**2. Tau pathology and neuro-axonal damage**

Tauopathies are a complex and heterogeneous group of neurodegenerative diseases characterized by the presence of hyper-phosphorylated and aggregated tau forms in neuronal and glial cells [11, 12]. The spectrum of tauopathies encloses more than 20 sporadic and familial diseases, in which their neuropathological phenotypes can be classified according to the involvement of different cell types (neurons of glial cells), affected brain regions, and the type of tau form/s associated to the pathological protein deposits [12]. In contrast to primary tauopathies where the common pathological hallmark is the presence of disease-related tau forms, AD is a neurodegenerative disease where tau pathology is accompanied by the accumulation of abnormally folded amyloid beta peptides in the tissue in form of extracellular amyloid plaques [13].

Keeping this in mind, the understanding of correlation between different tau forms present in the biological fluids regarding and the pathological changes occurring in the brain tissue is challenging. On one hand, there are neurodegenerative mechanisms not associated to tauopathies (or tauopathies associated to beta-amyloid deposition such as in AD), but leading to acute or chronic neuronal damage drive to a release of tau forms in their non-pathological (basal) state: i.e. basal phosphorylation levels and absence of truncated forms. On the other hand, in the presence of a tauopathy, tau release due to neuro-axonal damage could be accompanied by the release of its pathological forms (hyper-phosphorylated and truncated forms). In this regard, the tau biomarker field has been closely associated to the study of AD pathology since, among the group of tauopathies, AD cases are showing the most robust and clinically relevant alterations on tau levels in biological fluids. However, the precise cellular and molecular mechanisms leading to tau alterations in biological fluids remain elusive. Indeed, the current knowledge about the pathophysiological mechanisms of these diseases does not completely explain the disease-specific changes observed in biological fluids.
