title: 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.
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.
authors.affiliation: CEA, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etude du Métabolisme des Médicaments, Gif-sur-Yvette, France.|CHU Montpellier, IRMB, hôpital St Eloi, Laboratoire de Biochimie Protéomique Clinique et CRB, INSERM-UM U1183, Montpellier, France.
authors.forename: Nicolas R
authors.initials: NR
authors.lastname: Barthélemy
authors.affiliation: CHU Montpellier, IRMB, hôpital St Eloi, Laboratoire de Biochimie Protéomique Clinique et CRB, INSERM-UM U1183, Montpellier, France.|Centre Mémoire Ressources Recherche, CHU Montpellier, hôpital Gui de Chauliac, Montpellier. Université Montpellier I, Montpellier, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Gabelle
authors.affiliation: CHU Montpellier, IRMB, hôpital St Eloi, Laboratoire de Biochimie Protéomique Clinique et CRB, INSERM-UM U1183, Montpellier, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hirtz
authors.affiliation: CEA, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etude du Métabolisme des Médicaments, Gif-sur-Yvette, France.
authors.forename: François
authors.initials: F
authors.lastname: Fenaille
authors.affiliation: Inserm, UMR 837, Alzheimer & Tauopathies, Centre de Recherche Jean-Pierre Aubert, Institut de Médecine Prédictive et de Recherche Thérapeutique, Faculté de Médecine, Univ. Lille Nord de France, Université de Lille II, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sergeant
authors.affiliation: Inserm, UMR 837, Alzheimer & Tauopathies, Centre de Recherche Jean-Pierre Aubert, Institut de Médecine Prédictive et de Recherche Thérapeutique, Faculté de Médecine, Univ. Lille Nord de France, Université de Lille II, France.
authors.forename: Susanna
authors.initials: S
authors.lastname: Schraen-Maschke
authors.affiliation: CHU Montpellier, IRMB, hôpital St Eloi, Laboratoire de Biochimie Protéomique Clinique et CRB, INSERM-UM U1183, Montpellier, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Vialaret
authors.affiliation: Inserm, UMR 837, Alzheimer & Tauopathies, Centre de Recherche Jean-Pierre Aubert, Institut de Médecine Prédictive et de Recherche Thérapeutique, Faculté de Médecine, Univ. Lille Nord de France, Université de Lille II, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.affiliation: CEA, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etude du Métabolisme des Médicaments, Gif-sur-Yvette, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Junot
authors.affiliation: CEA, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etude du Métabolisme des Médicaments, Gif-sur-Yvette, France.
authors.forename: François
authors.initials: F
authors.lastname: Becher
authors.affiliation: CHU Montpellier, IRMB, hôpital St Eloi, Laboratoire de Biochimie Protéomique Clinique et CRB, INSERM-UM U1183, Montpellier, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lehmann
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000704:Analysis of Variance; D002853:Chromatography, Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D020961:Lewy Body Disease / Q000134:cerebrospinal fluid*; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D059906:Neuroimaging; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013223:Statistics as Topic; D013494:Supranuclear Palsy, Progressive / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Cerebrospinal fluid; mass spectrometry; neurodegenerative disease; tau protein