The γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester reduces Aβ levels in vivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice

Acute, s.c. administration of a gamma-secretase inhibitor, N-[N-(3,5difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), to young PDAPP mice dose dependently decreases cortical amyloid-beta (Abeta). The present studies replicated these findings in Tg2576 mice and examined further whether DAPT would reduce cerebrospinal fluid (CSF) Abeta comparably in young (plaque-free) and aged (plaque-bearing) mice. In the first study, vehicle or DAPT (10, 30, or 100 mg/kg s.c.) administered to young Tg2576 mice (6 months old) dose dependently reduced Abeta peptide levels in the cortex as seen previously in the PDAPP mice. Additionally, a dose-dependent decrease in plasma Abeta levels was evident. The same dosing regime was applied next to aged mice (17 months old) to assess Abeta changes in the CSF in addition to plasma and brains. DAPT dose dependently reduced Abeta levels in the CSF and plasma, but not in the brain wherein Abeta levels were 400 to 500 times higher than those in young mice, consistent with a large pool of Abeta extracted from amyloid deposits. In subsequent studies, effects of oral DAPT (100 or 200 mg/kg) were examined concurrently in young and aged mice. DAPT reduced Abeta levels in CSF and plasma to a similar extent at both ages. In contrast, DAPT reduced brain Abeta levels primarily in young mice, with minimal effects in aged mice. These results demonstrate that Abeta levels in CSF and plasma decrease dose dependently after gamma-secretase inhibition, and this response is not affected by amyloid plaque burden. We conclude that CSF and plasma Abeta may offer a clinically applicable, mechanism-based biomarker for inhibitors of Abeta production.