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J. Biol. Chem., Vol. 283, Issue 25, 17049-17054, June 20, 2008

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Independent Generation of Aβ42 and Aβ38 Peptide Species by -Secretase^*

Eva Czirr, Barbara A. Cottrell, Stefanie Leuchtenberger, Thomas Kukar^¶, Thomas B. Ladd^¶, Hermann Esselmann^||, Sabine Paul^||, Robert Schubenel, Justin W. Torpey, Claus U. Pietrzik^¶¶, Todd E. Golde^¶, Jens Wiltfang^||, Karlheinz Baumann, Edward H. Koo, and Sascha Weggen¹

From the Molecular Neuropathology Group, Department of Neuropathology, Heinrich Heine-University, D-40225 Duesseldorf, Germany, Department of Neurosciences and Biomolecular Mass Spectrometry Facility, University of California San Diego, La Jolla, California 92093, ^¶¶Molecular Neurodegeneration Group, Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University, D-55128 Mainz, Germany, Pharmaceuticals Division, Preclinical Research CNS, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland, ^¶Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, and ^||Department of Psychiatry and Psychotherapy, Rhine State Hospital, University of Duisburg-Essen, D-45147 Essen, Germany

Proteolytic processing of the amyloid precursor protein by β- and -secretase generates the amyloid-β (Aβ) peptides, which are principal drug targets in Alzheimer disease therapeutics. -Secretase has imprecise cleavage specificity and generates themostabundant Aβ40 and Aβ42 species together with longer and shorter peptides such as Aβ38. Several mechanisms could explain the production of multiple Aβ peptides by -secretase, including sequential processing of longer into shorter Aβ peptides. A novel class of -secretase modulators (GSMs) that includes some non-steroidal anti-inflammatory drugs has been shown to selectively lower Aβ42 levels without a change in Aβ40 levels. A signature of GSMs is the concomitant increase in shorter Aβ peptides, such as Aβ38, leading to the suggestion that generation of Aβ42 and Aβ38 peptide species by -secretase is coordinately regulated. However, no evidence for or against such a precursor-product relationship has been provided. We have previously shown that stable overexpression of aggressive presenilin-1 (PS1) mutations associated with early-onset familial Alzheimer disease attenuated the cellular response to GSMs, resulting in greatly diminished Aβ42 reductions as compared with wild type PS1. We have now used this model system to investigate whether Aβ38 production would be similarly affected indicating coupled generation of Aβ42 and Aβ38 peptides. Surprisingly, treatment with the GSM sulindac sulfide increased Aβ38 production to similar levels in four different PS1 mutant cell lines as compared with wild type PS1 cells. This was confirmed with the structurally divergent GSMs ibuprofen and indomethacin. Mass spectrometry analysis and high resolution urea gel electrophoresis further demonstrated that sulindac sulfide did not induce detectable compensatory changes in levels of other Aβ peptide species. These data provide evidence that Aβ42 and Aβ38 species can be independently generated by -secretase and argue against a precursor-product relationship between these peptides.

Received for publication, October 15, 2007 , and in revised form, April 16, 2008.

^* This work was supported by Emmy Noether Phase II Grant WE 2561/1–3 from the Deutsche Forschungsgemeinschaft (to S. W.). 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.

¹ To whom correspondence should be addressed. Tel.: 49-211-8104506; Fax: 49-211-8104577; E-mail: sweggen{at}uni-duesseldorf.de.

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