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NEUROPHARMACOLOGY

The -Secretase Inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl Ester Reduces A Levels in Vivo in Plasma and Cerebrospinal Fluid in Young (Plaque-Free) and Aged (Plaque-Bearing) Tg2576 Mice

Department of Neurobiology, Pharmacia Corporation, Kalamazoo, Michigan

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

Address correspondence to: Dr. Kalpana M. Merchant, Pharmacia Corporation, 301 Henrietta St., Mailstop 7251-209-506, Kalamazoo, MI 49007. E-mail: kalpana.m.merchant{at}pharmacia.com

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