Dynamics of Aβ42 reduction in plasma, CSF and brain of rats treated with the γ-secretase modulator, GSM-10h

Background:Allosteric modulation of γ-secretase is an attractive therapeutic approach for the treatment of Alzheimer’s disease. We recently identified a novel γ-secretase modulator, GSM-10h, which effectively lowers Aβ42 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 Aβ production. Methods: Rats were administered orally with GSM-10h, and the effect on Aβ 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 Aβ42 in plasma, CSF and brain, with little effect on the level of Aβ40 in these compartments. The magnitude of Aβ42 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 Aβ42 reduction in peripheral and CNS compartments, a time course study was conducted. In all compartments, the decrease in Aβ42 was greatest at 6 h after administration of GSM-10h. This decrease in Aβ42 was maintained for 9–15 h, after which time Aβ42 levels returned to baseline levels. Encouragingly, no rebound in Aβ42 levels beyond baseline levels was observed. Conclusions: These findings support the γ-secretase modulator profile of GSM-10h, and highlight the utility of the rat for assessing the pre-clinical efficacy of γ-secretase modulators.