Reduction of Abeta levels in the Sprague Dawley rat after oral administration of the functional gamma-secretase inhibitor, DAPT: a novel non-transgenic model for Abeta production inhibitors.
Considerable effort has been made to develop drugs that delay or prevent neurodegeneration. These include inhibitors of Abeta-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 Abeta 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 Abeta. 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 Abeta modulation. For this purpose, Wild-type adult Sprague Dawley rats were treated with DAPT, a functional gamma-secretase inhibitor, and the Abeta40 and Abeta42 levels in brain-tissue and body fluids were assessed. We showed that DAPT, given orally, significantly lowered Abeta40 and Abeta42 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 Abeta production.
Johnson & Johnson Pharma-ceutical Research & Development, Division of Janssen Pharmaceutica NV, Beerse, Belgium. mmercken@prdbe.jnj.com
Mohammed
M
El Mouedden
Marc
M
Vandermeeren
Theo
T
Meert
Marc
M
Mercken
D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000191:economics / Q000379:methods; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D016229:Amyloid beta-Peptides; D004151:Dipeptides; D004791:Enzyme Inhibitors; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D010446:Peptide Fragments; C086839:amyloid beta-protein (17-42); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human