CNS Amyloid-β, Soluble APP-α and-β Kinetics during BACE Inhibition

Justyna A. Dobrowolska, Maria S. Michener, Guoxin Wu, Bruce W. Patterson, Robert Chott, Vitaliy Ovod, Yuriy Pyatkivskyy, Kristin R. Wildsmith, Tom Kasten, Parker Mathers, Mandy Dancho, Christina Lennox, Brad E. Smith, David Gilberto, Debra McLoughlin, Daniel J. Holder, Andrew W. Stamford, Kevin E. Yarasheski, Matthew E. Kennedy, Mary J. SavageRandall J. Bateman

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

BACE, aβ-secretase, is an attractive potential disease-modifying therapeutic strategy for Alzheimer's disease (AD) as it results directly in the decrease of amyloid precursor protein (APP) processing through the β-secretase pathway and a lowering of CNS amyloid-β (Aβ) levels. The interaction of the β-secretase and α-secretase pathway-mediated processing of APP in the rhesus monkey (nonhuman primate; NHP) CNS is not understood. We hypothesized that CNS inhibition of BACE would result in decreased newly generated Aβ and soluble APPβ (sAPPβ), with increased newly generated sAPPα. A stable isotope labeling kinetics experiment in NHPs was performed with a 13C6-leucine infusion protocol to evaluate effects of BACE inhibition on CNS APP processing by measuring the kinetics of sAPPα, sAPPβ, andAβ in CSF. EachNHPreceived a low, medium, or high dose of MBI-5 (BACE inhibitor) or vehicle in a four-way crossover design. CSF sAPPα, sAPPβ, andAβ were measured by ELISA and newly incorporated label following immunoprecipitation and liquid chromatography-mass spectrometry. Concentrations, kinetics, and amount of newly generated APP fragments were calculated. sAPPβ and sAPPα kinetics were similar, but both significantly slower than Aβ. BACE inhibition resulted in decreased labeled sAPPβ and Aβ in CSF, without observable changes in labeled CSF sAPPα. ELISA concentrations of sAPPβ and Aβ both decreased and sAPPα increased. sAPPα increased by ELISA, with no difference by labeled sAPPα kinetics indicating increases in product may be due to APP shunting from the β-secretase to the α-secretase pathway. These results provide a quantitative understanding of pharmacodynamic effects of BACE inhibition on NHP CNS, which can inform about target development.

Original languageEnglish
Pages (from-to)8336-8346
Number of pages11
JournalJournal of Neuroscience
Volume34
Issue number24
DOIs
StatePublished - Jan 1 2014

Keywords

  • Amyloid beta
  • Amyloid precursor protein
  • BACE inhibitor
  • SAPP-α sAPP-β
  • SILK

Fingerprint Dive into the research topics of 'CNS Amyloid-β, Soluble APP-α and-β Kinetics during BACE Inhibition'. Together they form a unique fingerprint.

  • Cite this

    Dobrowolska, J. A., Michener, M. S., Wu, G., Patterson, B. W., Chott, R., Ovod, V., Pyatkivskyy, Y., Wildsmith, K. R., Kasten, T., Mathers, P., Dancho, M., Lennox, C., Smith, B. E., Gilberto, D., McLoughlin, D., Holder, D. J., Stamford, A. W., Yarasheski, K. E., Kennedy, M. E., ... Bateman, R. J. (2014). CNS Amyloid-β, Soluble APP-α and-β Kinetics during BACE Inhibition. Journal of Neuroscience, 34(24), 8336-8346. https://doi.org/10.1523/JNEUROSCI.0540-14.2014