P4‐020: Separation of Aβ Reduction from Notch Toxicity with Gamma Secretase Inhibitors in Rats

γ-Secretase inhibitors (GSI) are an attractive therapeutic approach for Alzheimer's disease (AD) since cleavage of the amyloid precursor protein (APP) by γ-secretase is required to form the Aβ peptides hypothesized to cause AD. In addition to APP, γ-secretase cleaves other proteins thereby complicating the development of GSIs. Of particular concern are the Notch-family of proteins which require γ-secretase cleavage to control cell fate decisions in several tissues, including the gastrointestinal tract. We have developed Notch-sparing GSIs using cell-based assays. To explore the in vivo translation of these in vitro results, rats were dosed for either 1- or 4-days with GSIs exhibiting a range of different Notch/APP potency ratios. Reductions in plasma Aβ40 levels were measured to monitor inhibition of APP processing while reductions in HES-1 expression in white blood cells (WBC) or formation of gastrointestinal lesions after 4-days of dosing were used to measure inhibition of Notch processing. We demonstrate that the separation of Aβ reductions from Notch toxicity in rats is possible and that the Notch/APP potency ratios established in vitro are predictive of the in vivo response. Our results illustrate that despite the complex nature of γ-secretase as a therapeutic target, the development of safe inhibitors may be possible.