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Differential effects of gamma-secretase and BACE1 inhibition on brain Abeta levels in vitro and in vivo.
J Neurochem. 2009 Sep; 110(5):1377-87.JN

Abstract

Alzheimer's disease (AD) is hypothesized to result from elevated brain levels of beta-amyloid peptide (Abeta) which is the main component of plaques found in AD brains and which cause memory impairment in mice. Therefore, there has been a major focus on the development of inhibitors of the Abeta producing enzymes gamma-secretase and beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1). In this study, we investigated the Abeta-lowering effects of the BACE1 inhibitor LY2434074 in vitro and in vivo, comparing it to the well characterized gamma-secretase inhibitor LY450139. We sampled interstitial fluid Abeta from awake APPswe/PS1dE9 AD mice by in vivo Abeta microdialysis. In addition, we measured levels of endogenous brain Abeta extracted from wildtype C57BL/6 mice. In our in vitro assays both compounds showed similar Abeta-lowering effects. However, while systemic administration of LY450139 resulted in transient reduction of Abeta in both in vivo models, we were unable to show any Abeta-lowering effect by systemic administration of the BACE1 inhibitor LY2434074 despite brain exposure exceeding the in vitro IC(50) value several fold. In contrast, significant reduction of 40-50% of interstitial fluid Abeta and wildtype cortical Abeta was observed when infusing LY2434074 directly into the brain by means of reverse microdialysis or by dosing the BACE1 inhibitor to p-glycoprotein (p-gp) mutant mice. The effects seen in p-gp mutant mice and subsequent data from our cell-based p-gp transport assay suggested that LY2434074 is a p-gp substrate. This may partly explain why BACE1 inhibition by LY2434074 has lower in vivo efficacy, with respect to decreased Abeta40 levels, compared with gamma-secretase inhibition by LY450139.

Authors+Show Affiliations

Department of In Vivo Neurobiology-Neurodegeneration, H. Lundbeck A/S, Ottiliavej 9, Valby 2500, Denmark. ABJO@lundbeck.comNo 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)

Comparative Study
Journal Article

Language

eng

PubMed ID

19519664

Citation

Elvang, Anders Brandt, et al. "Differential Effects of Gamma-secretase and BACE1 Inhibition On Brain Abeta Levels in Vitro and in Vivo." Journal of Neurochemistry, vol. 110, no. 5, 2009, pp. 1377-87.
Elvang AB, Volbracht C, Pedersen LØ, et al. Differential effects of gamma-secretase and BACE1 inhibition on brain Abeta levels in vitro and in vivo. J Neurochem. 2009;110(5):1377-87.
Elvang, A. B., Volbracht, C., Pedersen, L. Ø., Jensen, K. G., Karlsson, J. J., Larsen, S. A., Mørk, A., Stensbøl, T. B., & Bastlund, J. F. (2009). Differential effects of gamma-secretase and BACE1 inhibition on brain Abeta levels in vitro and in vivo. Journal of Neurochemistry, 110(5), 1377-87. https://doi.org/10.1111/j.1471-4159.2009.06215.x
Elvang AB, et al. Differential Effects of Gamma-secretase and BACE1 Inhibition On Brain Abeta Levels in Vitro and in Vivo. J Neurochem. 2009;110(5):1377-87. PubMed PMID: 19519664.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential effects of gamma-secretase and BACE1 inhibition on brain Abeta levels in vitro and in vivo. AU - Elvang,Anders Brandt, AU - Volbracht,Christiane, AU - Pedersen,Lars Østergaard, AU - Jensen,Klaus Gjervig, AU - Karlsson,Jens-Jakob, AU - Larsen,Stine Anna, AU - Mørk,Arne, AU - Stensbøl,Tine Bryan, AU - Bastlund,Jesper Frank, Y1 - 2009/06/10/ PY - 2009/6/13/entrez PY - 2009/6/13/pubmed PY - 2009/9/22/medline SP - 1377 EP - 87 JF - Journal of neurochemistry JO - J Neurochem VL - 110 IS - 5 N2 - Alzheimer's disease (AD) is hypothesized to result from elevated brain levels of beta-amyloid peptide (Abeta) which is the main component of plaques found in AD brains and which cause memory impairment in mice. Therefore, there has been a major focus on the development of inhibitors of the Abeta producing enzymes gamma-secretase and beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1). In this study, we investigated the Abeta-lowering effects of the BACE1 inhibitor LY2434074 in vitro and in vivo, comparing it to the well characterized gamma-secretase inhibitor LY450139. We sampled interstitial fluid Abeta from awake APPswe/PS1dE9 AD mice by in vivo Abeta microdialysis. In addition, we measured levels of endogenous brain Abeta extracted from wildtype C57BL/6 mice. In our in vitro assays both compounds showed similar Abeta-lowering effects. However, while systemic administration of LY450139 resulted in transient reduction of Abeta in both in vivo models, we were unable to show any Abeta-lowering effect by systemic administration of the BACE1 inhibitor LY2434074 despite brain exposure exceeding the in vitro IC(50) value several fold. In contrast, significant reduction of 40-50% of interstitial fluid Abeta and wildtype cortical Abeta was observed when infusing LY2434074 directly into the brain by means of reverse microdialysis or by dosing the BACE1 inhibitor to p-glycoprotein (p-gp) mutant mice. The effects seen in p-gp mutant mice and subsequent data from our cell-based p-gp transport assay suggested that LY2434074 is a p-gp substrate. This may partly explain why BACE1 inhibition by LY2434074 has lower in vivo efficacy, with respect to decreased Abeta40 levels, compared with gamma-secretase inhibition by LY450139. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/19519664/Differential_effects_of_gamma_secretase_and_BACE1_inhibition_on_brain_Abeta_levels_in_vitro_and_in_vivo_ L2 - https://doi.org/10.1111/j.1471-4159.2009.06215.x DB - PRIME DP - Unbound Medicine ER -