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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on December 21, 2007; DOI: 10.1124/jpet.107.130039

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Received for publication August 14, 2007.
Revised December 19, 2007.
Accepted for publication December 20, 2007.

In vivo BACE1 inhibition leads to brain A{beta} lowering and increased {alpha}-secretase processing of APP without effect on Neuregulin-1

Sethu Sankaranarayanan 1, Eric A. Price 1, Guoxin Wu 1, Ming-Chih Crouthamel 1, Xiao-Ping Shi 1, Katherine Tugusheva 1, Keala X Tyler 1, Jason Kahana 2, Joan Ellis 1, Lixia Jin 1, Thomas Steele 1, Shawn J Stachel 1, Craig Coburn 1, Adam J. Simon 1*

1 Merck Research Laboratories 2 Glaxo Smith Kline

* Address correspondence to: E-mail: adam_simon{at}merck.com

Abstract

{beta}-secretase (BACE) cleavage of Amyloid Precursor Protein (APP) is one of the first steps in the production of A{beta}42, 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-1 (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-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 A{beta}40 and A{beta}42. BACE1 inhibition also led to a robust brain sAPP{beta} lowering that was accompanied by an increase in brain sAPP{alpha} levels. While an increase in full-length NRG-1 levels was evident in 15 day old BACE1 homozygous KO (-/-) mice, in agreement with previous studies, this effect was also observed in 15 day old heterozygous (+/-) mice, but not evident in 30 day old and 2 yr 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 A{beta} lowering, was without any significant effect on brain NRG-1 processing. Taken together these results suggest that BACE1 is the major {beta}-site cleavage enzyme for APP and that its inhibition can lower brain A{beta} and redirect APP-processing via the potentially non-amyloidogenic {alpha}-secretase pathway, without significantly altering NRG-1 processing.


Key words: APP, Alzheimer's, Beta-secretase, Neuregulin-1, in-vivo, inhibition


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