CNS Amyloid- , Soluble APP- and - Kinetics during BACE Inhibition
| Autor: | Guoxin Wu, Kristin R. Wildsmith, Andrew Stamford, Kevin E. Yarasheski, Matthew E. Kennedy, David B. Gilberto, Yuriy Pyatkivskyy, Randall J. Bateman, Daniel J. Holder, Mary J. Savage, Robert Chott, Debra A. McLoughlin, Justyna Dobrowolska, Bruce W. Patterson, Mandy Dancho, Tom Kasten, Vitaliy Ovod, Parker Mathers, Maria S. Michener, Christina Lennox, Brad E. Smith |
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| Rok vydání: | 2014 |
| Předmět: |
Central Nervous System
Amyloid beta Immunoprecipitation Central nervous system Pharmacology Transfection Mass Spectrometry Amyloid beta-Protein Precursor Neuroblastoma Leucine Cell Line Tumor medicine Amyloid precursor protein Animals Humans Enzyme Inhibitors Carbon Isotopes Amyloid beta-Peptides Cross-Over Studies Dose-Response Relationship Drug biology Chemistry General Neuroscience Articles medicine.disease Macaca mulatta Peptide Fragments medicine.anatomical_structure Biochemistry biology.protein Amyloid Precursor Protein Secretases Amyloid precursor protein secretase |
| Zdroj: | Journal of Neuroscience. 34:8336-8346 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | BACE, a β-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, and Aβ in CSF. Each NHP received a low, medium, or high dose of MBI-5 (BACE inhibitor) or vehicle in a four-way crossover design. CSF sAPPα, sAPPβ, and Aβ 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. |
| Databáze: | OpenAIRE |
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