Dynamics of A[beta]42 Reduction in Plasma, CSF and Brain of Rats Treated with the [gamma]-Secretase Modulator, GSM-10h

• Published in: Neuro-degenerative diseases Vol. 8; no. 6; p. 455
• Main Authors: Hawkins, Julie, Harrison, David C, Ahmed, Sharlin, Davis, Robert P, Chapman, Trevor, Marshall, Ian, Smith, Beverley, Mead, Tania L, Medhurst, Andrew, Giblin, Ged M P, Hall, Adrian, Gonzalez, Maria I, Richardson, Jill, Hussain, Ishrut
• Format: Journal Article
• Language: English
• Published: Basel S. Karger AG 01.08.2011
• ISSN: 1660-2854; 1660-2862
• DOI: 10.1159/000324511

Background:Allosteric modulation of [gamma]-secretase is an attractive therapeutic approach for the treatment of Alzheimer's disease. We recently identified a novel [gamma]-secretase modulator, GSM-10h, which effectively lowers A[beta]42 production in cells and in amyloid precursor protein transgenic mice. Objective: Here, we describe the in vivo characterization of GSM-10h in a model of endogenous A[beta] production. Methods: Rats were administered orally with GSM-10h, and the effect on A[beta] levels in peripheral and central compartments was determined. In addition, the effect of GSM-10h on Notch processing was assessed. Results: Acute administration of GSM-10h to rats causes a dose-dependent decrease in the level of A[beta]42 in plasma, CSF and brain, with little effect on the level of A[beta]40 in these compartments. The magnitude of A[beta]42 lowering in the CSF and brain was further enhanced upon sub-chronic administration of GSM-10h. No deleterious effect on Notch processing was evident in either of these studies. To further explore the dynamics of A[beta]42 reduction in peripheral and CNS compartments, a time course study was conducted. In all compartments, the decrease in A[beta]42 was greatest at 6 h after administration of GSM-10h. This decrease in A[beta]42 was maintained for 9-15 h, after which time A[beta]42 levels returned to baseline levels. Encouragingly, no rebound in A[beta]42 levels beyond baseline levels was observed. Conclusions: These findings support the [gamma]-secretase modulator profile of GSM-10h, and highlight the utility of the rat for assessing the pre-clinical efficacy of [gamma]-secretase modulators. Copyright © 2011 S. Karger AG, Basel [PUBLICATION ABSTRACT]