title: Enhanced Phospholipase A2 Group 3 Expression by Oxidative Stress Decreases the Insulin-Degrading Enzyme.
abstract: Oxidative stress has a ubiquitous role in neurodegenerative diseases and oxidative damage in specific regions of the brain is associated with selective neurodegeneration. We previously reported that Alzheimer disease (AD) model mice showed decreased insulin-degrading enzyme (IDE) levels in the cerebrum and accelerated phenotypic features of AD when crossbred with alpha-tocopherol transfer protein knockout (Ttpa-/-) mice. To further investigate the role of chronic oxidative stress in AD pathophysiology, we performed DNA microarray analysis using young and aged wild-type mice and aged Ttpa-/- mice. Among the genes whose expression changed dramatically was Phospholipase A2 group 3 (Pla2g3); Pla2g3 was identified because of its expression profile of cerebral specific up-regulation by chronic oxidative stress in silico and in aged Ttpa-/- mice. Immunohistochemical studies also demonstrated that human astrocytic Pla2g3 expression was significantly increased in human AD brains compared with control brains. Moreover, transfection of HEK293 cells with human Pla2g3 decreased endogenous IDE expression in a dose-dependent manner. Our findings show a key role of Pla2g3 on the reduction of IDE, and suggest that cerebrum specific increase of Pla2g3 is involved in the initiation and/or progression of AD.
authors.affiliation: Department of Neurology and Neurological Science, Graduate school of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Daishi
authors.initials: D
authors.lastname: Yui
authors.affiliation: Department of Neurology and Neurological Science, Graduate school of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Nishida
authors.affiliation: Department of Neurology and Neurological Science, Graduate school of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nishina
authors.affiliation: Department of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Mogushi
authors.affiliation: Department of Neurology and Neurological Science, Graduate school of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mio
authors.initials: M
authors.lastname: Tajiri
authors.affiliation: Department of Neurology and Neurological Science, Graduate school of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Ishibashi
authors.affiliation: Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Itsuki
authors.initials: I
authors.lastname: Ajioka
authors.affiliation: Department of Neurology and Neurological Science, Graduate school of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kinya
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Mizusawa
authors.affiliation: Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.affiliation: Department of Neurology and Neurological Science, Graduate school of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Yokota
mesh_terms: D000375:Aging / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D054022:Cerebrum / Q000378:metabolism*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D054520:Group III Phospholipases A2 / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007339:Insulysin / Q000235:genetics*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity; D018384:Oxidative Stress; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; C017763:alpha-tocopherol transfer protein; D054520:Group III Phospholipases A2; C484163:PLA2G3 protein, human; C541931:PLA2G3 protein, mouse; D007339:Insulysin