular smooth muscle cells. Moreover, Fe(2+) induced lysosomal accumulation of endogenous Abeta and APOE in cultured cells, and Abeta deposition in vascular tunica media in organotypic cultures of brain vessels. Here we demonstrated that Fe(2+) enhanced an uptake of exogenous Abeta 1-40 and its deposition together with APOE in lysosomes in myocytes. Abeta deposits were associated with lipid-peroxidation and protein ubiquitination, and were more abundant and stable in epsilon4/epsilon4 than in epsilon3/epsilon3 cells. In organotypic cultures of brain vessels Fe(2+) induced deposition of non-fibrillar and fibrillar Abeta 1-40 in vascular tunica media. We hypothesize that locally increased concentrations of iron induce accumulation of exogenous and endogenous Abeta in SMCs, triggering beta-amyloid angiopathy. The greater susceptibility of epsilon4 carriers to Fe(2+) ions may result in an increased risk of beta-amyloidosis.
Mazur-Kolecka
Bozena
B
New York State Institute for Basic Research in Developmental Disabilities, Department of Developmental Neurobiology, 1050 Forest Hill Road, Staten Island, NY 10314, USA. BMKO_JFRA@msn.com
Dickson
Dennis
D
Frackowiak
Janusz
J
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000493:pharmacokinetics*; D000704:Analysis of Variance; D001057:Apolipoproteins E / Q000378:metabolism*; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D007501:Iron / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000493:pharmacokinetics*; D013997:Time Factors
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D007501:Iron