title: β-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces Aβ5-X peptides through alternative amyloid precursor protein cleavage.
abstract: BACKGROUND
  The β-secretase enzyme, β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), cleaves amyloid precursor protein (APP) in the first step in β-amyloid (Aβ) peptide production. Thus, BACE1 is a key target for candidate disease-modifying treatment of Alzheimer's disease. In a previous exploratory Aβ biomarker study, we found that BACE1 inhibitor treatment resulted in decreased levels of Aβ1-34 together with increased Aβ5-40, suggesting that these Aβ 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 Aβ peptides.
  
  
  RESULTS
  Here, we demonstrate dose-dependent changes in cerebrospinal fluid (CSF) Aβ1-34, Aβ5-40 and Aβ5-X after treatment with the BACE1-inhibitor LY2811376. Aβ5-40 and Aβ5-X increased dose-dependently, as reflected by two independent methods, while Aβ1-34 dose-dependently decreased.
  
  
  CONCLUSIONS
  Using HI-MS for the first time in a study where subjects have been treated with a BACE inhibitor, we confirm that CSF Aβ1-34 may be useful in clinical trials on BACE1 inhibitors to monitor target engagement. Since it is less hydrophobic than longer Aβ 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 Aβ peptides via a BACE1-independent pathway.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00838084. Registered: First received: January 23, 2009, Last updated: July 14, 2009, Last verified: July 2009.
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, S-431 80 Mölndal, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285 USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Dean
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, S-431 80 Mölndal, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Andreasson
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, S-431 80 Mölndal, Sweden ; San Francisco VA Medical Center, Center for Imaging of Neurodegenerative Diseases (CIND), University of California San Francisco, San Francisco, CA USA.
authors.forename: Niklas
authors.initials: N
authors.lastname: Mattsson
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, S-431 80 Mölndal, Sweden.
authors.forename: Anni
authors.initials: A
authors.lastname: Westerlund
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, S-431 80 Mölndal, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Olsson
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285 USA.
authors.forename: Ronald Bradley
authors.initials: RB
authors.lastname: Demattos
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285 USA.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Racke
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, S-431 80 Mölndal, Sweden ; UCL Institute of Neurology, Queen Square, London, WC1N 3BG UK.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285 USA.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: May
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, S-431 80 Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow