**2.1. Tau gene**

A particular gene, MAPT, that resides on chromosome 17q21 encodes tau protein [32]. The size of this gene is more than 50 kb and contains two differently modified haplotypes, H1 and H2 [33, 34]. Because of alternative splicing, several high and low molecular weight isoforms of tau are engendered. Normally, six isoforms of 352–441 amino acids are articulated in tau in the central nervous system (**Figure 1**), which are differentiated by the presence or absence of exons 2, 3 and 10 [3]. Exon 10-containing isoforms are known as four-repeat or 4R isoforms, whereas isoforms excluding exon 10 are known as three-repeat or 3R isoforms.

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

#### *2.1.1. Post-translation of tau*

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 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.

The main roles of tau protein are stimulating microtubule assembly and maintaining microtubule stability; these are regulated by its phosphorylation level. The preeminent activity of tau is maintained by its regular phosphorylation level, that is, 2–3 mol phosphate/mol of the protein [28]. The unusual functions of tau protein might be defined by this phosphorylation as well. Tau hyperphosphorylation reduces the microtubule binding and microtubule assemblyforming activity of tau [29, 30]. In case of in vitro experiments, cleaved tau has a high ten-

A particular gene, MAPT, that resides on chromosome 17q21 encodes tau protein [32]. The size of this gene is more than 50 kb and contains two differently modified haplotypes, H1 and H2 [33, 34]. Because of alternative splicing, several high and low molecular weight isoforms of tau are engendered. Normally, six isoforms of 352–441 amino acids are articulated in tau in the central nervous system (**Figure 1**), which are differentiated by the presence or absence of exons 2, 3 and 10 [3]. Exon 10-containing isoforms are known as four-repeat or 4R isoforms,

dency to unfasten from microtubules and subsequently, to aggregate [31].

whereas isoforms excluding exon 10 are known as three-repeat or 3R isoforms.

**2. Tau in tauopathies**

**2.1. Tau gene**

98 Cognitive Disorders

in fast-dividing cells, which in turn may have an effect on cancer pathogenesis.

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

**Figure 2.** Number of post-translation modifications of tau protein in function.

hyperphosphorylated tau cannot ensure a well-organized microtubule binding and leads to neuronal loss due to the disassembly of microtubules.

> identified by the examination of senile plaques of extracellular Aβ-amyloid peptide deposits and NFTs of intraneuronal tau deposits [116]. AD is also observed in neuropil threads and senile plaques consisting of dystrophic neurites [117]. Tau biochemical analysis revealed that all of the six isoforms of tau are present in AD and that the filaments of NFTs are in a paired helical filamentous form or in twisted ribbons at some places. The apolipoprotein E-4 allele

**Disease References** Alzheimer's disease [66, 67, 74] Down's syndrome [75–77] Frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) [78–80] Pick's disease [81–84] Progressive supranuclear palsy (PSP) [85–88] Creutzfeldt-Jakob disease [89, 90] Dementia pugilistica [91, 92] Inclusion-body myositis [19, 93–95] Gerstmann-Sträussler-Scheinker disease (GSS) [96, 97] Amyotrophic lateral sclerosis/Parkinsonism-dementia complex [98] Argyrophilic grain dementia [82, 99, 100] Corticobasal degeneration (CBD) [101–104] Diffuse neurofibrillary tangles with calcification [105, 106] Hallervorden–Spatz disease [107, 108] Multiple system atrophy (MSA) [109, 110] Niemann-Pick disease, type C [111–113] Progressive subcortical gliosis [114] Myotonic dystrophy [115]

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PSP is a neurological syndrome characterized by postural instability and mild dementia, where tangles are present mainly in the subcortical and cortical areas of the brain. PSP is caused by the accretion of NFTs and is a four-repeat tauopathy [119]. It has been reported that a mutation of the tau gene may cause autosomal dominant PSP; environmental risk factors are not involved in PSP. In sporadic cases, the H1 MAPT haplotype has been constantly connected with PSP [119], whereas a different haplotype, H2, seems to be defensive against PSP [120].

