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P-glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors in mice.
J Pharmacol Exp Ther. 2008 Aug; 326(2):502-13.JP

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Amyloid beta (Abeta) peptides are hypothesized to cause the initiation and progression of AD based on pathologic data from AD patients, genetic analysis of mutations that cause early onset forms of AD, and preclinical studies. Based on this hypothesis, beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) inhibitors are an attractive therapeutic approach for AD because cleavage of the APP by BACE1 is required to form Abeta. In this study, three potent BACE1 inhibitors are characterized. All three inhibitors decrease Abeta formation in cultured cells with IC(50) values less than 10 nM. Analysis of APP C-terminal fragments by immunoblotting and Abeta peptides by mass spectrometry showed that these inhibitors decreased Abeta by inhibiting BACE1. An assay for Abeta1-40 in mice was developed and used to show that these BACE1 inhibitors decreased plasma Abeta1-40, but not brain Abeta1-40, in wild-type mice. Because these BACE1 inhibitors were substrates for P-glycoprotein (P-gp), a member of the ATP-binding cassette superfamily of efflux transporters, these inhibitors were administered to P-gp knockout (KO) mice. These studies showed that all three BACE1 inhibitors decreased brain Abeta1-40 in P-gp KO mice, demonstrating that P-gp is a major limitation for development of BACE1 inhibitors to test the amyloid hypothesis. A comparison of plasma Abeta1-40 and brain Abeta1-40 dose responses for these three compounds revealed differences in relative ED(50) values, indicating that factors other than P-gp can also contribute to poor brain activity by BACE1 inhibitors.

Authors+Show Affiliations

Research and Development, Bristol Myers Squibb, 5 Research Parkway, Wallingford, CT, USA. jere.meredith@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 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

18499745

Citation

Meredith, Jere E., et al. "P-glycoprotein Efflux and Other Factors Limit Brain Amyloid Beta Reduction By Beta-site Amyloid Precursor Protein-cleaving Enzyme 1 Inhibitors in Mice." The Journal of Pharmacology and Experimental Therapeutics, vol. 326, no. 2, 2008, pp. 502-13.
Meredith JE, Thompson LA, Toyn JH, et al. P-glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors in mice. J Pharmacol Exp Ther. 2008;326(2):502-13.
Meredith, J. E., Thompson, L. A., Toyn, J. H., Marcin, L., Barten, D. M., Marcinkeviciene, J., Kopcho, L., Kim, Y., Lin, A., Guss, V., Burton, C., Iben, L., Polson, C., Cantone, J., Ford, M., Drexler, D., Fiedler, T., Lentz, K. A., Grace, J. E., ... Albright, C. F. (2008). P-glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors in mice. The Journal of Pharmacology and Experimental Therapeutics, 326(2), 502-13. https://doi.org/10.1124/jpet.108.138974
Meredith JE, et al. P-glycoprotein Efflux and Other Factors Limit Brain Amyloid Beta Reduction By Beta-site Amyloid Precursor Protein-cleaving Enzyme 1 Inhibitors in Mice. J Pharmacol Exp Ther. 2008;326(2):502-13. PubMed PMID: 18499745.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - P-glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors in mice. AU - Meredith,Jere E,Jr AU - Thompson,Lorin A, AU - Toyn,Jeremy H, AU - Marcin,Lawrence, AU - Barten,Donna M, AU - Marcinkeviciene,Jovita, AU - Kopcho,Lisa, AU - Kim,Young, AU - Lin,Alan, AU - Guss,Valerie, AU - Burton,Catherine, AU - Iben,Lawrence, AU - Polson,Craig, AU - Cantone,Joe, AU - Ford,Michael, AU - Drexler,Dieter, AU - Fiedler,Tracey, AU - Lentz,Kimberley A, AU - Grace,James E,Jr AU - Kolb,Janet, AU - Corsa,Jason, AU - Pierdomenico,Maria, AU - Jones,Kelli, AU - Olson,Richard E, AU - Macor,John E, AU - Albright,Charles F, Y1 - 2008/05/22/ PY - 2008/5/24/pubmed PY - 2008/8/13/medline PY - 2008/5/24/entrez SP - 502 EP - 13 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 326 IS - 2 N2 - Alzheimer's disease (AD) is a progressive neurodegenerative disease. Amyloid beta (Abeta) peptides are hypothesized to cause the initiation and progression of AD based on pathologic data from AD patients, genetic analysis of mutations that cause early onset forms of AD, and preclinical studies. Based on this hypothesis, beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) inhibitors are an attractive therapeutic approach for AD because cleavage of the APP by BACE1 is required to form Abeta. In this study, three potent BACE1 inhibitors are characterized. All three inhibitors decrease Abeta formation in cultured cells with IC(50) values less than 10 nM. Analysis of APP C-terminal fragments by immunoblotting and Abeta peptides by mass spectrometry showed that these inhibitors decreased Abeta by inhibiting BACE1. An assay for Abeta1-40 in mice was developed and used to show that these BACE1 inhibitors decreased plasma Abeta1-40, but not brain Abeta1-40, in wild-type mice. Because these BACE1 inhibitors were substrates for P-glycoprotein (P-gp), a member of the ATP-binding cassette superfamily of efflux transporters, these inhibitors were administered to P-gp knockout (KO) mice. These studies showed that all three BACE1 inhibitors decreased brain Abeta1-40 in P-gp KO mice, demonstrating that P-gp is a major limitation for development of BACE1 inhibitors to test the amyloid hypothesis. A comparison of plasma Abeta1-40 and brain Abeta1-40 dose responses for these three compounds revealed differences in relative ED(50) values, indicating that factors other than P-gp can also contribute to poor brain activity by BACE1 inhibitors. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/18499745/P_glycoprotein_efflux_and_other_factors_limit_brain_amyloid_beta_reduction_by_beta_site_amyloid_precursor_protein_cleaving_enzyme_1_inhibitors_in_mice_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=18499745 DB - PRIME DP - Unbound Medicine ER -