title: Analysis of the Cerebrospinal Fluid Proteome in Alzheimer's Disease.
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.
authors.affiliation: Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden.
authors.forename: Payam Emami
authors.initials: PE
authors.lastname: Khoonsari
authors.affiliation: Affinity Proteomics, Science for Life Laboratory, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Häggmark
authors.affiliation: Analytical Chemistry, Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Lönnberg
authors.affiliation: Affinity Proteomics, Science for Life Laboratory, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Mikus
authors.affiliation: Department of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Kilander
authors.affiliation: Department of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lannfelt
authors.affiliation: Analytical Chemistry, Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergquist
authors.affiliation: Department of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Ingelsson
authors.affiliation: Affinity Proteomics, Science for Life Laboratory, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Nilsson
authors.affiliation: Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden.
authors.forename: Kim
authors.initials: K
authors.lastname: Kultima
authors.affiliation: Analytical Chemistry, Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden.
authors.forename: Ganna
authors.initials: G
authors.lastname: Shevchenko
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid / Q000378:metabolism; D016022:Case-Control Studies; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000134:cerebrospinal fluid / Q000378:metabolism; D040901:Proteomics; D015203:Reproducibility of Results; D012984:Software
chemical_list: D015415:Biomarkers; D010446:Peptide Fragments