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J. Biol. Chem., Vol. 280, Issue 45, 37516-37525, November 11, 2005

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RAC1 Inhibition Targets Amyloid Precursor Protein Processing by -Secretase and Decreases A Production in Vitro and in Vivo^*

From the Exonhit Therapeutics, 63 Bd. Masséna, Paris 75013, France

-Amyloid peptides (A) that form the senile plaques of Alzheimer disease consist mainly of 40- and 42-amino acid (A 40 and A 42) peptides generated from the cleavage of the amyloid precursor protein (APP). Generation of A involves -secretase and -secretase activities and is regulated by membrane trafficking of the proteins involved in A production. Here we describe a new small molecule, EHT 1864, which blocks the Rac1 signaling pathways. In vitro, EHT 1864 blocks A 40 and A 42 production but does not impact sAPP levels and does not inhibit -secretase. Rather, EHT 1864 modulates APP processing at the level of -secretase to prevent A 40 and A 42 generation. This effect does not result from a direct inhibition of the -secretase activity and is specific for APP cleavage, since EHT 1864 does not affect Notch cleavage. In vivo, EHT 1864 significantly reduces A 40 and A 42 levels in guinea pig brains at a threshold that is compatible with delaying plaque accumulation and/or clearing the existing plaque in brain. EHT 1864 is the first derivative of a new chemical series that consists of candidates for inhibiting A formation in the brain of AD patients. Our findings represent the first pharmacological validation of Rac1 signaling as a target for developing novel therapies for Alzheimer disease.

Received for publication, July 20, 2005 , and in revised form, September 6, 2005.

^* 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.: 33-1-53947718; Fax: 33-1-53947715; E-mail: laurent.desire{at}exonhit.com.

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