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J. Biol. Chem., Vol. 283, Issue 34, 22992-23003, August 22, 2008

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The Amyloid-β Rise and -Secretase Inhibitor Potency Depend on the Level of Substrate Expression^*

Catherine R. Burton, Jere E. Meredith, Donna M. Barten, Margi E. Goldstein, Carol M. Krause, Cathy J. Kieras, Lisa Sisk¹, Lawrence G. Iben, Craig Polson, Mark W. Thompson², Xu-Alan Lin, Jason Corsa³, Tracey Fiedler, Maria Pierdomenico, Yang Cao, Arthur H. Roach⁴, Joseph L. Cantone, Michael J. Ford, Dieter M. Drexler, Richard E. Olson^¶, Michael G. Yang^¶, Carl P. Bergstrom^¶, Kate E. McElhone^¶5, Joanne J. Bronson^¶, John E. Macor^¶, Yuval Blat^||, Robert H. Grafstrom^||, Andrew M. Stern^||6, Dietmar A. Seiffert^||7, Robert Zaczek, Charles F. Albright, and Jeremy H. Toyn⁸

From the Neuroscience Biology, Discovery Analytical Sciences, and ^¶Discovery Chemistry, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut 06492 and ^||Chemical Enzymology, Bristol-Myers Squibb Research and Development, Pennington, New Jersey 08534

The amyloid-β (Aβ) peptide, which likely plays a key role in Alzheimer disease, is derived from the amyloid-β precursor protein (APP) through consecutive proteolytic cleavages by β-site APP-cleaving enzyme and -secretase. Unexpectedly -secretase inhibitors can increase the secretion of Aβ peptides under some circumstances. This "Aβ rise" phenomenon, the same inhibitor causing an increase in Aβ at low concentrations but inhibition at higher concentrations, has been widely observed. Here we show that the Aβ rise depends on the β-secretase-derived C-terminal fragment of APP (βCTF) or C99 levels with low levels causing rises. In contrast, the N-terminally truncated form of Aβ, known as "p3," formed by -secretase cleavage, did not exhibit a rise. In addition to the Aβ rise, low βCTF or C99 expression decreased -secretase inhibitor potency. This "potency shift" may be explained by the relatively high enzyme to substrate ratio under conditions of low substrate because increased concentrations of inhibitor would be necessary to affect substrate turnover. Consistent with this hypothesis, -secretase inhibitor radioligand occupancy studies showed that a high level of occupancy was correlated with inhibition of Aβ under conditions of low substrate expression. The Aβ rise was also observed in rat brain after dosing with the -secretase inhibitor BMS-299897. The Aβ rise and potency shift are therefore relevant factors in the development of -secretase inhibitors and can be evaluated using appropriate choices of animal and cell culture models. Hypothetical mechanisms for the Aβ rise, including the "incomplete processing" and endocytic models, are discussed.

Received for publication, May 30, 2008

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Present address: Brookside Clinical Laboratory Inc., 4000 Edgemont Ave., Brookhaven, PA 19015.

² Present address: Applied Biotechnology, Bristol-Myers Squibb Research and Development, Wallingford, CT 06492.

³ Present address: Regulatory and Clinical Operations, Bristol-Myers Squibb Research and Development, Wallingford, CT 06492.

⁴ Present address: Merck Serono Research Center, Geneva CH-1211, Switzerland.

⁵ Present address: Johnson and Johnson Pharmaceutical Research and Development, LLC, San Diego, CA 92121.

⁶ Present address: Dept. of Novel Therapeutics, The Broad Inst. of Harvard and the Massachusetts Inst. of Technology, Cambridge, MA 02142.

⁷ Present address: Cardiovascular Disease, Bristol-Myers Squibb Research and Development, Pennington, NJ 08534.

⁸ To whom correspondence should be addressed: Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492. Tel.: 203-677-7511; Fax: 203-677-7569; E-mail: jeremy.toyn{at}bms.com.

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