TY - JOUR
T1 - 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
AU - Barthélemy, Nicolas R.
AU - Gabelle, Audrey
AU - Hirtz, Christophe
AU - Fenaille, François
AU - Sergeant, Nicolas
AU - Schraen-Maschke, Susanna
AU - Vialaret, Jérôme
AU - Buée, Luc
AU - Junot, Christophe
AU - Becher, François
AU - Lehmann, Sylvain
PY - 2016/4/12
Y1 - 2016/4/12
N2 - 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.
AB - 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.
KW - Cerebrospinal fluid
KW - mass spectrometry
KW - neurodegenerative disease
KW - tau protein
UR - http://www.scopus.com/inward/record.url?scp=84964917095&partnerID=8YFLogxK
U2 - 10.3233/JAD-150962
DO - 10.3233/JAD-150962
M3 - Article
C2 - 26923020
AN - SCOPUS:84964917095
VL - 51
SP - 1033
EP - 1043
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - 4
ER -