Abstract

Neurodegenerative diseases are a growing burden, and there is an urgent need for better biomarkers for diagnosis, prognosis, and treatment efficacy. Structural and functional brain alterations are reflected in the protein composition of cerebrospinal fluid (CSF). Alzheimer's disease (AD) patients have higher CSF levels of tau, but we lack knowledge of systems‐wide changes of CSF protein levels that accompany AD. Here, we present a highly reproducible mass spectrometry (MS)‐based proteomics workflow for the in‐depth analysis of CSF from minimal sample amounts. From three independent studies (197 individuals), we characterize differences in proteins by AD status (> 1,000 proteins, CV < 20%). Proteins with previous links to neurodegeneration such as tau, SOD1, and PARK7 differed most strongly by AD status, providing strong positive controls for our approach. CSF proteome changes in Alzheimer's disease prove to be widespread and often correlated with tau concentrations. Our unbiased screen also reveals a consistent glycolytic signature across our cohorts and a recent study. Machine learning suggests clinical utility of this proteomic signature.

Details

Title
Proteome profiling in cerebrospinal fluid reveals novel biomarkers of Alzheimer's disease
Author
Bader, Jakob M 1   VIAFID ORCID Logo  ; Geyer, Philipp E 2   VIAFID ORCID Logo  ; Müller, Johannes B 1   VIAFID ORCID Logo  ; Strauss, Maximilian T 1   VIAFID ORCID Logo  ; Koch, Manja 3   VIAFID ORCID Logo  ; Leypoldt, Frank 4 ; Koertvelyessy, Peter 5 ; Bittner, Daniel 6 ; Schipke, Carola G 7 ; Incesoy, Enise I 8 ; Peters, Oliver 9 ; Deigendesch, Nikolaus 10 ; Simons, Mikael 11 ; Jensen, Majken K 12 ; Zetterberg, Henrik 13 ; Mann, Matthias 2   VIAFID ORCID Logo 

 Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany 
 Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany; NNF Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark 
 Departments of Nutrition & Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA 
 Institute of Clinical Chemistry, Faculty of Medicine, Kiel University, Kiel, Germany; Department of Neurology, Faculty of Medicine, Kiel University, Kiel, Germany 
 Department of Neurology, Medical Faculty, Otto von Guericke University Magdeburg, Magdeburg, Germany; Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany 
 Department of Neurology, Medical Faculty, Otto von Guericke University Magdeburg, Magdeburg, Germany 
 Experimental & Clinical Research Center (ECRC), Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlin, & Berlin Institute of Health, Berlin, Germany 
 Department of Psychiatry, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlin & Berlin Institute of Health, Charité Universitätsmedizin Berlin, Berlin, Germany 
 Department of Psychiatry, corporate member of Freie Universität Berlin, Humboldt‐Universität zu Berlin & Berlin Institute of Health, Charité Universitätsmedizin Berlin, Berlin, Germany; German Center for Neurodegenerative Diseases, Berlin, Germany 
10  Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland 
11  German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany 
12  Departments of Nutrition & Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Public Health, University of Copenhagen, Copenhagen, Denmark 
13  Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; UK Dementia Research Institute at UCL, London, UK; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK 
Section
Articles
Publication year
2020
Publication date
Jun 2020
Publisher
EMBO Press
e-ISSN
17444292
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2447198007
Copyright
© 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.