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 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)197-207
Number of pages11
JournalJournal of Neurochemistry
Volume107
Issue number1
DOIs
StatePublished - Oct 1 2008

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Keywords

  • Alzheimer's disease
  • Amyloid precursor protein transgenic mice
  • Glutathione peroxidase 4
  • Lipid peroxidation
  • β-amyloid
  • β-site amyloid precursor protein cleavage enzyme 1

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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