Enhanced Phospholipase A2 Group 3 Expression by Oxidative Stress Decreases the Insulin-Degrading Enzyme

• DOI: 10.1371/journal.pone.0143518
• Publication Date: 2015-12-04T18:40:40Z
• Authors: Daishi Yui; Yoichiro Nishida; Tomoko Nishina; Kaoru Mogushi; Mio Tajiri; Satoru Ishibashi; Itsuki Ajioka; Kinya Ishikawa; Hidehiro Mizusawa; Shigeo Murayama; Takanori Yokota
• Keywords: 0301 basic medicine; Aging; Science; Insulysin; Gene Knockout Techniques; Mice; 03 medical and health sciences; Alzheimer Disease; Animals; Humans; Cerebrum; Cells, Cultured; Oligonucleotide Array Sequence Analysis; Gene Expression Profiling; Group III Phospholipases A2; Q; R; Up-Regulation; Disease Models, Animal; Oxidative Stress; HEK293 Cells; Organ Specificity; Medicine; Carrier Proteins; Research Article

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.