TY - JOUR
T1 - The effect of oxidative stress on amyloid precursor protein processing in cells engaged in β-amyloidosis is related to apolipoprotein E genotype
AU - Mazur-Kolecka, Bozena
AU - Kowal, Dagmar
AU - Sukontasup, Thirasak
AU - Dickson, Dennis
AU - Frackowiak, Janusz
N1 - Funding Information:
Acknowledgements Anti-LAMP-1 mAb, developed by J.T. August and J.E.K. Hildreth, was obtained from DSHB, developed under the auspices of the NICHD, and maintained by The University of Iowa, Department of Biological Sciences, Iowa City, IA 52242. We thank Dr. Pankaj Mehta (IBRDD) for antiserum R57; and Dr. George Merz (IBRDD) for assistance with confocal microscopy studies. This research was supported by funds from the New York State Office of Mental Retardation and Developmental Disabilities (NYS OMRDD).
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2004/10
Y1 - 2004/10
N2 - The reduced antioxidative defense in allele E4 carriers is suggested to contribute to β-amyloidosis in Alzheimer's disease and Down's syndrome. We studied the effect of oxidative stress on accumulation of amyloid-β peptide (Aβ) in vascular smooth muscle cells (SMCs) that are engaged in production of amyloid-β in vivo. Previously, we found that oxidative stress caused by ferrous ions induced accumulation of Aβ-apolipoprotein E deposits in lysosomes and was associated with a greater oxidative protein damage in E4 carriers. Here, we demonstrate that ferrous ions induce formation of Aβ deposits also in vascular tunica media in organotypic cultures of whole brain vessels, suggesting the role of oxidative stress in development of vascular β-amyloidosis. Cellular accumulation of Aβ in SMCs treated with ferrous ions was associated with a greater accumulation of C-terminal amyloid precursor protein (APP) fragments in E-4/E-4 than in E3/E3 myocytes and reduced the amount of soluble APPα in E3/E3, but not E-4/E-4, cultures. Antioxidant vitamin E prevented these effects, and, when applied alone, diminished the amount of APP C-terminal fragments and increased the amount of secreted APP in E3/E3, but not E-4/E-4, cells. C-terminal APP-immunoreacive material was accumulated in lysosomes partly with Aβ- and N-terminal APP immunoreactivities. These results suggest that the increased accumulation of APP and its fragments in lysosomes may yield additional amounts of cellular Aβ, particularly in E4 carriers. We hypothesize that the altered processing of APP in SMCs locally exposed to oxidative stress facilitates cellular deposition of Aβ and contribute to the increased risk of development of β-amyloidosis in E4/E4 carriers.
AB - The reduced antioxidative defense in allele E4 carriers is suggested to contribute to β-amyloidosis in Alzheimer's disease and Down's syndrome. We studied the effect of oxidative stress on accumulation of amyloid-β peptide (Aβ) in vascular smooth muscle cells (SMCs) that are engaged in production of amyloid-β in vivo. Previously, we found that oxidative stress caused by ferrous ions induced accumulation of Aβ-apolipoprotein E deposits in lysosomes and was associated with a greater oxidative protein damage in E4 carriers. Here, we demonstrate that ferrous ions induce formation of Aβ deposits also in vascular tunica media in organotypic cultures of whole brain vessels, suggesting the role of oxidative stress in development of vascular β-amyloidosis. Cellular accumulation of Aβ in SMCs treated with ferrous ions was associated with a greater accumulation of C-terminal amyloid precursor protein (APP) fragments in E-4/E-4 than in E3/E3 myocytes and reduced the amount of soluble APPα in E3/E3, but not E-4/E-4, cultures. Antioxidant vitamin E prevented these effects, and, when applied alone, diminished the amount of APP C-terminal fragments and increased the amount of secreted APP in E3/E3, but not E-4/E-4, cells. C-terminal APP-immunoreacive material was accumulated in lysosomes partly with Aβ- and N-terminal APP immunoreactivities. These results suggest that the increased accumulation of APP and its fragments in lysosomes may yield additional amounts of cellular Aβ, particularly in E4 carriers. We hypothesize that the altered processing of APP in SMCs locally exposed to oxidative stress facilitates cellular deposition of Aβ and contribute to the increased risk of development of β-amyloidosis in E4/E4 carriers.
KW - Amyloid precursor protein turnover
KW - Amyloid-β peptide accumulation
KW - Apolipoprotein E genotype
KW - Oxidative stress
KW - Smooth muscle cells
UR - http://www.scopus.com/inward/record.url?scp=4844224419&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=4844224419&partnerID=8YFLogxK
U2 - 10.1007/s00401-004-0890-7
DO - 10.1007/s00401-004-0890-7
M3 - Article
C2 - 15221339
AN - SCOPUS:4844224419
SN - 0001-6322
VL - 108
SP - 287
EP - 294
JO - Acta neuropathologica
JF - Acta neuropathologica
IS - 4
ER -