A γ-secretase inhibitor decreases amyloid-β production in the central nervous system

Randall J. Bateman, Eric R. Siemers, Kwasi G. Mawuenyega, Guolin Wen, Karen R. Browning, Wendy C. Sigurdson, Kevin E. Yarasheski, Stuart W. Friedrich, Ronald B. DeMattos, Patrick C. May, Steven M. Paul, David M. Holtzman

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254 Scopus citations

Abstract

Objective: Accumulation of amyloid-β (Aβ) by overproduction or underclearance in the central nervous system (CNS) is hypothesized to be a necessary event in the pathogenesis of Alzheimer's disease. However, previously, there has not been a method to determine drug effects on Aβ production or clearance in the human CNS. The objective of this study was to determine the effects of a γ-secretase inhibitor on the production of Aβ in the human CNS. Methods: We utilized a recently developed method of stable-isotope labeling combined with cerebrospinal fluid sampling to directly measure Aβ production during treatment of a γ-secretase inhibitor, LY450139. We assessed whether this drug could decrease CNS Aβ production in healthy men (age range, 21-50 years) at single oral doses of 100, 140, or 280mg (n = 5 per group). Results: LY450139 significantly decreased the production of CNS Aβ in a dose-dependent fashion, with inhibition of Aβ generation of 47, 52, and 84% over a 12-hour period with doses of 100, 140, and 280mg, respectively. There was no difference in Aβ clearance. Interpretation: Stable isotope labeling of CNS proteins can be utilized to assess the effects of drugs on the production and clearance rates of proteins targeted as potential disease-modifying treatments for Alzheimer's disease and other CNS disorders. Results from this approach can assist in making decisions about drug dosing and frequency in the design of larger and longer clinical trials for diseases such as Alzheimer's disease, and may accelerate effective drug validation.

Original languageEnglish
Pages (from-to)48-54
Number of pages7
JournalAnnals of neurology
Volume66
Issue number1
DOIs
StatePublished - Jul 1 2009

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    Bateman, R. J., Siemers, E. R., Mawuenyega, K. G., Wen, G., Browning, K. R., Sigurdson, W. C., Yarasheski, K. E., Friedrich, S. W., DeMattos, R. B., May, P. C., Paul, S. M., & Holtzman, D. M. (2009). A γ-secretase inhibitor decreases amyloid-β production in the central nervous system. Annals of neurology, 66(1), 48-54. https://doi.org/10.1002/ana.21623