Additionally, since tau is hyper-phosphorylated in patients suffering from primary tauopathies and Alzheimer’s disease (AD), a tauopathy associated with beta-amyloid deposition, increased phospho-tau (p-tau) levels in biological fluids may reflect the undergoing tau pathology in the brain tissue.Ĭonsequently, the quantification of tau levels in biological fluids is extensively studied as a diagnostic and prognostic biomarker in a broad range of neurological conditions either associated or not to a concomitant tauopathy. Therefore, alterations of tau levels in biological fluids may mirror the pathological state of the brain in those conditions associated to neuronal degeneration. Tau released into the interstitial fluid may drain into the cerebrospinal fluid (CSF) within the subarachnoid space as well as into blood. Additionally, under certain pathological conditions associated to neuronal degeneration tau can be released from the neurons to the brain interstitial fluid, usually correlating with the degree of neuro-axonal damage. The mechanisms of tau secretion under physiological conditions are not well understood, but it can be induced by neuronal hyperexcitability and its release through ectosomal and exosomal vesicles or alternative secretory pathways has been proposed. Although tau is mainly an intracellular protein, it can also be actively secreted by neurons to the brain interstitial fluid. Besides its neuronal localization, tau is also expressed in oligodendrocytes, where it stabilizes microtubules during process outgrowth and myelination and in astrocytes at trace levels, where it does not appear to be a major cytoskeletal protein. To a lesser extent tau is also localized in the synaptic compartments where it is suggested to modulate postsynaptic receptor activity by interaction with a broad range of synaptic proteins. Tau is highly abundant in the axons of nerve cells where it plays a role in the stabilization and dynamics of the microtubules. Tau is a microtubule-associated protein produced through alternative splicing of the MAPT (microtubule-associated protein tau) gene. Additionally, we explore how tau alterations in the brain tissue may explain the etiology of its regulated levels in CSF and blood. In this chapter, we summarize the current knowledge on the alterations of diverse tau forms in biological fluids of neurodegenerative dementias and its relevance in the differential diagnostic context.
In this complex scenario the diagnostic accuracy of diverse tau forms as disease-specific biomarkers needs to be established. Additionally, isoforms and different structural and truncated tau forms have also been reported to be altered in neurodegenerative dementias. 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, total-tau rises temporarily due to cerebral infarction. 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. 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. The presence of elevated total-tau in the CSF is assumed to reflect the degree of axonal damage in the brain tissue. 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. In several neurodegenerative dementias, either associated or not to a primary tauopathy, tau levels are altered in a disease-specific pattern, which can be used as a biomarker for disease diagnosis and prognosis. Tau can be detected in biological fluids in physiological and pathological conditions. 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. In physiological conditions tau is abundant in neurons while its expression in glial populations is low and restricted to astrocytes and oligodendrocytes. Tau is a microtubule-associated protein, whose main function is the modulation of the stability of axonal microtubules.
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