The effect of oxidative stress on amyloid precursor protein processing in cells engaged in β-amyloidosis is related to apolipoprotein E genotype

Bozena Mazur-Kolecka, Dagmar Kowal, Thirasak Sukontasup, Dennis W Dickson, Janusz Frackowiak

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)287-294
Number of pages8
JournalActa Neuropathologica
Volume108
Issue number4
DOIs
StatePublished - Oct 2004

Fingerprint

Amyloid beta-Protein Precursor
Apolipoproteins E
Amyloidosis
Oxidative Stress
Genotype
Lysosomes
Amyloid
Tunica Media
Smooth Muscle Myocytes
Ions
Alzheimer Disease
Down Syndrome
Protein C
Vitamin E
Vascular Smooth Muscle
Muscle Cells
Blood Vessels
Antioxidants
Alleles
Brain

Keywords

  • Amyloid precursor protein turnover
  • Amyloid-β peptide accumulation
  • Apolipoprotein E genotype
  • Oxidative stress
  • Smooth muscle cells

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Neuroscience(all)

Cite this

The effect of oxidative stress on amyloid precursor protein processing in cells engaged in β-amyloidosis is related to apolipoprotein E genotype. / Mazur-Kolecka, Bozena; Kowal, Dagmar; Sukontasup, Thirasak; Dickson, Dennis W; Frackowiak, Janusz.

In: Acta Neuropathologica, Vol. 108, No. 4, 10.2004, p. 287-294.

Research output: Contribution to journalArticle

Mazur-Kolecka, Bozena ; Kowal, Dagmar ; Sukontasup, Thirasak ; Dickson, Dennis W ; Frackowiak, Janusz. / The effect of oxidative stress on amyloid precursor protein processing in cells engaged in β-amyloidosis is related to apolipoprotein E genotype. In: Acta Neuropathologica. 2004 ; Vol. 108, No. 4. pp. 287-294.
@article{e0b13057024c44d196739ce7c9c42499,
title = "The effect of oxidative stress on amyloid precursor protein processing in cells engaged in β-amyloidosis is related to apolipoprotein E genotype",
abstract = "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.",
keywords = "Amyloid precursor protein turnover, Amyloid-β peptide accumulation, Apolipoprotein E genotype, Oxidative stress, Smooth muscle cells",
author = "Bozena Mazur-Kolecka and Dagmar Kowal and Thirasak Sukontasup and Dickson, {Dennis W} and Janusz Frackowiak",
year = "2004",
month = "10",
doi = "10.1007/s00401-004-0890-7",
language = "English (US)",
volume = "108",
pages = "287--294",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "4",

}

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 W

AU - Frackowiak, Janusz

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

VL - 108

SP - 287

EP - 294

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 4

ER -