Analysis of the Cerebrospinal Fluid Proteome in Alzheimer's Disease

PLoS One. 2016 Mar 7;11(3):e0150672. doi: 10.1371/journal.pone.0150672. eCollection 2016.

Abstract

Alzheimer's disease is a neurodegenerative disorder accounting for more than 50% of cases of dementia. Diagnosis of Alzheimer's disease relies on cognitive tests and analysis of amyloid beta, protein tau, and hyperphosphorylated tau in cerebrospinal fluid. Although these markers provide relatively high sensitivity and specificity for early disease detection, they are not suitable for monitor of disease progression. In the present study, we used label-free shotgun mass spectrometry to analyse the cerebrospinal fluid proteome of Alzheimer's disease patients and non-demented controls to identify potential biomarkers for Alzheimer's disease. We processed the data using five programs (DecyderMS, Maxquant, OpenMS, PEAKS, and Sieve) and compared their results by means of reproducibility and peptide identification, including three different normalization methods. After depletion of high abundant proteins we found that Alzheimer's disease patients had lower fraction of low-abundance proteins in cerebrospinal fluid compared to healthy controls (p<0.05). Consequently, global normalization was found to be less accurate compared to using spiked-in chicken ovalbumin for normalization. In addition, we determined that Sieve and OpenMS resulted in the highest reproducibility and PEAKS was the programs with the highest identification performance. Finally, we successfully verified significantly lower levels (p<0.05) of eight proteins (A2GL, APOM, C1QB, C1QC, C1S, FBLN3, PTPRZ, and SEZ6) in Alzheimer's disease compared to controls using an antibody-based detection method. These proteins are involved in different biological roles spanning from cell adhesion and migration, to regulation of the synapse and the immune system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid*
  • Biomarkers / cerebrospinal fluid
  • Biomarkers / metabolism
  • Case-Control Studies
  • Humans
  • Male
  • Peptide Fragments / cerebrospinal fluid
  • Peptide Fragments / metabolism
  • Proteomics*
  • Reproducibility of Results
  • Software

Substances

  • Biomarkers
  • Peptide Fragments

Grant support

This research was supported by Uppsala Berzelii Technology Centre for Neurodiagnostics, with financing from the Swedish Governmental Agency for Innovation Systems, the Knut and Alice Wallenberg Foundation, KTH Center for Applied Proteomics, ProNova Vinn Excellence Center, Marianne and Marcus Wallenbergs Foundation, Swedish Alzheimer’s foundation, Swedish Brain Foundation, Gun och Bertil Stohnes stiftelse, Geriatriska fonden, the Swedish Research Council FORMAS, the Swedish Research Council P29797-1 JB grant (621-2011-4423) as well from SciLifeLab. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.