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J. Biol. Chem., Vol. 283, Issue 17, 11302-11311, April 25, 2008

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Independent Inhibition of Alzheimer Disease β- and -Secretase Cleavage by Lowered Cholesterol Levels^*

Marcus O. W. Grimm, Heike S. Grimm, Inge Tomic, Konrad Beyreuther, Tobias Hartmann¹², and Christine Bergmann^¶1

From the Departments of Neurology and Neurobiology, Saarland University, Kirrbergerstrasse, 66421 Homburg/Saar, the Center for Molecular Biology Heidelberg, University of Heidelberg, Im Neuenheimer Feld 282, 69120 Heidelberg, and the ^¶Central Institute for Mental Health, Division of Geriatric Psychiatry, J5, 68159 Mannheim, Germany

The major molecular risk factor for Alzheimer disease so far identified is the amyloidogenic peptide Aβ₄₂. In addition, growing evidence suggests a role of cholesterol in Alzheimer disease pathology and Aβ generation. However, the cellular mechanism of lipid-dependent Aβ production remains unclear. Here we describe that the two enzymatic activities responsible for Aβ production, β-secretase and -secretase, are inhibited in parallel by cholesterol reduction. Importantly, our data indicate that cholesterol depletion within the cellular context inhibits both secretases additively and independently from each other. This is unexpected because the β-secretase β-site amyloid precursor protein cleaving enzyme and the presenilin-containing -secretase complex are structurally different from each other, and these enzymes are apparently located in different subcellular compartments. The parallel and additive inhibition has obvious consequences for therapeutic research and may indicate an intrinsic cross-talk between Alzheimer disease-related amyloid precursor protein processing, amyloid precursor protein function, and lipid biology.

Received for publication, February 25, 2008

^* This work was supported by grants from the Deutsche Forschungsgemeinschaftg and the Bundesministerium für Bildung und Forschung. 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Neurobiology, Kirrbergerstrasse, Bldg. 90, 66421 Homburg/Saar, Germany. E-mail: tobias.hartmann{at}uniklinikum-saarland.de.

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