β-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces Aβ5-X peptides through alternative amyloid precursor protein cleavage

被引:33
|
作者
Portelius, Erik [1 ]
Dean, Robert A. [2 ]
Andreasson, Ulf [1 ]
Mattsson, Niklas [1 ,3 ]
Westerlund, Anni [1 ]
Olsson, Maria [1 ]
Demattos, Ronald Bradley [2 ]
Racke, Margaret M. [2 ]
Zetterberg, Henrik [1 ,4 ]
May, Patrick C. [2 ]
Blennow, Kaj [1 ]
机构
[1] Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Clin Neurochem Lab,Inst Neurosci & Phys, S-43180 Molndal, Sweden
[2] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA
[3] Univ Calif San Francisco, Ctr Imaging Neurodegenerat Dis, San Francisco VA Med Ctr, San Francisco, CA 94143 USA
[4] UCL Inst Neurol, London WC1N 3BG, England
来源
ALZHEIMERS RESEARCH & THERAPY | 2014年 / 6卷 / 09期
基金
瑞典研究理事会;
关键词
GAMMA-SECRETASE INHIBITION; ALZHEIMERS-DISEASE; CEREBROSPINAL-FLUID; ISOFORM PATTERN; QUANTIFICATION; DEPOSITION; CSF;
D O I
10.1186/s13195-014-0075-0
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Introduction: The beta-secretase enzyme, beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1), cleaves amyloid precursor protein (APP) in the first step in beta-amyloid (A beta) peptide production. Thus, BACE1 is a key target for candidate disease-modifying treatment of Alzheimer's disease. In a previous exploratory A beta biomarker study, we found that BACE1 inhibitor treatment resulted in decreased levels of A beta 1-34 together with increased A beta 5-40, suggesting that these A beta species may be novel pharmacodynamic biomarkers in clinical trials. We have now examined whether the same holds true in humans. Methods: In an investigator-blind, placebo-controlled and randomized study, healthy subjects (n = 18) were randomly assigned to receive a single dose of 30 mg of LY2811376 (n = 6), 90 mg of LY2811376 (n = 6), or placebo (n = 6). We used hybrid immunoaffinity-mass spectrometry (HI-MS) and enzyme-linked immunosorbent assays to monitor a variety of A beta peptides. Results: Here, we demonstrate dose-dependent changes in cerebrospinal fluid (CSF) A beta 1-34, A beta 5-40 and A beta 5-X after treatment with the BACE1-inhibitor LY2811376. A beta 5-40 and A beta 5-X increased dose-dependently, as reflected by two independent methods, while A beta 1-34 dose-dependently decreased. Conclusion: Using HI-MS for the first time in a study where subjects have been treated with a BACE inhibitor, we confirm that CSF A beta 1-34 may be useful in clinical trials on BACE1 inhibitors to monitor target engagement. Since it is less hydrophobic than longer A beta species, it is less susceptible to preanalytical confounding factors and may thus be a more stable marker. By independent measurement techniques, we also show that BACE1 inhibition in humans is associated with APP-processing into N-terminally truncated A beta peptides via a BACE1-independent pathway.
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页数:8
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