**1. Introduction**

The microtubule-associated protein tau was originally identified as a heat-stable protein that was co-purified with tubulin [1] and is solely expressed in higher eukaryotes [2–4]. Its main functions include controlling microtubule assembly [1, 5, 6], contributing to the polymerization of microtubules [7] and acting as a parameter of axonal transport [8] and axonal diameter [9]. Tau protein is also involved in the formation polarity during neuromas and in neurodegeneration [10]. It also acts as a protein framework to control the signaling pathways. Phosphorylation is the most common post-translation modification of tau protein. Hyperphosphorylation of tau

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

protein is detected in neurofibrillary tangles (NFTs). NFTs are noticeable in many age-dependent diseases, which are collectively called tauopathies. Tau was not only observed in the nucleoli of non-dividing cells but also in high amounts in the nuclei of cancerous cells that specified a precise protagonist of tau in dividing cells [11]. Hence, tau might have some important functions in fast-dividing cells, which in turn may have an effect on cancer pathogenesis.

In addition to neurons, tau expression has been noticed in human breast, prostate, gastric, colorectal and pancreatic cancer cell lines and tissues [12–18]. Tau is also found in patients with twisted tubulofilamentous of inclusion-body myositis [19]. The activity of non-neuronal tau, especially in cancer cells, still needs to be exemplified. The hyperphosphorylation of tau leads to Alzheimer's disease (AD) and tumor suppressor protein pRB, as well as different cell cycle activators like Cdk4, Cdk2, cyclin D, cyclin B and PCNA are present in the neurons of AD patients; this indicates re-commencement of the cell cycle, which may be a mechanism of neurodegeneration [20]. There are more associations between tauopathies and cancer, as high levels of cancerrelated proteins like Fos, Jun and BRCA1 are found in AD [21, 22]. Cancer pathogenesis and tauopathies are also linked with respect to signal transduction, where the prolyl isomerase, Pin1, acts as a main factor [23]. Tauopathies also leads to cognitive discrepancies in for AD.

Tau protein activity is predominantly controlled by its phosphorylation. Two important aspects of cancer, cell signaling pathway and cell cycle progression, can be modulated by tau. Tau might work as a possible modulator of the efficacy of cancer chemotherapy drugs. In some previous experiments involving tau in different cancers, a connection between tau expression and drug resistance was noted [12, 14, 24–27], as a competition between tau and the drugs for microtubule-binding sites occurred. Deregulation of Pin1 can be a crucial protagonist in the pathogenesis of tauopathies and cancer and might be the basis for remarkable new therapies in the future [23]. Finally, there could be a good liaison between age-related tauopathies that leads to dementia that is significant category of cognitive disorders and cancer, mainly because both involve aberrant tau phosphorylation.

*2.1.1. Post-translation of tau*

**Figure 1.** Graphic representation of human tau gene.

There may be several types of post-translation modifications of tau protein, of which phosphorylation is the most common. Phosphorylation occurs when a phosphate group is added by esterification to one of the three amino acids, serine (S), threonine (T) and tyrosine (Y). Increase in phosphorylation decreases the affinity of tau toward microtubules and finally destabilizes cytoskeleton. There are 85 recognized phosphorylation sites described in human AD brain tissue. Among them, 53% phosphorylation sites of tau [45] are serine, 41% sites [41] are threonine while only 6% sites [5] are tyrosine [35–37]. Tau protein also comprises 11 recognized O-glycosylation sites, where the covalent attachment of oligosaccharides to a protein occurs [38]; 12 glycation sites, where non-enzymatic protein glycosylation is routinely detected in mature tissues [39–41], 1 prolyl-isomerization site, where the reaction that relocates the protein disulfide bonds occurs [42, 43]; 3 tau truncation sites, which improve the tau aggregation ability and implement neuronal apoptosis [44–46]; 4 tau nitration sites, where nitrogen oxide adjuncts to the tyrosine of an organic molecule for tau aggregation [47]; 8 tau polyamination sites, which are involved in the NFT formation process [48, 49]; 3 sites of ubiquitination, which is subordinately implicated in tau pathology [50, 51]; 1 site of sumoylation and 1 site of oxidation, which stabilizes ubiquitination and is associated in tau lesion development, respectively [52–55]; and lastly 2 sites of selfaggregation, which reconciles cell toxicity to prime for AD [56]. All of the post-translation modifications are shown in **Figure 2**. Phosphorylation impacts tau's solubility localization, and role and connections, and vulnerability to other post-translational modifications. Additionally, the hyperphosphorylation of tau simulates pathological stoichiometric tau phosphorylation and replicates the structural and functional characteristics of AD [57]. Several phosphorylated sites explicit to diseased tau were discovered by the analysis of soluble and insoluble tau fractions using mass spectrometry [58]. Tau ensures that the axonal microtubules work properly, and lets the neurons function normally, whereas

Tau in Tauopathies That Leads to Cognitive Disorders and in Cancer

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