**1. Introduction**

Tau is a microtubule-associated protein produced through alternative splicing of the MAPT (microtubule-associated protein tau) gene. Tau is highly abundant in the axons of nerve cells [1] where it plays a role in the stabilization and dynamics of the microtubules. To a lesser extent tau is also localized in the synaptic compartments [2] where it is suggested to modulate postsynaptic receptor activity by interaction with a broad range of synaptic proteins [3]. Besides its neuronal localization, tau is also expressed in oligodendrocytes, where it stabilizes microtubules during process outgrowth and myelination [4–6] and in astrocytes at trace levels [4], where it does not appear to be a major cytoskeletal protein. Although tau is mainly an intracellular protein, it can also be actively secreted by neurons to the brain interstitial fluid. The mechanisms of tau secretion under physiological conditions are not well understood, but it can be induced by neuronal hyperexcitability [7] and its release through ectosomal and exosomal vesicles [8, 9] or alternative secretory pathways [10] has been proposed. 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.

Tau released into the interstitial fluid may drain into the cerebrospinal fluid (CSF) within the subarachnoid space as well as into blood. Therefore, alterations of tau levels in biological fluids may mirror the pathological state of the brain in those conditions associated to neuronal degeneration. 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.

Consequently, 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. Additionally, the analysis of different tau forms is also explored in the evaluation of the efficacy of disease-modifying therapies and to better understand the underlying molecular mechanisms associated to neuronal degeneration and tau pathology.
