Tau Protein as a Biological Fluid Biomarker in Neurodegenerative Dementias

Abstract

Tau is a microtubule-associated protein, whose main function is the modulation of the stability of axonal microtubules. In physiological conditions tau is abundant in neurons while its expression in glial populations is low and restricted to astrocytes and oligodendrocytes. The aggregation of tau in neurofibrillary or gliofibrillary tangles is the main hallmark of tauopathies, a complex group of human neurodegenerative conditions where tau hyper-phosphorylation causes its increased insolubility and aggregation leading to tangle formation and microtubule destabilization. Tau can be detected in biological fluids in physiological and pathological conditions. In several neurodegenerative dementias, either associated or not to a primary tauopathy, tau levels are altered in a diseasespecific pattern, which can be used as a biomarker for disease diagnosis and prognosis. The study of tau levels in biological fluids has been mainly performed in the cerebrospinal fluid (CSF), although the recent development of ultrasensitive techniques allows the robust quantification of tau in blood-based biofluids such as serum and plasma. The presence of elevated total-tau in the CSF is assumed to reflect the degree of axonal damage in the brain tissue. Consequently, highest total-tau CSF levels are found in sporadic Creutzfeldt-Jakob disease, which is characterized by massive neuronal damage and a rapid progressive course. Elevated total-tau is also detected in Alzheimer's disease and dementia with Lewy bodies, while in other dementia conditions such as vascular dementia, frontotemporal dementia and corticobasal degeneration are unchanged, inconclusive or not determined. Additionally, total-tau rises temporarily due to cerebral infarction. In contrast, elevated phospho-tau levels seem to be restricted to Alzheimer's disease pathology, most likely mirroring the presence of the hyper-phosphorylated form in the brain tissue, although phospho-tau levels are mainly unaffected in tauopathies. Additionally, isoforms and different structural and truncated tau forms have also been reported to be altered in neurodegenerative dementias. In this complex scenario the diagnostic accuracy of diverse tau forms as disease-specific biomarkers needs to be established. In this chapter, we summarize the current knowledge on the alterations of diverse tau forms

Longitudinal Association of Total Tau Concentrations and Physical Activity With Cognitive Decline in a Population Sample

“…In recent years, tau measurement in blood using a single molecular array has provided a stable assessment of tau concentrations in the human brain. 3 , 4 Blood assays offer a less intrusive and more cost-effective way of measuring total tau concentrations. Increased concentrations of total tau in plasma are associated with cognitive decline, 5 specifically in memory, cognition, visuospatial capacity, attention, and progression from mild cognitive impairment to AD, 6 , 7 and distinguish between individuals with AD and controls.…”

“…Examination of tau levels has generally been conducted using cerebrospinal fluid (CSF). In recent years, tau measurement in blood using a single molecular array has provided a stable assessment of tau concentrations in the human brain . Blood assays offer a less intrusive and more cost-effective way of measuring total tau concentrations.…”

Diagnostic Utility of Selected Serum Dementia Biomarkers: Amyloid β-40, Amyloid β-42, Tau Protein, and YKL-40: A Review

“…It is believed that the concentration of tau protein in CSF relates to the degree of brain cells damage [37]. Tau protein is secreted from neurons to the cerebrospinal fluid, where it penetrates through the blood-brain barrier and the arachnoid granules to the bloodstream, which is why it can be identified in peripheral blood [38].…”

A Quantitative LC-MS/MS Method for Distinguishing the Tau Protein Forms Phosphorylated and Nonphosphorylated at Serine-396

“…Numerous studies have investigated specific phosphorylation sites and the correlation to disease progression. Although there has been tremendous advancement in the understanding of tauopathies in recent years, new or refined biomarker methods to follow progression of tau pathologies such as AD are still of great relevance. , Such a biomarker can be used for diagnosis and to monitor disease progression, as well as to demonstrate treatment effects of new medicines in drug development. Historically, biomarker methods for analysis of tau and phosphorylated tau (p-tau) have been based on ligand-binding platforms, including the core cerebrospinal fluid (CSF) biomarkers currently used for diagnosis and clinical research of AD, i.e., total tau and threonine-181-phosphorylated tau (pT181-tau) together with measurements of amyloid-beta 42. − In addition, LC-MS has been widely explored for proteomics studies, mostly using post-mortem human brain tissue to investigate different disease stages of AD.…”

“…Although there has been tremendous advancement in the understanding of tauopathies in recent years, new or refined biomarker methods to follow progression of tau pathologies such as AD are still of great relevance. 7,8 Such a biomarker can be used for diagnosis and to monitor disease progression, as well as to demonstrate treatment effects of new medicines in drug development.…”