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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

, : P-glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors in mice. Journal of Pharmacology and Experimental Therapeutics 326(2): 502-513

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.


PMID: 18499745

DOI: 10.1124/jpet.108.138974

Other references

Gudbjerg, C.E., 1954: Bronchography: technique and choice of contrast media. Acta Radiologica 42(5): 367-373

Richardson, J.K.; Sandman, D.; Vela, S., 2001: A focused exercise regimen improves clinical measures of balance in patients with peripheral neuropathy. To determine the effect of a specific exercise regimen on clinical measures of postural stability and confidence in a population with peripheral neuropathy (PN). Prospective, controlled, single blind study. Outpatient clinic of a university hospit...

Betz V., 1982: Mount Semiol; rare zeolites in France. Lapis (Muenchen) 7(12): 9-11

Soldovskii, Vi, 1980: Determination of the size of calving sections and isolation premises on animal husbandry farms with commercial technology. Mekhanizatsiia i elektrifikatsiia sel'skogo khoziaistva: (11) 24-26

Gorburov, G.F., 1967: Some problems of surgical aid to children. Klinicheskaia Khirurgiia 2: 77-79

Riedel, G.; Wetzel, W.; Reymann, K.G., 1994: (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG) blocks spatial learning in rats and long-term potentiation in the dentate gyrus in vivo. Recently, it was demonstrated by the use of the competitive and selective antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG) that metabotropic glutamate receptor (mGluR) activation is required to induce long-term potentiation (LTP) in the...

Marcinkowska, J., 1973: Estimation of the resistance of some tomato varieties to Phytophthora infestans (Mont) de Bary. Of the 12 vars. tested in the field New Yorker, Rockingham, West Virginia 63 and N.H. Surecrop were the least susceptible.

Arhipova, V.D., 1958: Development of mycorrhiza on roots of seedlings grown from fungicide-treated acorns.. The development of mycorrhiza was investigated in 1- to 3-year Oak seedlings from acorns treated with granosan and formalin solution in 3 zones of the Ukraine (forest, forest-steppe and steppe) in 1954. No difference was noted between seedlings fr...

Martinez-Almeida, Victor, M., 1999: Los generos Docidium, Penium, Haplotaenium, Pleurotaenium, Tetmemorus y Triploceras (Desmidiales, Chlorophyta) en Cuba. This is a further contribution to the knowledge of the desmid flora of Cuba. One hundred and sixty samples collected from the most important regions in regard to occurrence of desmids and diversity of microalgae species in Cuba (Pinar del Rio, Isl...

Liu, S.; Lu, H.; Hu, R.; Shupe, A.; Lin, L.; Liang, B., 2012: A sustainable woody biomass biorefinery. Woody biomass is renewable only if sustainable production is imposed. An optimum and sustainable biomass stand production rate is found to be one with the incremental growth rate at harvest equal to the average overall growth rate. Utilization of...