| First Author | Chen L | Year | 2008 |
| Journal | J Neurochem | Volume | 107 |
| Issue | 1 | Pages | 197-207 |
| PubMed ID | 18680556 | Mgi Jnum | J:140135 |
| Mgi Id | MGI:3811975 | Doi | 10.1111/j.1471-4159.2008.05603.x |
| Citation | Chen L, et al. (2008) Lipid peroxidation up-regulates BACE1 expression in vivo: a possible early event of amyloidogenesis in Alzheimer's disease. J Neurochem 107(1):197-207 |
| abstractText | 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 beta-secretase activity than their age-matched wildtype controls, and the increased beta-secretase activity in Gpx4+/- mice was a result of up-regulation of beta-site amyloid precursor protein cleavage enzyme 1 (BACE1) expression at the protein level. The high level of BACE1 protein led to increased endogenous beta-amyloid (Abeta)(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 Abeta(1-40) and Abeta(1-42) 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. |
