RT Journal Article SR Electronic T1 Quantitative Measurement of Changes in Amyloid-β(40) in the Rat Brain and Cerebrospinal Fluid following Treatment with the γ-Secretase Inhibitor LY-411575 [N2-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide] JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 902 OP 908 DO 10.1124/jpet.104.081174 VO 313 IS 2 A1 Jonathan D. Best A1 Mark T. Jay A1 Franklin Otu A1 Jerome Ma A1 Alan Nadin A1 Semantha Ellis A1 Huw D. Lewis A1 Christine Pattison A1 Michael Reilly A1 Timothy Harrison A1 Mark S. Shearman A1 Toni L. Williamson A1 John R. Atack YR 2005 UL http://jpet.aspetjournals.org/content/313/2/902.abstract AB The efficacy of γ-secretase inhibitors in vivo has, to date, been generally assessed in transgenic mouse models expressing increased levels of amyloid-β (Aβ) peptide thereby allowing the detection of changes in Aβ production. However, it is not clear whether the in vivo potency of γ-secretase inhibitors is independent of the level of amyloid precursor protein expression. In other words, does a γ-secretase inhibitor have the same effect in nontransgenic physiological animals versus transgenic overexpressing animals? In the present study, an immunoassay has been developed which can detect Aβ(40) in the rat brain, where concentrations are much lower than those seen in transgenic mice such as Tg2576 (c. 0.7 and 25 nM, respectively) and in cerebrospinal fluid (CSF, c. 0.3 nM). Using this immunoassay, the effects of the γ-secretase inhibitor LY-411575 [N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide] were assessed and robust dose-dependent reductions in rat brain and CSF Aβ(40) levels were observed with ID50 values of 1.3 mg/kg for both brain and CSF. These values were comparable with those calculated for LY-411575 in transgenic mice. Time course experiments using LY-411575 demonstrated comparable temporal reductions in rat brain and CSF Aβ(40), further suggesting these two pools of Aβ are related. Accordingly, when all the data for the dose-response curve and time course were correlated, a strong association was observed between the brain and CSF Aβ(40) levels. These data demonstrate the utility of the rat as a novel approach for assessing the effects of γ-secretase inhibitors on central nervous system Aβ(40) levels in vivo. The American Society for Pharmacology and Experimental Therapeutics