Lipid peroxidation up-regulates BACE1 expression in vivo: A possible early event of amyloidogenesis in Alzheimer's disease

Liuji Chen, Ren Na, Mingjun Gu, Arlan Richardson, Qitao Ran

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Original languageEnglish
Pages (from-to)197-207
Number of pages11
JournalJournal of Neurochemistry
Volume107
Issue number1
DOIs
StatePublished - Oct 2008

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phospholipid-hydroperoxide glutathione peroxidase
Lipid Peroxidation
Alzheimer Disease
Up-Regulation
Lipids
Amyloid Precursor Protein Secretases
Amyloid
Amyloid beta-Protein Precursor
Amyloid Plaques
Enzymes
Brain
Proteins
Antioxidants
mouse glutathione peroxidase 4

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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Lipid peroxidation up-regulates BACE1 expression in vivo : A possible early event of amyloidogenesis in Alzheimer's disease. / Chen, Liuji; Na, Ren; Gu, Mingjun; Richardson, Arlan; Ran, Qitao.

In: Journal of Neurochemistry, Vol. 107, No. 1, 10.2008, p. 197-207.

Research output: Contribution to journalArticle

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title = "Lipid peroxidation up-regulates BACE1 expression in vivo: A possible early event of amyloidogenesis in Alzheimer's disease",
abstract = "Increased lipid peroxidation is shown to be an early event of Alzheimer's disease (AD). However, it is not clear whether and how increased lipid peroxidation might lead to amyloidogenesis, a hallmark of AD. Glutathione peroxidase 4 (Gpx4) is an essential antioxidant defense enzyme that protects an organism against lipid peroxidation. Gpx4+/- mice show increased lipid peroxidation in brain, as evidenced by their elevated levels of 4-hydroxy-2-nonenal. To understand the role of lipid peroxidation in amyloidogenesis, we studied secretase activities in Gpx4+/- mice as a function of age. Both young (6 months) and middle-aged (17-20 months) Gpx4+/- mice had higher levels of β-secretase activity than their age-matched wildtype controls, and the increased β-secretase activity in Gpx4+/- mice was a result of up-regulation of β-site amyloid precursor protein cleavage enzyme 1 (BACE1) expression at the protein level. The high level of BACE1 protein led to increased endogenous β-amyloid (Aβ)1-40 in middle-aged Gpx4+/- mice. We further studied amyloidogenesis in APPGpx4+/- mice. Our data indicate that APPGpx4+/- mice had significantly increased amyloid plaque burdens and increased Aβ1-40 and Aβ1-42 levels compared with APPGpx4+/+ mice. Therefore, our results indicate that increased lipid peroxidation leads to increased amyloidogenesis through up-regulation of BACE1 expression in vivo, a mechanism that may be important in pathogenesis of AD at early stages.",
keywords = "β-amyloid, β-site amyloid precursor protein cleavage enzyme 1, Alzheimer's disease, Amyloid precursor protein transgenic mice, Glutathione peroxidase 4, Lipid peroxidation",
author = "Liuji Chen and Ren Na and Mingjun Gu and Arlan Richardson and Qitao Ran",
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T1 - Lipid peroxidation up-regulates BACE1 expression in vivo

T2 - A possible early event of amyloidogenesis in Alzheimer's disease

AU - Chen, Liuji

AU - Na, Ren

AU - Gu, Mingjun

AU - Richardson, Arlan

AU - Ran, Qitao

PY - 2008/10

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N2 - Increased lipid peroxidation is shown to be an early event of Alzheimer's disease (AD). However, it is not clear whether and how increased lipid peroxidation might lead to amyloidogenesis, a hallmark of AD. Glutathione peroxidase 4 (Gpx4) is an essential antioxidant defense enzyme that protects an organism against lipid peroxidation. Gpx4+/- mice show increased lipid peroxidation in brain, as evidenced by their elevated levels of 4-hydroxy-2-nonenal. To understand the role of lipid peroxidation in amyloidogenesis, we studied secretase activities in Gpx4+/- mice as a function of age. Both young (6 months) and middle-aged (17-20 months) Gpx4+/- mice had higher levels of β-secretase activity than their age-matched wildtype controls, and the increased β-secretase activity in Gpx4+/- mice was a result of up-regulation of β-site amyloid precursor protein cleavage enzyme 1 (BACE1) expression at the protein level. The high level of BACE1 protein led to increased endogenous β-amyloid (Aβ)1-40 in middle-aged Gpx4+/- mice. We further studied amyloidogenesis in APPGpx4+/- mice. Our data indicate that APPGpx4+/- mice had significantly increased amyloid plaque burdens and increased Aβ1-40 and Aβ1-42 levels compared with APPGpx4+/+ mice. Therefore, our results indicate that increased lipid peroxidation leads to increased amyloidogenesis through up-regulation of BACE1 expression in vivo, a mechanism that may be important in pathogenesis of AD at early stages.

AB - Increased lipid peroxidation is shown to be an early event of Alzheimer's disease (AD). However, it is not clear whether and how increased lipid peroxidation might lead to amyloidogenesis, a hallmark of AD. Glutathione peroxidase 4 (Gpx4) is an essential antioxidant defense enzyme that protects an organism against lipid peroxidation. Gpx4+/- mice show increased lipid peroxidation in brain, as evidenced by their elevated levels of 4-hydroxy-2-nonenal. To understand the role of lipid peroxidation in amyloidogenesis, we studied secretase activities in Gpx4+/- mice as a function of age. Both young (6 months) and middle-aged (17-20 months) Gpx4+/- mice had higher levels of β-secretase activity than their age-matched wildtype controls, and the increased β-secretase activity in Gpx4+/- mice was a result of up-regulation of β-site amyloid precursor protein cleavage enzyme 1 (BACE1) expression at the protein level. The high level of BACE1 protein led to increased endogenous β-amyloid (Aβ)1-40 in middle-aged Gpx4+/- mice. We further studied amyloidogenesis in APPGpx4+/- mice. Our data indicate that APPGpx4+/- mice had significantly increased amyloid plaque burdens and increased Aβ1-40 and Aβ1-42 levels compared with APPGpx4+/+ mice. Therefore, our results indicate that increased lipid peroxidation leads to increased amyloidogenesis through up-regulation of BACE1 expression in vivo, a mechanism that may be important in pathogenesis of AD at early stages.

KW - β-amyloid

KW - β-site amyloid precursor protein cleavage enzyme 1

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