Differential mass spectrometry profiles of tau protein in the cerebrospinal fluid of patients with Alzheimer's disease, progressive supranuclear palsy, and dementia with lewy bodies

Nicolas R. Barthélemy, Audrey Gabelle, Christophe Hirtz, François Fenaille, Nicolas Sergeant, Susanna Schraen-Maschke, Jérôme Vialaret, Luc Buée, Christophe Junot, François Becher, Sylvain Lehmann

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Microtubule-associated Tau proteins are major actors in neurological disorders, the so-called tauopathies. In some of them, and specifically in Alzheimer's disease (AD), hyperphosphorylated forms of Tau aggregate into neurofibrillary tangles.∗Following and understanding the complexity of Tau's molecular profile with its multiple isoforms and post-translational modifications represent an important issue, and a major analytical challenge.∗Immunodetection methods are, in fact, limited by the number, specificity, sensitivity, and capturing property of the available antibodies.∗Mass spectrometry (MS) has recently allowed protein quantification in complex biological fluids using isotope-labeled recombinant standard for absolute quantification (PSAQ).∗To study Tau proteins, which are found at very low concentrations within the cerebrospinal fluid (CSF), we relied on an innovative two-step pre-fractionation strategy, which was not dependent on immuno-enrichment.∗We then developed a sensitive multiplex peptide detection capability using targeted high-resolution MS to quantify Tau-specific peptides covering its entire sequence.∗This approach was used on a clinical cohort of patients with AD, progressive supranuclear palsy (PSP), and dementia with Lewy body (DLB) and with control non-neurodegenerative disorders.∗We uncovered a common CSF Tau molecular profile characterized by a predominance of central core expression and 1N/3R isoform detection.∗While PSP and DLB tau profiles showed minimal changes, AD was characterized by a unique pattern with specific modifications of peptide distribution.∗Taken together these results provide important information on Tau biology for future therapeutic interventions, and improved molecular diagnosis of tauopathies.

Original languageEnglish
Pages (from-to)1033-1043
Number of pages11
JournalJournal of Alzheimer's Disease
Volume51
Issue number4
DOIs
StatePublished - Apr 12 2016
Externally publishedYes

Keywords

  • Cerebrospinal fluid
  • mass spectrometry
  • neurodegenerative disease
  • tau protein

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