Acute γ-Secretase Inhibition of Nonhuman Primate CNS Shifts Amyloid Precursor Protein (APP) Metabolism from Amyloid-β Production to Alternative APP Fragments without Amyloid-β Rebound
| Autor: | Eric A. Price, Gene G. Kinney, Randall J. Bateman, Maria S. Michener, Marie A. Holahan, Parker Mathers, Adam J. Simon, Kristin R. Wildsmith, Guoxin Wu, David B. Gilberto, Kevin E. Yarasheski, Mark S. Shearman, Jennifer X. Wang, Jacquelynn J. Cook |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Time Factors Amyloid beta Article Amyloid beta-Protein Precursor Species Specificity In vivo mental disorders Amyloid precursor protein Extracellular Animals Humans Carbon Radioisotopes Beta (finance) Gamma secretase Amyloid beta-Peptides Cross-Over Studies biology General Neuroscience P3 peptide Brain Macaca mulatta nervous system diseases Cell biology Kinetics Spinal Cord Biochemistry Isotope Labeling Models Animal biology.protein Amyloid Precursor Protein Secretases Amyloid precursor protein secretase |
| Zdroj: | The Journal of Neuroscience. 30:6743-6750 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | The accumulation of amyloid β (Aβ) in Alzheimer's disease is caused by an imbalance of production and clearance, which leads to increased soluble Aβ species and extracellular plaque formation in the brain. Multiple Aβ-lowering therapies are currently in development: an important goal is to characterize the molecular mechanisms of action and effects on physiological processing of Aβ, as well as other amyloid precursor protein (APP) metabolites, in models which approximate human Aβ physiology. To this end, we report the translation of the humanin vivostable-isotope-labeling kinetics (SILK) method to a rhesus monkey cisterna magna ported (CMP) nonhuman primate model, and use the model to test the mechanisms of action of a γ-secretase inhibitor (GSI). A major concern of inhibiting the enzymes which produce Aβ (β- and γ-secretase) is that precursors of Aβ may accumulate and cause a rapid increase in Aβ production when enzyme inhibition discontinues. In this study, the GSI MK-0752 was administered to conscious CMP rhesus monkeys in conjunction within vivostable-isotope-labeling, and dose-dependently reduced newly generated CNS Aβ. In contrast to systemic Aβ metabolism, CNS Aβ production was not increased after the GSI was cleared. These results indicate that most of the CNS APP was metabolized to products other than Aβ, including C-terminal truncated forms of Aβ: 1-14, 1-15 and 1-16; this demonstrates an alternative degradation pathway for CNS amyloid precursor protein during γ-secretase inhibition. |
| Databáze: | OpenAIRE |
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