Dynamics of Ab Turnover and Deposition in Different APP Transgenic Mouse Models Following Gamma-Secretase Inhibition.

Abramowski, D., Wiederhold, K. Furrer, U., Jaton, A., Neuenschwander, A., Runser, M., Danner, S., Reichwald, J., Ammaturo, D., Staab, D., Stoeckli, M., Rueeger, H., Neumann, U., Staufenbiel, M.
Journal   Pharmacol Exp Ther.
Analytes Measured   Abeta 40 , Abeta 42 , APP
Matrix Tested   Brain homogenates (transgenics), Plasma
Year   2008
Volume   327
Page Numbers   411-24
Application   Alzheimers
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.

View Publications

Related Products

R-PLEX Aβ42 (4G8) Antibody Set
Aβ42 (4G8) | Human, Mouse, Rat
R-PLEX Aβ40 (4G8) Antibody Set
Aβ40 (4G8) | Human, Mouse, Rat
R-PLEX Human Aβ40 (6E10) Antibody Set
Aβ40 (6E10) | Human
R-PLEX Human Aβ42 (6E10) Antibody Set
Aβ42 (6E10) | Human
Neurodegeneration Control Pack 1
Aβ38, Aβ40, Aβ42, Tau (total) | Human, Mouse, Rat
Human (6E10) Aβ40 Ultra-Sensitive Kit
Aβ40 | Human
Human (6E10) Aβ42 Ultra-Sensitive Kit
Aβ42 | Human
sAPPα Kit
APP | Human
sAPPβ Kit
APP | Human
sAPPα/sAPPβ Kit
APP | Human
Browse Our Products

By Analytes
By Applications
Customer Service/Orders

Scientific/Technical Support

Instrument Support

Company Headquarters