Dynamics of Aβ Turnover and Deposition in Different β-Amyloid Precursor Protein Transgenic Mouse Models Following γ-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 t…
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Previous studies have measured Aβ clearance from the brain either using 35S]methionine labeling or by measuring the disappearance of Aβ following the pharmacological inhibition of Aβ production.
“Previous studies have measured Aβ clearance from the brain either using 35 S]methionine labeling [48], or by measuring the disappearance of Aβ following the pharmacological inhibition of Aβ production [49-51].”
From Measurement of apolipoprotein E and amyloid β clearance rates in the mouse brain using bolus stable isotope labeling (2012) · cites this paper as [51]
The half-life of Aβ clearance in previous studies ranged from 30 min to 2 h.
“The half-life of Aβ clearance in these studies ranged from 30 min to 2 h.”
From Measurement of apolipoprotein E and amyloid β clearance rates in the mouse brain using bolus stable isotope labeling (2012) · cites this paper as [51]
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- Authors
- Abramowski, D., Wiederhold, K.-H., Furrer, U., Jaton, A.-L., Neuenschwander, A., Runser, M.-J., Danner, S., Reichwald, J., Ammaturo, D., Staab, D., Stoeckli, M., Rueeger, H., Neumann, U., & Staufenbiel, M.
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2008-11
- Volume
- 327
- Issue
- 2
- Pages
- 411-424
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2172066391
- Cited by
- 89
- References
- 7
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 1 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 2 · 2016: 1 · 2015: 10 · 2014: 5 · 2013: 9 · 2012: 8
- FWCI
- 8.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta deposition, gamma-secretase inhibition, APP transgenic mice, Alzheimer's disease, amyloid plaques, APP C-terminal fragments, C99, cerebrospinal fluid amyloid, familial Alzheimer's disease mutations, amyloid plaque formation
- MeSH terms
- Alanine, Animals, Azepines, Brain, Enzyme Inhibitors, Half-Life, Humans, Mice, Inbred C57BL, Mice, Transgenic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, Amyloid Precursor Protein Secretases
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