Pick's disease is an infrequent dementia of older people that affects the frontal lobes of the brain and causes speech complications like aphasia, and behavior problems, ultimately leading to death. Pick's disease is a sporadic 3R tauopathy, where insoluble tau accumulates

genetically amends periodic AD [118].

**Table 1.** List of neurodegenerative disorders that are categorized as tauopathies.

*2.2.2. Progressive supranuclear palsy*

*2.2.3. Pick's disease*

#### **2.2. Tauopathies**

Neurodegenerative diseases that are caused by abnormally phosphorylated tau mainly in older people are collectively known as tauopathies [59]. In tauopathies, such as AD, tau is uncharacteristically hyperphosphorylated and amassed as NFTs of paired helical filaments (PHFs) [60–65]. The main obsessive mediator of the most prevalent tauopathy, AD, is misfolded tau [66]. Besides AD, several other neuronal diseases such as frontotemporal dementia, Pick's disease, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are also related to microtubule-binding protein tau [67, 68], and these types of central nervous system disorders are called tauopathies. The brains of patients with tauopathies consist of insoluble tau deposition, and the fibrils involved, which are located mainly in the cell bodies and neuronal dendrites, are called as NFTs [69]. Though the reasons of tau aggregation are not clearly identified, the post-translation modification of tau, mainly, hyperphosphorylation, is one of the main reasons for all tauopathies. Tau is phosphorylated at various serine and threonine residues, and hyperphosphorylation subsequently reduces the binding abilities of microtubules [30, 70–72] and increases aggregation [41, 73].

A few tauopathies are briefly described below (**Table 1**).

#### *2.2.1. Alzheimer's disease*

AD is the most common type of dementia accounting for anywhere between 50 and 80% of all dementias and can cause a treacherous decline in cognition day by day. Clinically, AD is


**Table 1.** List of neurodegenerative disorders that are categorized as tauopathies.

identified by the examination of senile plaques of extracellular Aβ-amyloid peptide deposits and NFTs of intraneuronal tau deposits [116]. AD is also observed in neuropil threads and senile plaques consisting of dystrophic neurites [117]. Tau biochemical analysis revealed that all of the six isoforms of tau are present in AD and that the filaments of NFTs are in a paired helical filamentous form or in twisted ribbons at some places. The apolipoprotein E-4 allele genetically amends periodic AD [118].

#### *2.2.2. Progressive supranuclear palsy*

PSP is a neurological syndrome characterized by postural instability and mild dementia, where tangles are present mainly in the subcortical and cortical areas of the brain. PSP is caused by the accretion of NFTs and is a four-repeat tauopathy [119]. It has been reported that a mutation of the tau gene may cause autosomal dominant PSP; environmental risk factors are not involved in PSP. In sporadic cases, the H1 MAPT haplotype has been constantly connected with PSP [119], whereas a different haplotype, H2, seems to be defensive against PSP [120].

#### *2.2.3. Pick's disease*

hyperphosphorylated tau cannot ensure a well-organized microtubule binding and leads

Neurodegenerative diseases that are caused by abnormally phosphorylated tau mainly in older people are collectively known as tauopathies [59]. In tauopathies, such as AD, tau is uncharacteristically hyperphosphorylated and amassed as NFTs of paired helical filaments (PHFs) [60–65]. The main obsessive mediator of the most prevalent tauopathy, AD, is misfolded tau [66]. Besides AD, several other neuronal diseases such as frontotemporal dementia, Pick's disease, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are also related to microtubule-binding protein tau [67, 68], and these types of central nervous system disorders are called tauopathies. The brains of patients with tauopathies consist of insoluble tau deposition, and the fibrils involved, which are located mainly in the cell bodies and neuronal dendrites, are called as NFTs [69]. Though the reasons of tau aggregation are not clearly identified, the post-translation modification of tau, mainly, hyperphosphorylation, is one of the main reasons for all tauopathies. Tau is phosphorylated at various serine and threonine residues, and hyperphosphorylation subsequently reduces the binding abilities of

AD is the most common type of dementia accounting for anywhere between 50 and 80% of all dementias and can cause a treacherous decline in cognition day by day. Clinically, AD is

to neuronal loss due to the disassembly of microtubules.

