title: Differential effects of gamma-secretase and BACE1 inhibition on brain Abeta levels in vitro and in vivo.
abstract: Alzheimer's disease (AD) is hypothesized to result from elevated brain levels of beta-amyloid peptide (Abeta) which is the main component of plaques found in AD brains and which cause memory impairment in mice. Therefore, there has been a major focus on the development of inhibitors of the Abeta producing enzymes gamma-secretase and beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1). In this study, we investigated the Abeta-lowering effects of the BACE1 inhibitor LY2434074 in vitro and in vivo, comparing it to the well characterized gamma-secretase inhibitor LY450139. We sampled interstitial fluid Abeta from awake APPswe/PS1dE9 AD mice by in vivo Abeta microdialysis. In addition, we measured levels of endogenous brain Abeta extracted from wildtype C57BL/6 mice. In our in vitro assays both compounds showed similar Abeta-lowering effects. However, while systemic administration of LY450139 resulted in transient reduction of Abeta in both in vivo models, we were unable to show any Abeta-lowering effect by systemic administration of the BACE1 inhibitor LY2434074 despite brain exposure exceeding the in vitro IC(50) value several fold. In contrast, significant reduction of 40-50% of interstitial fluid Abeta and wildtype cortical Abeta was observed when infusing LY2434074 directly into the brain by means of reverse microdialysis or by dosing the BACE1 inhibitor to p-glycoprotein (p-gp) mutant mice. The effects seen in p-gp mutant mice and subsequent data from our cell-based p-gp transport assay suggested that LY2434074 is a p-gp substrate. This may partly explain why BACE1 inhibition by LY2434074 has lower in vivo efficacy, with respect to decreased Abeta40 levels, compared with gamma-secretase inhibition by LY450139.
authors.affiliation: Department of In Vivo Neurobiology-Neurodegeneration, H. Lundbeck A/S, Ottiliavej 9, Valby 2500, Denmark. ABJO@lundbeck.com
authors.forename: Anders Brandt
authors.initials: AB
authors.lastname: Elvang
authors.forename: Christiane
authors.initials: C
authors.lastname: Volbracht
authors.forename: Lars Østergaard
authors.initials: LØ
authors.lastname: Pedersen
authors.forename: Klaus Gjervig
authors.initials: KG
authors.lastname: Jensen
authors.forename: Jens-Jakob
authors.initials: JJ
authors.lastname: Karlsson
authors.forename: Stine Anna
authors.initials: SA
authors.lastname: Larsen
authors.forename: Arne
authors.initials: A
authors.lastname: Mørk
authors.forename: Tine Bryan
authors.initials: TB
authors.lastname: Stensbøl
authors.forename: Jesper Frank
authors.initials: JF
authors.lastname: Bastlund
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002460:Cell Line; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011480:Protease Inhibitors / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D001381:Azepines; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D000409:Alanine