title: Dynamics of Abeta turnover and deposition in different beta-amyloid precursor protein transgenic mouse models following gamma-secretase inhibition.
abstract: Human beta-amyloid precursor protein (APP) transgenic mice are commonly used to test potential therapeutics for Alzheimer's disease. We have characterized the dynamics of beta-amyloid (Abeta) generation and deposition following gamma-secretase inhibition with compound LY-411575 [N(2)-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide]. Kinetic studies in preplaque mice distinguished a detergent-soluble Abeta pool in brain with rapid turnover (half-lives for Abeta40 and Abeta42 were 0.7 and 1.7 h) and a much more stable, less soluble pool. Abeta in cerebrospinal fluid (CSF) reflected the changes in the soluble brain Abeta pool, whereas plasma Abeta turned over more rapidly. In brain, APP C-terminal fragments (CTF) accumulated differentially. The half-lives for gamma-secretase degradation were estimated as 0.4 and 0.1 h for C99 and C83, respectively. Three different APP transgenic lines responded very similarly to gamma-secretase inhibition regardless of the familial Alzheimer's disease mutations in APP. Amyloid deposition started with Abeta42, whereas Abeta38 and Abeta40 continued to turn over. Chronic gamma-secretase inhibition lowered amyloid plaque formation to a different degree in different brain regions of the same mice. The extent was inversely related to the initial amyloid load in the region analyzed. No evidence for plaque removal below baseline was obtained. gamma-Secretase inhibition led to a redistribution of intracellular Abeta and an elevation of CTFs in neuronal fibers. In CSF, Abeta showed a similar turnover as in preplaque animals demonstrating its suitability as marker of newly generated, soluble Abeta in plaque-bearing brain. This study supports the use of APP transgenic mice as translational models to characterize Abeta-lowering therapeutics.
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Abramowski
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Wiederhold
authors.forename: Ulrich
authors.initials: U
authors.lastname: Furrer
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Jaton
authors.forename: Anton
authors.initials: A
authors.lastname: Neuenschwander
authors.forename: Marie-Josephine
authors.initials: MJ
authors.lastname: Runser
authors.forename: Simone
authors.initials: S
authors.lastname: Danner
authors.forename: Julia
authors.initials: J
authors.lastname: Reichwald
authors.forename: Domenico
authors.initials: D
authors.lastname: Ammaturo
authors.forename: Dieter
authors.initials: D
authors.lastname: Staab
authors.forename: Markus
authors.initials: M
authors.lastname: Stoeckli
authors.forename: Heinrich
authors.initials: H
authors.lastname: Rueeger
authors.forename: Ulf
authors.initials: U
authors.lastname: Neumann
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001381:Azepines; D004791:Enzyme Inhibitors; 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; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine