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 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.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, Texas, USA.
authors.forename: Liuji
authors.initials: L
authors.lastname: Chen
authors.forename: Ren
authors.initials: R
authors.lastname: Na
authors.forename: Mingjun
authors.initials: M
authors.lastname: Gu
authors.forename: Arlan
authors.initials: A
authors.lastname: Richardson
authors.forename: Qitao
authors.initials: Q
authors.lastname: Ran
mesh_terms: D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D004789:Enzyme Activation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D005979:Glutathione Peroxidase / Q000235:genetics; D006579:Heterozygote; D015227:Lipid Peroxidation / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics*; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse