Lysosomal deposition of Abeta in cultures of brain vascular smooth muscle cells is enhanced by iron.
Recently, we found that brain vascular smooth muscle cells from Tg2576 mice over-expressed the APP transgene in culture, secreted amyloid-beta peptide (Abeta) and accumulated Abeta intracellularly. Now we detected this intracellular Abeta inside lysosomes, which were also rich in C-terminal domain of APP, but not in endoplasmic reticulum, Golgi apparatus, or trans-Golgi network. Treatment of cultures with ferrous ions (50-150 microM) increased the proportion of muscle cells with Abeta immunoreactive granules and the amounts of intracellular Abeta1-40 and Abeta1-42 in a dose-dependent manner. This increase of intracellular Abeta1-40 by iron was inhibited by alpha-tocopherol, but not by a water-soluble antioxidant melatonin. The increase of intracellular Abeta1-42 by iron was not inhibited by alpha-tocopherol or melatonin. Cell treatment with iron did not alter the lysosomal localization of Abeta immunoreactivity. Cell treatment with iron (II and III), copper (II), zinc (II) and aluminum (III) increased cellular levels of carbonyls. However, the effect of zinc on Abeta accumulation in cultures was weak, and there were no effects of copper and aluminum. The data suggest that iron may be the factor that triggers vascular amyloidosis. Lysosomal accumulation of APP and Abeta initiates deposition of amyloid in blood vessels in Tg2576 mice.
Frackowiak
Janusz
J
Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Rd., Staten Island, NY 10314, USA. Janusz.Frackowiak@omr.state.ny.us
Sukontasup
Thirasak
T
Potempska
Anna
A
Mazur-Kolecka
Bozena
B
D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000235:genetics; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007501:Iron / Q000494:pharmacology*; D008247:Lysosomes / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000187:drug effects*
D016229:Amyloid beta-Peptides; D007501:Iron