CNS amyloid-β, soluble APP-α and -β kinetics during BACE inhibition.

Autor:	Dobrowolska JA; Departments of Neurology and., Michener MS; Safety and Laboratory Animal Resources., Wu G; Molecular Biomarkers., Patterson BW; Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 and., Chott R; Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 and., Ovod V; Departments of Neurology and., Pyatkivskyy Y; Departments of Neurology and., Wildsmith KR; Departments of Neurology and., Kasten T; Departments of Neurology and., Mathers P; Safety and Laboratory Animal Resources., Dancho M; Safety and Laboratory Animal Resources., Lennox C; Safety and Laboratory Animal Resources., Smith BE; Safety and Laboratory Animal Resources., Gilberto D; Safety and Laboratory Animal Resources., McLoughlin D; Preclinical Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486 and Kenilworth, New Jersey 07033., Holder DJ; Early Development Statistics, and., Stamford AW; Medicinal Chemistry., Yarasheski KE; Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 and., Kennedy ME; Neuroscience., Savage MJ; Molecular Biomarkers., Bateman RJ; Departments of Neurology and batemanr@wustl.edu.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2014 Jun 11; Vol. 34 (24), pp. 8336-46.
DOI:	10.1523/JNEUROSCI.0540-14.2014
Abstrakt:	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 (13)C6-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. (Copyright © 2014 the authors 0270-6474/14/348336-11$15.00/0.)
Databáze:	MEDLINE
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