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J. Biol. Chem., Vol. 283, Issue 2, 677-683, January 11, 2008

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Generation of Aβ₃₈ and Aβ₄₂ Is Independently and Differentially Affected by Familial Alzheimer Disease-associated Presenilin Mutations and -Secretase Modulation^*

Richard M. Page, Karlheinz Baumann¹², Masanori Tomioka, Blanca I. Pérez-Revuelta, Akio Fukumori, Helmut Jacobsen, Alexander Flohr, Thomas Luebbers, Laurence Ozmen, Harald Steiner¹³, and Christian Haass¹⁴

From the Center for Integrated Protein Science Munich and Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Ludwig Maximilians University, 80336 Munich, Germany and Preclinical CNS Research, Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland

Alzheimer disease amyloid β-peptide (Aβ) is generated via proteolytic processing of the β-amyloid precursor protein by β- and -secretase. -Secretase can be blocked by selective inhibitors but can also be modulated by a subset of non-steroidal anti-inflammatory drugs, including sulindac sulfide. These drugs selectively reduce the generation of the aggregation-prone 42-amino acid Aβ₄₂ and concomitantly increase the levels of the rather benign Aβ₃₈. Here we show that Aβ₄₂ and Aβ₃₈ generation occur independently from each other. The amount of Aβ₄₂ produced by cells expressing 10 different familial Alzheimer disease (FAD)-associated mutations in presenilin (PS) 1, the catalytic subunit of -secretase, appeared to correlate with the respective age of onset in patients. However, Aβ₃₈ levels did not show a negative correlation with the age of onset. Modulation of -secretase activity by sulindac sulfide reduced Aβ₄₂ in the case of wild type PS1 and two FAD-associated PS1 mutations (M146L and A285V). The remaining eight PS1 FAD mutants showed either no reduction of Aβ₄₂ or only rather subtle effects. Strikingly, even the mutations that showed no effect on Aβ₄₂ levels allowed a robust increase of Aβ₃₈ upon treatment with sulindac sulfide. Similar observations were made for fenofibrate, a compound known to increase Aβ₄₂ and to decrease Aβ₃₈. For mutants that predominantly produce Aβ₄₂, the ability of fenofibrate to further increase Aβ₄₂ levels became diminished, whereas Aβ₃₈ levels were altered to varying extents for all mutants analyzed. Thus, we conclude that Aβ₃₈ and Aβ₄₂ production do not depend on each other. Using an independent non-steroidal anti-inflammatory drug derivative, we obtained similar results for PS1 as well as for PS2. These in vitro results were confirmed by in vivo experiments in transgenic mice expressing the PS2 N141I FAD mutant. Our findings therefore have strong implications on the selection of transgenic mouse models used for screening of the Aβ₄₂-lowering capacity of -secretase modulators. Furthermore, human patients with certain PS mutations may not respond to -secretase modulators.

Received for publication, October 23, 2007

^* This work was supported in part by the Deutsche Forschungsgemeinschaft Gottfried Wilhelm Leibniz Award (to C. H.), Collaborative Research Center (SFB596) "Molecular Mechanisms of Neurodegeneration" (to H. S. and C. H.), and the Bundesministerium für Bildung und Forschung ("Degenerative Dementias: Target Identification, Validation, and Translation into Treatment Strategies" (to C. H. and H. S.). 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 These authors contributed equally to this work.

⁴ Supported by a research professorship from the Ludwig Maximilians University Excellence program. To whom correspondence may be addressed. E-mail: chaass{at}med.uni-muenchen.de.

² To whom correspondence may be addressed. E-mail: karlheinz.baumann{at}roche.com. ³ To whom correspondence may be addressed. E-mail: hsteiner{at}med.uni-muenchen.de.

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