Transcriptional Regulation of β-Secretase by p25/cdk5 Leads to Enhanced Amyloidogenic Processing

Yi Wen, W. Haung Yu, Bryan Maloney, Jason Bailey, Junrong Ma, Isabelle Marié, Thomas Maurin, Lili Wang, Helen Figueroa, Mathieu Herman, Pavan Krishnamurthy, Li Liu, Emmanuel Planel, Lit Fui Lau, Debomoy K. Lahiri, Karen Duff

Research output: Contribution to journalArticle

149 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)680-690
Number of pages11
JournalNeuron
Volume57
Issue number5
DOIs
StatePublished - Mar 13 2008

Keywords

  • CELLBIO
  • HUMDISEASE
  • MOLNEURO

ASJC Scopus subject areas

  • Neuroscience(all)

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    Wen, Y., Yu, W. H., Maloney, B., Bailey, J., Ma, J., Marié, I., Maurin, T., Wang, L., Figueroa, H., Herman, M., Krishnamurthy, P., Liu, L., Planel, E., Lau, L. F., Lahiri, D. K., & Duff, K. (2008). Transcriptional Regulation of β-Secretase by p25/cdk5 Leads to Enhanced Amyloidogenic Processing. Neuron, 57(5), 680-690. https://doi.org/10.1016/j.neuron.2008.02.024