RAC1 inhibition targets amyloid precursor protein processing by γ-secretase and decreases Aβ production in vitro and in vivo

beta-Amyloid peptides (A beta) that form the senile plaques of Alzheimer disease consist mainly of 40- and 42-amino acid (A beta 40 and A beta 42) peptides generated from the cleavage of the amyloid precursor protein (APP). Generation of A beta involves beta-secretase and gamma-secretase activities and is regulated by membrane trafficking of the proteins involved in A beta production. Here we describe a new small molecule, EHT1864, which blocks the Rac1 signaling pathways. In vitro, EHT 1864 blocks A beta 40 and A beta 42 production but does not impact sAPP alpha levels and does not inhibit beta-secretase. Rather, EHT 1864 modulates APP processing at the level of gamma-secretase to prevent A beta 40 and A beta 42 generation. This effect does not result from a direct inhibition of the gamma-secretase activity and is specific for APP cleavage, since EHT 1864 does not affect Notch cleavage. In vivo, EHT 1864 significantly reduces A beta 40 and A beta 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 beta 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.