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- Title
Lipid peroxidation up-regulates BACE1 expression in vivo: a possible early event of amyloidogenesis in Alzheimer’s disease.
- Authors
Liuji Chen; Na, Ren; Gu, Mingjun; Richardson, Arlan; Qitao Ran
- 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.
- Publication
Journal of Neurochemistry, 2008, Vol 107, Issue 1, p197
- ISSN
0022-3042
- Publication type
Academic Journal
- DOI
10.1111/j.1471-4159.2008.05603.x