title: Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing.
abstract: Cyclin-dependent kinase 5 (cdk5) has been implicated in Alzheimer's disease (AD) pathogenesis. Here, we demonstrate that overexpression of p25, an activator of cdk5, led to increased levels of BACE1 mRNA and protein in vitro and in vivo. A p25/cdk5 responsive region containing multiple sites for signal transducer and activator of transcription (STAT1/3) was identified in the BACE1 promoter. STAT3 interacts with the BACE1 promoter, and p25-overexpressing mice had elevated levels of pSTAT3 and BACE1, whereas cdk5-deficient mice had reduced levels. Furthermore, mice with a targeted mutation in the STAT3 cdk5 responsive site had lower levels of BACE1. Increased BACE levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor. These data demonstrate a pathway by which p25/cdk5 increases the amyloidogenic processing of APP through STAT3-mediated transcriptional control of BACE1 that could have implications for AD pathogenesis.
authors.affiliation: Taub Institute at Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wen
authors.forename: W Haung
authors.initials: WH
authors.lastname: Yu
authors.forename: Bryan
authors.initials: B
authors.lastname: Maloney
authors.forename: Jason
authors.initials: J
authors.lastname: Bailey
authors.forename: Junrong
authors.initials: J
authors.lastname: Ma
authors.forename: Isabelle
authors.initials: I
authors.lastname: Marié
authors.forename: Thomas
authors.initials: T
authors.lastname: Maurin
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Helen
authors.initials: H
authors.lastname: Figueroa
authors.forename: Mathieu
authors.initials: M
authors.lastname: Herman
authors.forename: Pavan
authors.initials: P
authors.lastname: Krishnamurthy
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Planel
authors.forename: Lit-Fui
authors.initials: LF
authors.lastname: Lau
authors.forename: Debomoy K
authors.initials: DK
authors.lastname: Lahiri
authors.forename: Karen
authors.initials: K
authors.lastname: Duff
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D016716:PC12 Cells; D010770:Phosphotransferases; D051381:Rats; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C492236:Cdk5r1 protein, mouse; D009419:Nerve Tissue Proteins; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; D053829:Amyloid Precursor Protein Secretases