RESEARCH ARTICLE
High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer’s Disease in Human Cerebrospinal Fluid Ronald C. Hendrickson1☯¤a*, Anita Y. H. Lee1, Qinghua Song2¤b, Andy Liaw2, Matt Wiener3, Cloud P. Paweletz1¤c, Jeffrey L. Seeburger4, Jenny Li1, Fanyu Meng1, Ekaterina G. Deyanova1¤d, Matthew T. Mazur1¤e, Robert E. Settlage1¤f, Xuemei Zhao1, Katie Southwick1¤g, Yi Du1, Dan Holder5, Jeffrey R. Sachs3, Omar F. Laterza6, Aimee Dallob6, Derek L. Chappell6, Karen Snyder6, Vijay Modur7¤h, Elizabeth King8, Catharine Joachim8, Andrey Y. Bondarenko9¤i, Mark Shearman7¤j, Keith A. Soper5, A. David Smith8, William Z. Potter4, Ken S. Koblan7, Alan B. Sachs1¤k, Nathan A. Yates1☯¤l
OPEN ACCESS Citation: Hendrickson RC, Lee AYH, Song Q, Liaw A, Wiener M, Paweletz CP, et al. (2015) High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer’s Disease in Human Cerebrospinal Fluid. PLoS ONE 10(8): e0135365. doi:10.1371/journal.pone.0135365 Editor: Stephen D Ginsberg, Nathan Kline Institute and New York University School of Medicine, UNITED STATES Received: October 13, 2014 Accepted: July 21, 2015 Published: August 13, 2015 Copyright: © 2015 Hendrickson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are available. The Massive accession number is MSV000079192 and the ProteomeXchange accession number is PXD002546 Follow this link for more information: http://massive.ucsd.edu/ ProteoSAFe/status.jsp?task = c141de8216924efd98dc8f67511158e3 Funding: This discovery proteomics and analysis work was supported by Merck & Co. The manuscript was reviewed and approved for publication by Merck. The funders had no other role in the study design,
1 Departments of Exploratory and Translational Sciences, Merck & Co., Rahway, NJ, United States of America, 2 Biometrics, Merck & Co., Rahway, NJ, United States of America, 3 Applied Computer Science and Mathematics, Merck & Co., Rahway, NJ, United States of America, 4 Clinical Neuroscience and Ophthalmology, Merck & Co., West Point, PA, United States of America, 5 Biometrics, Merck & Co., West Point, PA, United States of America, 6 Clinical Development Laboratory, Merck & Co., Rahway, NJ, United States of America, 7 Neuroscience Basic Research, Merck & Co., West Point, PA, United States of America, 8 OPTIMA, University of Oxford, Department of Pharmacology, Oxford United Kingdom, 9 Rosetta Biosoftware, Seattle, WA, United States of America ☯ These authors contributed equally to this work. ¤a Current Address: Memorial Sloan Kettering Cancer Center, New York, NY, United States of America, ¤b Current Address: Gilead, San Francisco, CA, United States of America, ¤c Current Address: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, United States of America, ¤d Current Address: Bristol Myers Squibb, Princeton, NJ, United States of America, ¤e Current Address: Imclone, New York, NY, United States of America, ¤f Current Address: Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA, United States of America, ¤g Current Address: ThermoFisher Scientific, San Jose, CA, United States of America, ¤h Current Address: Genzyme, Cambridge, MA, United States of America, ¤i Current Address: InfoClinika, Seattle, WA, United States of America, ¤j Current Address: Applied Genetic Technologies Corporation, Boston, MA, United States of America, ¤k Current Address: ThermoFisher Scientific, Carlsbad, CA, United States of America, ¤l Current Address: University of Pittsburg School of Medicine, Pittsburgh, PA, United States of America *
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Abstract Disease modifying treatments for Alzheimer’s disease (AD) constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF) biochemical markers such as total tau, ptau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we
PLOS ONE | DOI:10.1371/journal.pone.0135365 August 13, 2015
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Candidate Disease Progression Markers in AD
data collection and analysis or preparation of the manuscript. The specific roles of the authors are articulated in the "author contribution" section. Competing Interests: All authors performed this study while employees at Merck & Co. or Oxford University or Rosetta Biosoftware. Some authors own stock or stock options in Merck & Co. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.
applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/nondemented (control) patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p
