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Dynamics of {beta}-amyloid reductions in brain, cerebrospinal fluid, and plasma of {beta}-amyloid precursor protein transgenic mice treated with a {gamma}-secretase inhibitor.
J Pharmacol Exp Ther. 2005 Feb; 312(2):635-43.JP

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 the maturation of CD8(+) thymocytes or of intestinal goblet cells were observed in mice treated with BMS-299897, showing that it is possible for gamma-secretase inhibitors to reduce brain Abeta without causing Notch-mediated toxicity.

Authors+Show Affiliations

Neuroscience Drug Discovery, Bristol-Myers Squibb, P.O. Box 5100, 3CD-405, 5 Research Pkwy., Wallingford, CT 06492, USA. donna.barten@bms.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15452193

Citation

Barten, D M., et al. "Dynamics of {beta}-amyloid Reductions in Brain, Cerebrospinal Fluid, and Plasma of {beta}-amyloid Precursor Protein Transgenic Mice Treated With a {gamma}-secretase Inhibitor." The Journal of Pharmacology and Experimental Therapeutics, vol. 312, no. 2, 2005, pp. 635-43.
Barten DM, Guss VL, Corsa JA, et al. Dynamics of {beta}-amyloid reductions in brain, cerebrospinal fluid, and plasma of {beta}-amyloid precursor protein transgenic mice treated with a {gamma}-secretase inhibitor. J Pharmacol Exp Ther. 2005;312(2):635-43.
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. (2005). Dynamics of {beta}-amyloid reductions in brain, cerebrospinal fluid, and plasma of {beta}-amyloid precursor protein transgenic mice treated with a {gamma}-secretase inhibitor. The Journal of Pharmacology and Experimental Therapeutics, 312(2), 635-43.
Barten DM, et al. Dynamics of {beta}-amyloid Reductions in Brain, Cerebrospinal Fluid, and Plasma of {beta}-amyloid Precursor Protein Transgenic Mice Treated With a {gamma}-secretase Inhibitor. J Pharmacol Exp Ther. 2005;312(2):635-43. PubMed PMID: 15452193.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dynamics of {beta}-amyloid reductions in brain, cerebrospinal fluid, and plasma of {beta}-amyloid precursor protein transgenic mice treated with a {gamma}-secretase inhibitor. AU - Barten,D M, AU - Guss,V L, AU - Corsa,J A, AU - Loo,A, AU - Hansel,S B, AU - Zheng,M, AU - Munoz,B, AU - Srinivasan,K, AU - Wang,B, AU - Robertson,B J, AU - Polson,C T, AU - Wang,J, AU - Roberts,S B, AU - Hendrick,J P, AU - Anderson,J J, AU - Loy,J K, AU - Denton,R, AU - Verdoorn,T A, AU - Smith,D W, AU - Felsenstein,K M, Y1 - 2004/09/27/ PY - 2004/9/29/pubmed PY - 2005/3/19/medline PY - 2004/9/29/entrez SP - 635 EP - 43 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 312 IS - 2 N2 - 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 the maturation of CD8(+) thymocytes or of intestinal goblet cells were observed in mice treated with BMS-299897, showing that it is possible for gamma-secretase inhibitors to reduce brain Abeta without causing Notch-mediated toxicity. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15452193/Dynamics_of_{beta}_amyloid_reductions_in_brain_cerebrospinal_fluid_and_plasma_of_{beta}_amyloid_precursor_protein_transgenic_mice_treated_with_a_{gamma}_secretase_inhibitor_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15452193 DB - PRIME DP - Unbound Medicine ER -