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NEUROPHARMACOLOGY

In Vivo β-Secretase 1 Inhibition Leads to Brain Aβ Lowering and Increased -Secretase Processing of Amyloid Precursor Protein without Effect on Neuregulin-1

Departments of Alzheimer's Research (S.Sa., E.A.P., G.W., M.-C.C., X.-P.S., K.T., K.X.T., J.K., A.J.S.), Drug Metabolism (J.E., L.J.), and Medicinal Chemistry (T.S., S.St., C.C.), Merck Research Laboratories, West Point, Pennsylvania

β-Secretase (BACE) cleavage of amyloid precursor protein (APP) is one of the first steps in the production of amyloid β peptide Aβ42, the putative neurotoxic species in Alzheimer's disease. Recent studies have shown that BACE1 knockdown leads to hypomyelination, putatively caused by a decline in neuregulin (NRG)-1 processing. In this study, we have tested a potent cell-permeable BACE1 inhibitor (IC₅₀ 30 nM) by administering it directly into the lateral ventricles of mice, expressing human wild-type (WT)-APP, to determine the consequences of BACE1 inhibition on brain APP and NRG-1 processing. BACE1 inhibition, in vivo, led to a significant dose- and time-dependent lowering of brain Aβ40 and Aβ42. BACE1 inhibition also led to a robust brain secreted (s)APPβ lowering that was accompanied by an increase in brain sAPP levels. Although an increase in full-length NRG-1 levels was evident in 15-day-old BACE1 homozygous knockout (KO) (–/–) mice, in agreement with previous studies, this effect was also observed in 15-day-old heterozygous (+/–) mice, but it was not evident in 30-day-old and 2-year-old BACE1 KO (–/–) mice. Thus, BACE1 knockdown led to a transient decrease in NRG-1 processing in mice. Pharmacological inhibition of BACE1 in adult mice, which led to significant Aβ lowering, was without any significant effect on brain NRG-1 processing. Taken together, these results suggest that BACE1 is the major β-site cleavage enzyme for APP and that its inhibition can lower brain Aβ and redirect APP processing via the potentially nonamyloidogenic -secretase pathway, without significantly altering NRG-1 processing.

Address correspondence to: Dr. Adam J. Simon, Department of Alzheimer's Research, WP 26A-2000, Merck Research Laboratories, 770, Sumneytown Pike, West Point, PA 19486. E-mail: adam_simon{at}merck.com

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