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

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 Tauspecific peptides covering its entire sequence. This approach was used on a clinical cohort of patients with AD, progressive supranuclear 1 These authors jointly directed this work. N.R. Barthélemy et al. / Tau Cerebrospinal Fluid Molecular Profilepalsy (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.

Mass-Spectrometry-Based Method To Quantify in Parallel Tau and Amyloid β 1–42 in CSF for the Diagnosis of Alzheimer’s Disease

“…In addition, Barthelemy et al . (32) also observed a twenty fold difference when comparing their ELISA and SRM assays, illustrating the difference we could expect when comparing ELISA and SRM on the same region of the protein. When comparing the absolute concentration for tau, measured with SRM, our current values are consistent with previous studies (19), and the concentrations in both cases are in the nanogram per milliliter range.…”

Function and regulation of tau conformations in the development and treatment of traumatic brain injury and neurodegeneration

“…The disappointing results from amyloid beta treatment studies has caused a shift in focus to the treatment of tau in AD. More recently, CSF biomarker studies have indicated that tau is superior to amyloid beta markers in following the progression of cognitive deficits in AD and other tauopathies [46, 47]. Furthermore, a newly developed PET technique to track changes in tau deposition in living patients with AD also shows that tau deposition more closely tracked dementia status and was a better indicator of cognitive deficits, thus indicating that treatments targeting tau could provide a superior alternative to amyloid beta therapies [45].…”

Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls1

“…Hence, in those less common conditions, tau antibodies may need to work intracellularly to be effective. In this context, it is also important to note that recent mass spectroscopy studies show that most of CSF tau consists of tau fragments with ragged N- and C-termini that approximately consist of Tau150–250 [61,62]. Although there should be less tau degradation in interstitial fluid, a gradient of such cleavage likely exists in biological fluids that should influence antibody target engagement and clearance of pathological tau.…”