TY - JOUR 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 [<em>N</em><sup>2</sup>-[(2<em>S</em>)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-<em>N</em><sup>1</sup>-[(7<em>S</em>)-5-methyl-6-oxo-6,7-dihydro-5<em>H</em>-dibenzo[<em>b</em>,<em>d</em>]azepin-7-yl]-<span class="sc">l</span>-alaninamide] JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 902 LP - 908 DO - 10.1124/jpet.104.081174 VL - 313 IS - 2 AU - Jonathan D. Best AU - Mark T. Jay AU - Franklin Otu AU - Jerome Ma AU - Alan Nadin AU - Semantha Ellis AU - Huw D. Lewis AU - Christine Pattison AU - Michael Reilly AU - Timothy Harrison AU - Mark S. Shearman AU - Toni L. Williamson AU - John R. Atack Y1 - 2005/05/01 UR - http://jpet.aspetjournals.org/content/313/2/902.abstract N2 - 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 ER -