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A more recent version of this article appeared on November 11, 2005
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Papers In Press, published online ahead of print September 8, 2005
J. Biol. Chem, 10.1074/jbc.M507913200
Submitted on July 20, 2005
Revised on September 6, 2005
Accepted on September 8, 2005

RAC1 inhibition targets APP processing by gamma -secretase and decreases Abeta production in vitro and in vivo

Laurent Désiré, Jerome Bourdin, Nadia Loiseau, Helene Peillon, Virginie Picard, Catherine De Oliveira, Florence Bachelot, Bertrand Leblond, Thierry Taverne, Eric Beausoleil, Sandrine Lacombe, Dominique Drouin, and Fabien Schweighoffer

Department of Neurology, ExonHit Therapeutics, Paris 75013

Corresponding Author: laurent.desire{at}exonhit.com

Beta amyloid peptides (Aß) that form the senile plaques of Alzheimer’s disease consist mainly of 40 and 42 aa (Aß 40 and Aß 42) peptides generated from the cleavage of the amyloid precursor APP. Generation of Aß involves ß-secretase (BACE) and -secretase activities and is regulated by membrane trafficking of the proteins involved in Aß production. Here we describe a new small molecule, EHT 1864, which blocks the Rac1 signaling pathways. In vitro, EHT 1864 blocks Aß 40 and Aß 42 production but does not impact sAPPa levels and does not inhibit BACE. Rather, EHT 1864 modulates APP processing at the level of -secretase to prevent Aß 40 and Aß 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 Aß 40 and Aß 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 are candidates for inhibiting Aß 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’s disease.


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