The Gamma Secretase Modulator EVP-0015962 Improves Cognitive Deficits in Tg2576 Mice Concomitant With Decreases In Aβ42

Abstract

A classical hallmark of Alzheimer's disease (AD) is the presence of plaques in the brain that are composed primarily of a toxic peptide known as Aβ42. Aβ42 is generated through cleavage of amyloid prescursor protein (APP) by the enzyme gamma secretase (GS). Inhibition of GS activity is presumed to decrease the amount of Aβ42 in the brain and thus has been the focus of numerous drug discovery efforts. EVP-0015962 is a compound that modulates GS activity by altering production of Aβ42 to favor production of Aβ38, a shorter peptide presumed to be less toxic than Aβ42. Here we report the effects of chronic drug administration on the production of Aβ42 and cognitive improvement in the Tg2576 transgenic model of Alzheimer's disease. Male Tg2576 at 20 weeks of age were placed on diet containing EVP-0015962 equivalent to 20 mg/kg/day or 60 mg/kg/day. At 30-33 weeks animals were tested in contextual fear conditioning (CFC) or at 47 weeks in the Morris water maze (MWM) assay. Following cognitive testing, animals were sacrificed and soluble and formic acid extractable Aβ peptides were isolated from brains and quantified. In the CFC, a significant decrease in total % freezing was observed between vehicle-treated Tg2576 mice and control non-transgenic mice. This cognitive deficit was reversed with either dose of EVP-0015962. During MWM probe trial testing, vehicle-treated Tg2576 mice exhibited fewer platform crosses compared to non-transgenic mice. In contrast, the 60 mg/kg/day group did not significantly differ from either the vehicle-treated non-transgenic or Tg25756 mice demonstrating a partial recovery / blockade of this deficit. Significant reductions in soluble and formic acid extractable Aβ42 as well as decreases in Aβ aggregates were observed at both doses of EVP-0015962. A concomitant increase in Aβ38 was observed with no overall changes in the amount total Aβ peptides. These data demonstrate that cognitive deficits in contextual and spatial working memory of Tg2576 can be reversed following treatment with EVP-0015962 and that the observed effects are not due to nonspecific memory enhancement. The decrease in Aβ42 and aggregated Aβ suggests a disease modifying effect resulting from treatment with EVP-0015962.