Dynamics of Aβ Turnover and Deposition in Different β-Amyloid Precursor Protein Transgenic Mouse Models Following γ-Secretase Inhibition

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 ( A beta) generation and deposition following beta-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 A beta pool in brain with rapid turnover (half-lives for A beta 40 and A beta 42 were 0.7 and 1.7 h) and a much more stable, less soluble pool. A beta in cerebrospinal fluid (CSF) reflected the changes in the soluble brain A beta pool, whereas plasma A beta 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 A beta 42, whereas A beta 38 and A beta 40 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 A beta and an elevation of CTFs in neuronal fibers. In CSF, A beta showed a similar turnover as in preplaque animals demonstrating its suitability as marker of newly generated, soluble A beta in plaque-bearing brain. This study supports the use of APP transgenic mice as translational models to characterize A beta-lowering therapeutics.