Reduction of Aβ Levels in the Sprague Dawley Rat After Oral Administration of the Functional g-Secretase Inhibitor, DAPT: A Novel Non- Transgenic Model for Aβ Production Inhibitors

Mohammed   El   Mouedden; Marc      Vandermeeren; Theo      Meert; Marc      Mercken

doi:10.2174/138161206775474233

Abstract

Considerable effort has been made to develop drugs that delay or prevent neurodegeneration. These include inhibitors of Aβ-generating proteases for the treatment of Alzheimers disease. Testing the amyloid hypothesis in vivo requires molecules that are capable of entering the CNS and that produce a substantial reduction in brain Aβ levels. Plaque-developing APP transgenic mice are currently widely used as an in vivo model of choice as these animals produce readily measurable amounts of human Aβ. They are very useful in the testing of a variety of amyloid-lowering approaches but their use for compound screening is often limited by their cost. Transgenic animals also require extensive, timeconsuming breeding programs and can show high inter-animal differences in the expression level of the transgene. Hence, we considered it important to develop and characterize a new and simple non-transgenic animal model for testing Aβ modulation. For this purpose, Wild-type adult Sprague Dawley rats were treated with DAPT, a functional γ-secretase inhibitor, and the Aβ40 and Aβ42 levels in brain-tissue and body fluids were assessed. We showed that DAPT, given orally, significantly lowered Aβ40 and Aβ42 peptide levels in brain extract, CSF, and the plasma dose- and timedependently. We can conclude that our data establish the usefulness of the wild-type rat model for testing small-molecule inhibitors of Aβ production.

Keywords: BACE1 inhibitors, ELISA, Monoclonal antibody, presenilin 1 (PS1), APP transgenic mice

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