title: Enhancement of BACE1 Activity by p25/Cdk5-Mediated Phosphorylation in Alzheimer's Disease.
abstract: The activity of beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is elevated during aging and in sporadic Alzheimer's disease (AD), but the underlying mechanisms of this change are not well understood. p25/Cyclin-dependent kinase 5 (Cdk5) has been implicated in the pathogenesis of several neurodegenerative diseases, including AD. Here, we describe a potential mechanism by which BACE activity is increased in AD brains. First, we show that BACE1 is phosphorylated by the p25/Cdk5 complex at Thr252 and that this phosphorylation increases BACE1 activity. Then, we demonstrate that the level of phospho-BACE1 is increased in the brains of AD patients and in mammalian cells and transgenic mice that overexpress p25. Furthermore, the fraction of p25 prepared from iodixanol gradient centrifugation was unexpectedly protected by protease digestion, suggesting that p25/Cdk5-mediated BACE1 phosphorylation may occur in the lumen. These results reveal a link between p25 and BACE1 in AD brains and suggest that upregulated Cdk5 activation by p25 accelerates AD pathogenesis by enhancing BACE1 activity via phosphorylation.
authors: Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, Korea; Institute for Brain Science and Technology, Inje University, Busan, Korea.
authors: Woo-Joo
authors: WJ
authors: Song
authors: Institute for Brain Science and Technology, Inje University, Busan, Korea.
authors: Mi-Young
authors: MY
authors: Son
authors: Institute for Brain Science and Technology, Inje University, Busan, Korea.
authors: Hye-Won
authors: HW
authors: Lee
authors: Division of Molecular and Life Sciences, College of Sciences and Technology, Hanyang University, Ansan, Gyeonggi Do, Korea.
authors: Hyemyung
authors: H
authors: Seo
authors: Department of Oral Biochemistry and Molecular Biology, School of Dentistry, Kyung Hee University, Seoul, Korea; Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, Korea.
authors: Jeong Hee
authors: JH
authors: Kim
authors: Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, Korea; Institute for Brain Science and Technology, Inje University, Busan, Korea.
authors: Sul-Hee
authors: SH
authors: Chung
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: D009419:Nerve Tissue Proteins; C118136:TPPP protein, human; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human