Studies of Aβ Pharmacodynamics in the Brain, Cerebrospinal Fluid, and Plasma in Young (Plaque-Free) Tg2576 Mice Using the γ-Secretase Inhibitor N2-[(2 S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7 S)-5-methyl-6-oxo-6,7-dihydro-5 H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY-411575)

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Abstract
A previous study by us suggests the utility of cerebrospinal fluid (CSF) and plasma Aβ as biomarkers of β- or γ-secretase inhibition. The present study characterized further Aβ pharmacodynamics in these tissues from Tg2576 mice and examined their correlation with brain Aβ after acute treatment with a potent γ-secretase inhibitor, 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 (LY-411575). A single dose of LY-411575 dose-dependently (0.1–10 mg/kg p.o.) reduced Aβ(1-40) and Aβ(1-42) in the CSF and the brain. In contrast, plasma Aβ levels were increased by 0.1 mg/kg LY-411575 and were followed by a dose-dependent reduction at higher doses. The time courses of Aβ reduction and recovery were distinct for the three tissues: maximal declines in Aβ levels were evident by 3 h in the CSF and plasma but not until 9 h in the brain. A recovery in Aβ levels was underway in the CSF by 9 h and nearly completed by 24 h in all tissues. The differential time courses in the three compartments do not seem to be due to pharmacokinetic factors. Five days of twice-daily treatment with LY-411575 not only sustained the Aβ reductions in all tissues but also significantly augmented the efficacy in the brain and plasma. The increased efficacy occurred in the absence of compound accumulation and was consistent with the recovery rates in each compartment. Overall, Aβ in the CSF and not plasma seems to be a better biomarker of brain Aβ reduction; however, the time course of Aβ changes needs to be established in clinical studies.

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