title: A single dose of the γ-secretase inhibitor semagacestat alters the cerebrospinal fluid peptidome in humans.
abstract: BACKGROUND
  In Alzheimer's disease, beta-amyloid peptides in the brain aggregate into toxic oligomers and plaques, a process which is associated with neuronal degeneration, memory loss, and cognitive decline. One therapeutic strategy is to decrease the production of potentially toxic beta-amyloid species by the use of inhibitors or modulators of the enzymes that produce beta-amyloid from amyloid precursor protein (APP). The failures of several such drug candidates by lack of effect or undesired side-effects underscore the importance to monitor the drug effects in the brain on a molecular level. Here we evaluate if peptidomic analysis in cerebrospinal fluid (CSF) can be used for this purpose.
  
  
  METHODS
  Fifteen human healthy volunteers, divided into three groups, received a single dose of placebo or either 140 mg or 280 mg of the γ-secretase inhibitor semagacestat (LY450139). Endogenous peptides in CSF, sampled prior to administration of the drug and at six subsequent time points, were analyzed by liquid chromatography coupled to mass spectrometry, using isobaric labeling based on the tandem mass tag approach for relative quantification.
  
  
  RESULTS
  Out of 302 reproducibly detected peptides, 11 were affected by the treatment. Among these, one was derived from APP and one from amyloid precursor-like protein 1. Nine peptides were derived from proteins that may not be γ-secretase substrates per se, but that are regulated in a γ-secretase-dependent manner.
  
  
  CONCLUSIONS
  These results indicate that a CSF peptidomic approach may be a valuable tool both to verify target engagement and to identify other pharmacodynamic effects of the drug. Data are available via ProteomeXchange with identifier PXD003075.
  
  
  BACKGROUND
  NCT00765115 , registered 30/09/2008.
authors.affiliation: Department of Psychiatry and Neurochemistry, Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, SU/Mölndal Hospital, 431 80, Mölndal, Sweden. mikko_holtta@hotmail.com.
authors.forename: Mikko
authors.initials: M
authors.lastname: Hölttä
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Headquarters, Indianapolis, IN, 46285, USA. dean_robert_a@lilly.com.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Dean
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Headquarters, Indianapolis, IN, 46285, USA. siemers_eric_r@lilly.com.
authors.forename: Eric
authors.initials: E
authors.lastname: Siemers
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St. Louis, MO, 63110, USA. mawuenyegak@neuro.wustl.edu.
authors.forename: Kwasi G
authors.initials: KG
authors.lastname: Mawuenyega
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St. Louis, MO, 63110, USA. sigurdsonw@neuro.wustl.edu.|Alzheimer's Disease Research Center, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St. Louis, MO, 63110, USA. sigurdsonw@neuro.wustl.edu.
authors.forename: Wendy
authors.initials: W
authors.lastname: Sigurdson
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Headquarters, Indianapolis, IN, 46285, USA. may_patrick_c@lilly.com.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: May
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St. Louis, MO, 63110, USA. holtzman@neuro.wustl.eduqaw.|Alzheimer's Disease Research Center, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St. Louis, MO, 63110, USA. holtzman@neuro.wustl.eduqaw.|Hope Center for Neurological Disorders, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St. Louis, MO, 63110, USA. holtzman@neuro.wustl.eduqaw.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: Department of Psychiatry and Neurochemistry, Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, SU/Mölndal Hospital, 431 80, Mölndal, Sweden. erik.portelius@neuro.gu.se.
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
authors.affiliation: Department of Psychiatry and Neurochemistry, Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, SU/Mölndal Hospital, 431 80, Mölndal, Sweden. henrik.zetterberg@clinchem.gu.se.|UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. henrik.zetterberg@clinchem.gu.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St. Louis, MO, 63110, USA. batemanr@neuro.wustl.edu.|Alzheimer's Disease Research Center, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St. Louis, MO, 63110, USA. batemanr@neuro.wustl.edu.|Hope Center for Neurological Disorders, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St. Louis, MO, 63110, USA. batemanr@neuro.wustl.edu.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Bateman
authors.affiliation: Department of Psychiatry and Neurochemistry, Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, SU/Mölndal Hospital, 431 80, Mölndal, Sweden. kaj.blennow@neuro.gu.se.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Department of Psychiatry and Neurochemistry, Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, SU/Mölndal Hospital, 431 80, Mölndal, Sweden. johan.gobom@neuro.gu.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Gobom
mesh_terms: D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid*; D001381:Azepines / Q000008:administration & dosage*; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D006801:Humans; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D010455:Peptides / Q000134:cerebrospinal fluid
chemical_list: C489697:APLP1 protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001381:Azepines; D015415:Biomarkers; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D010446:Peptide Fragments; D010455:Peptides; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine