**4. Tau in chemotherapy**

and U297 lymphoma cells were studied, and both total and phosphor-specific tau were observed [151]. Several other experiments also exposed the availability of tau in different cell lines and tissues. Some of those experiments were very brief and only a northern or western blot was done to show the availability of tau mRNA or protein, respectively, from the liver and kidney of mice and other tissues of rats [126, 127]. Some of the experiments detected multiple tau isoforms and pointed out the correspondence between non-neuronal tau and neuronal tau [152], whereas others showed the microtubule-binding properties of tau from hepatoma and fibroblast cells [153]. From these experiments, it is clear that tau from both neuronal and non-neuronal cells might show similar properties. In one experiment using several human cell types including HeLa cells, lymphocytes and non-transformed skin fibroblasts, tau was not only observed in the nucleoli of nondividing cells but also observed in higher 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

Tau might work as a possible modulator of drug resistance. Microtubule-targeting drug estramustine-resistant [154] E4 cells expressed a massive amount of tau at both the mRNA and the protein levels, unlike DU145 cells [13]. This experiment exposed significance of the incidence of tau in non-neuronal cells; this might have a connection with signal transduction and tau's microtubule-binding properties. The expression of tau is considerably diverse in cases of residual disease or in those with a pathological complete response (pCR) in patients with breast cancer undergoing chemotherapy by the microtubule-depolymerizing drug, paclitaxel. The residual disease group expressed more tau than the pCR group [14]. siRNA knockdown tau is more vulnerable to paclitaxel treatment than the wild-type tau in case of breast cancer cells [14, 26]. A nearly similar report was published, about the relationship between tau and

As hyperphosphorylation of tau leads to AD, and tumor suppressor pRB protein as well as different cell cycle activators like Cdk4, Cdk2, cyclin D, cyclin B and PCNA are also present in the neurons of patients with AD, there might be an insinuation of the re-commencement of the cell cycle, which could be a mechanism of neurodegeneration [20]. In case of other neurodegenerative disorders that might be caused by tau protein including FTDP-17, PSP and CBD, these cell cycle activators were found [155]. Tau phosphorylation occurred at disease-relevant sites of primary rat neurons after insertion of oncogenes [156]. This is suggested by the fact that abnormal tau-related diseases are linked to cell cycle markers in several diseases, including cancer. The aged control mouse does not express the increase of the cell cycle marker, PCNA and cyclin D; this was responsible for the sign of neurodegeneration [157]. For normal human tau-expressing transgenic mice, increased tau phosphorylation occurred, along with insoluble tau being found in the brains of aged mice [157]. This suggests that irregular cell cycle re-entry might explain the presence of tau. CNS tissue from the *Drosophila* model used to study neurodegenerative diseases exhibited an increase in the cell cycle markers, PCNA and phosphor-histone 3, as well as neuronal loss [158], which is also evidence that tau drives cell cycle re-entry. The visible neuronal loss in *Drosophila* for either wild-type or mutant tau was overturned by hindering the mammalian target-of-rapamycin (mTOR) pathway, as well as by obstructing the cell cycle in different ways [158]. This finding also links cell signaling with tau-activated neurodegeneration. There are further associations between AD and cancer, as high levels of cancer-related proteins like Fos, Jun and BRCA1 are found in AD [21, 22].

in fast-dividing cells, which might have an effect on cancer.

104 Cognitive Disorders

paclitaxel resistance in case of gastric cancer [15].

Folic acid (also called folate or vitamin B9) intensities can plummet due to the influence of certain chemotherapy drugs used for cancer treatment. Chemotherapy-initiated folic acid insufficiency prompts abnormal tau phosphorylation, which can lead to different tauopathies like AD [164].

Paclitaxel is one of the most important chemotherapy drugs for cancer treatment; it binds to beta-tubulin in the same place as tau protein. Cancer cells with a low tau expression show a higher sensitivity to paclitaxel, whereas those with a high expression of tau display a resistance to paclitaxel-related chemotherapy. In case of breast cancer, low tau expressions are favorable for paclitaxel administration during chemotherapy.

Tau-negative expression can be used to select gastric cancer patients for paclitaxel treatment, on the basis whether paclitaxel is more functional in cells with low or no tau expression [165]. Tau expression analysis should be considered for taxane-based chemotherapy for some types of bladder cancer, as tumors with low tau expression display an enhanced response to chemotherapy [166]. Tau expression is associated with the sensitivity of breast cancer cells to taxanebased chemotherapy; patients with low or no tau expression should be more responsive to chemotherapy than patients with high expression of tau [24, 167]. Tau expression is also a potential marker for response to chemotherapy and subsequent survival in lung, ovarian, pancreatic and prostate cancer.

Nowadays, some drugs used for the treatment of cancer are also used for the treatment of different neurological disorders like Parkinson's disease and AD. Nilotinib is an FDA-approved protein tyrosine kinase inhibitor (TKI), which is used for the treatment of chronic myeloid leukemia. It also targets AD, which produces neuroinflammation and misfolded proteins, to ultimately reduce cognitive damage. In Parkinson's disease, nilotinib triggers autophagy to remove hyperphosphorylated tau from the brain before they accumulate as plaques [168, 169].
