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Dynamics of β-Amyloid Reductions in Brain, Cerebrospinal Fluid, and Plasma of β-Amyloid Precursor Protein Transgenic Mice Treated with a γ-Secretase Inhibitor
Abstract
gamma-Secretase inhibitors are one promising approach to the development of a therapeutic for Alzheimer's disease (AD). gamma-Secretase inhibitors reduce brain beta-amyloid peptide (Abeta), which is believed to be a major contributor in the etiology of AD. Transgenic mice overexpressing the human beta-amyloid precursor protein (APP) are valuable models to examine the dynamics of Abeta changes with gamma-secretase inhibitors in plaque-free and plaque-bearing animals. BMS-299897 2-[(1R)-1-[[(4-chlorophenyl)sulfony](2,5-difluorophenyl)amino]ethyl]-5-fluorobenzenepropanoic acid, a gamma-secretase inhibitor, showed dose- and time dependent reductions of Abeta in brain, cerebrospinal fluid (CSF), and plasma in young transgenic mice, with a significant correlation between brain and CSF Abeta levels. Because CSF and brain interstitial fluid are distinct compartments in composition and location, this correlation could not be assumed. In contrast, aged transgenic mice with large accumulations of Abeta in plaques showed reductions in CSF Abeta in the absence of measurable changes in plaque Abeta in the brain after up to 2 weeks of treatment. Hence, CSF Abeta levels were a valuable measure of gamma-secretase activity in the central nervous system in either the presence or absence of plaques. Transgenic mice were also used to examine potential side effects due to Notch inhibition. BMS-299897 was 15-fold more effective at preventing the cleavage of APP than of Notch in vitro. No changes in…
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“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 [50]
In the citing paper
“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 [50]
In the citing paper
“The rapid degradation of Aβ in the periphery (t1/2 = 2–3 min) precludes a direct and sensitive measurement of the rate of Aβ appearance from brain into blood (27, 28).”
From Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis (2012) · cites this paper as [28]
In the citing paper
“The rapid degradation of Aβ once it enters the blood from brain precludes direct and reliable measurement of its influx rate by conventional means (27, 28).”
From Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis (2012) · cites this paper as [28]
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Metadata
- Authors
- Barten, D. M., Guss, V. L., Corsa, J. A., Loo, A., Hansel, S. B., Zheng, M., Munoz, B., Srinivasan, K., Wang, B., Robertson, B. J., Polson, C. T., Wang, J., Roberts, S. B., Hendrick, J. P., Anderson, J. J., Loy, J. K., Denton, R., Verdoorn, T. A., Smith, D. W., & Felsenstein, K. M.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2005-02
- Volume
- 312
- Issue
- 2
- Pages
- 635-643
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2167864502
- Cited by
- 159
- References
- 44
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 1 · 2018: 1 · 2017: 6 · 2016: 3 · 2015: 3 · 2014: 8 · 2013: 5 · 2012: 13
- FWCI
- 12.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Keywords
- amyloid-beta, gamma-secretase inhibitors, Alzheimer's disease, APP transgenic mice, cerebrospinal fluid, amyloid plaques, Notch signaling, CD8+ thymocytes, intestinal goblet cells, amyloid precursor protein
- MeSH terms
- Aging, Animals, Brain Chemistry, Cell Separation, Dose-Response Relationship, Drug, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Humans, Membrane Proteins, Mice, Inbred C57BL, Mice, Transgenic, Endopeptidases, Protease Inhibitors, T-Lymphocytes, Blotting, Western, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Immunoprecipitation, Mice, Receptors, Notch, Amyloid Precursor Protein Secretases, Plaque, Amyloid
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