Reduction of A beta levels in the Sprague Dawley rat after oral administration of the functional gamma-secretase inhibitor, DAPT: A novel non-transgenic model for A beta production inhibitors
El Mouedden, M × Vandermeeren, M Meert, Theo Mercken, M #
Bentham science publ ltd
Current pharmaceutical design vol:12 issue:6 pages:671-676
Considerable effort has been made to develop drugs that delay or prevent neurodegeneration. These include inhibitors of A beta-generating proteases for the treatment of Alzheimer's disease. Testing the amyloid hypothesis in vivo requires molecules that are capable of entering the CNS and that produce a substantial reduction in brain A beta 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 A beta. 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, time-consuming 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 A beta modulation. For this purpose, Wild-type adult Sprague Dawley rats were treated with DAPT, a functional gamma-sccretase inhibitor, and the A beta 40 and A beta 42 levels in brain-tissue and body fluids were assessed. We showed that DAPT, given orally, significantly lowered A beta 40 and A beta 42 peptide levels in brain extract, CSF, and the plasma dose- and time-dependently. We can conclude that our data establish the usefulness of the wild-type rat model for testing small-molecule inhibitors of A beta production.