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

Jacquelynn J. Cook, Kristin R. Wildsmith, David B. Gilberto, Marie A. Holahan, Gene G. Kinney, Parker D. Mathers, Maria S. Michener, Eric A. Price, Mark S. Shearman, Adam J. Simon, Jennifer X. Wang, Guoxin Wu, Kevin E. Yarasheski, Randall J. Bateman

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

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 human in vivo stable-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 with in vivo stable-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.

Original languageEnglish
Pages (from-to)6743-6750
Number of pages8
JournalJournal of Neuroscience
Volume30
Issue number19
DOIs
StatePublished - May 12 2010

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