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O5‐05‐06: Discovery of multiple phosphorylated tau biomarkers in CSF using a novel mass spectrometry method
Author(s) -
Russell Claire,
Mitra Vikram,
Hiltunen Mikko,
Zetterberg Henrik,
Ward Malcolm,
Pike Ian
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.07.474
Subject(s) - isobaric labeling , phosphorylation , brain tissue , chemistry , biomarker , biomarker discovery , proteomics , peptide , mass spectrometry , alzheimer's disease , pathology , neuroscience , biochemistry , biology , chromatography , disease , quantitative proteomics , medicine , gene
mutations (n1⁄418, CDR 1⁄4 0.5 in 12) or at 50% risk for inheriting such mutations (n1⁄425). Among the 31 mutation carriers (MCs), 26 had PSEN1 mutations and 5 had the V717I APP mutation. CSF was depleted of 14 high abundance proteins, digested with trypsin and the resulting peptides were analyzed by liquid chromatography-mass spectrometry (LCMS). Peptides were identified by shotgun sequencing and clustered into their parent proteins. Peptide peaks were aligned across all samples and peak intensities were measured and compared to determine relative peptide and protein abundance in each sample. Protein levels were separately compared between mutation non-carriers (NCs, n1⁄412) versus all ADADMCs and versus all presymptomaticMCs (n1⁄413).Results: 1,018 proteins were differentially quantified and identified. Using an intensity difference of 2-fold, and pand q-values (false discovery rate) of 0.05 as cut-offs for significance, we identified 12 proteins that were differentially expressed between ADAD MCs and NCs. Thrombospondin-2, LRP 11, NPDC1, Complement factor H, Fibronectin, Complement component C7, Transcription factor SOX-13, Clusterin, Fatty acid-binding protein, and APP were increased and Folate receptor alpha and CRP were decreased in ADAD MCs. An additional 22 proteins were differentially expressed with significant but smaller differences. When only presymptomatic ADAD mutation carriers were included, no protein was expressed with a 2-fold difference and only one (LRP1) was elevated with pand q-values 0.05. Conclusions: Proteins associated with the cell matrix, inflammation, vascular remodeling, and Abeta transport are elevated in ADAD MCs Only LRP1 was elevated in presymptomatic MCs, suggesting that its overexpression represents an adaptive response to Abeta overproduction.