**Figure 2.** Number of post-translation modifications of tau protein in function.

microtubules [30, 70–72] and increases aggregation [41, 73].

A few tauopathies are briefly described below (**Table 1**).

**2.2. Tauopathies**

100 Cognitive Disorders

*2.2.1. Alzheimer's disease*

Pick's disease is an infrequent dementia of older people that affects the frontal lobes of the brain and causes speech complications like aphasia, and behavior problems, ultimately leading to death. Pick's disease is a sporadic 3R tauopathy, where insoluble tau accumulates mainly in neuronal cells and in glial cells, such as prickle-shaped astrocytes and twisted bodies [121]. Like PSP, Pick's disease is also associated with a mutation in the tau gene. However, Pick's disease is not a distinct entity but one of the subtypes of the variety of diseases associated with temporal dementia [122].

show a considerably higher level of tau than androgen-dependent cells lines. Even androgenindependent derivative cell line isolated from androgen-dependent line shows higher amount of tau than that of the original cells. Also, in case of ovarian cancer cells, endometrioid carcinoma cell types express higher levels of tau protein compared to other cells. Estrogen also regulates tau protein expression [129]. A more extensive analysis will be required to confirm

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Tau escalates the deceiving and reconnection of isolated breast tumor cells, and circulatory tumor cells might be responsible for increased risk of disease repetition. That is why the pathological assessment of tau may be useful for patients by diminishing metastasis through

Heat shock protein (Hsp90) inhibitors are used as possible cancer treatment agents as several cancer-related proteins become stable by cooperating with Hsp90. Numerous Hsp90 inhibitors reduced tau phosphorylation at different sites of phosphorylation in cells overexpressing

Pin1 (peptidyl-prolyl cis/trans isomerase (PPIase)) bonds to phosphorylated tau on the Thr231-pro site and catalyzes the isomerization of pSer/Thr-pro motifs, to prompt conformational changes in tau. These changes keep back the ability of phosphorylated tau to bind microtubules and inspire microtubule-binding abilities, thereby dephosphorylating tau protein via its phosphatase, the protein phosphatase 2 (PP2A) [135]. It is noteworthy that Pin1 is overexpressed in various types of human cancers and is also an outstanding prognostic marker in different cancers [136–138]. Pin1 is a molecular target for cancer therapeutics, as its inhibition in cancer cells can elicit apoptosis and conquer the renovated phenotype [139–141].

The deficiency of active Pin1 is responsible for unusual tau accumulation whereas Pin1 controls cell cycle and is essential for cell division. Pin1 overexpression increases oncogenesis by different cell signaling pathways. There might have been an antithetical association between

Many proline-directed protein kinases, such as cyclin-dependent kinases (CDKs), mitogenactivated protein kinase (MAPKs), glycogen synthesis kinases (GSKs) and PP2A, govern the

Tau has some roles in signal transduction. There is a high volume of proline residues found in different domains of tau [146] that can interrelate with Src homology 3 (SH3) domain [147]. Tau can also interrelate with the SH3 domain of Src, Fyn and Lck, as revealed by the Glutathione S-transferase (GST) fusion binding assay [148]. The bonding of tau to microtubules has a significant effect on the tau-Fyn interactions, as observed by the biochemical analysis of tau-Fyn binding affinity [149]. Tau could encourage the activity of Src family kinases to measure tau's binding affinity for microtubules, thus resulting in tyrosine phosphorylation. In taxol-stabilized microtubules, Fyn can perform tyrosine phosphorylation without tau; phosphorylation of tubulin increases drastically if tau is added [150]. Hence, the relationship between tau and

non-microtubule proteins might have a possibly noteworthy functional significance.

Initially, tau was isolated from the brain, but shortly after that, tau availability was not limited to neurons. In one of the initial experiments, non-neuronal tau from both primary human monocytes

all of these causes of tau expression level of different cell lines.

circulatory tumor cells mobilization [130].

tauopathies and cancer explained by Pin1 [142].

reversible phosphorylation of tau [143–145].

mutated human tau [131–134].
