Pharmacological agents that selectively inhibit production of the highly amyloidogenic Aβ42 peptide and do not interfere with other physiological functions of γ-secretase may have superior features for the treatment of Alzheimer’s disease (AD). Here we report the identification of a class of compounds that selectively decreased the secretion of Aβ42 from a variety of cultured cells of both neural and non-neural origin through a novel mechanism. The reduction in Aβ42 levels ranged from 30 to 70% without significant changes in total Aβ levels, especially Aβ40 species. Moreover, short-term administration in APP-transgenic mice lowered brain Aβ42 levels (Eriksen, J. et. al., SFN abstract, 2001). In contrast to published γ-secretase inhibitors, these compounds did not significantly perturb APP or notch processing. In particular, the reduction in Aβ42 levels was not accompanied by an increase in APP C-terminal fragments, nor any changes in APPs secretion, APP internalization, or APP turnover. Significantly, tran...