RAC1 Inhibition Targets Amyloid Precursor Protein Processing by γ-Secretase and Decreases Aβ Production in Vitro and in Vivo

β-Amyloid peptides (Aβ) that form the senile plaques of Alzheimer disease consist mainly of 40- and 42-amino acid (Aβ 40 and Aβ 42) peptides generated from the cleavage of the amyloid precursor protein (APP). Generation of Aβ involves β-secretase and γ-secretase activities and is regulated by membrane trafficking of the proteins involved in Aβ production. Here we describe a new small molecule, EHT 1864, which blocks the Rac1 signaling pathways. In vitro, EHT 1864 blocks Aβ 40 and Aβ 42 production but does not impact sAPPα levels and does not inhibit β-secretase. Rather, EHT 1864 modulates APP processing at the level of γ-secretase to prevent Aβ 40 and Aβ 42 generation. This effect does not result from a direct inhibition of the γ-secretase activity and is specific for APP cleavage, since EHT 1864 does not affect Notch cleavage. In vivo, EHT 1864 significantly reduces Aβ 40 and Aβ 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 Aβ 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.