*3.2.4. Other posttranslational modifications*

So far, our understanding of other tau modifications is still limited [82]. Take glycosylation as an example, glycosylation of tau was only found under pathological conditions but not physiological conditions [145], indicating that this type of posttranslational modification has a significant impact toward cell function. However, probed glycosylation sites of tau are limited, and some of the proposed sites might overlap with the known phosphorylation sites, suggesting a potential competition between glycosyltransferase and phosphorylation kinases [145]. The role of glycosylation in tauopathy is unknown [82]. A recent study using *Drosophila* showed that different gene locus of glycosyltransferases might have a different impact on tauopathy [146].

overexpressing a cocktail of different tau isoforms were incubated in wells. This setting could yield tau aggregations inside the cells, and compounds were tested to compare the labeled tau immunofluorescence as the readout [153]. Although this platform was a lower throughput, it overcame the shortages of the first platform in which cytotoxicity was unknown [153, 154]. With this platform, TRx0237 was later selected to be the lead candidate and went into clinical trials [151]. Unfortunately, the drug did not work in phase 3 as it failed to slow cognitive

Tauopathy

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http://dx.doi.org/10.5772/intechopen.73198

Biochemically, the inhibitors could be categorized into two types, covalently and no-covalently tau aggregation inhibitors [156]. However, although they are called "tau" inhibitors, these chemicals are most likely inhibitors to other protein aggregations, and their selectivity is highly questionable [151]. Therefore, a highly selective with high-affinity tau inhibitor is still

The aim of immunotherapy is to clear pathological tau through the immune system [157]. It could be achieved either by applying antibodies that could recognize pathological tau or by vaccination to elicit activation of antigen presenting cells and subsequently the B cells and T cells to clear up pathological tau [157, 158]. Ten years have passed since the publication of the first study on tau immunotherapy [159]. In the study, the researchers showed that inoculation of a tau peptide aa R379-L408, which covers two critical phosphorylation sites S396 and S404 that being phosphorylated in P301L tau mice, could successfully elicit endogenous immune system to generate antibodies against tau, and the animal showed ameliorated symptoms of tauopathy-related behavior and decreased tau aggregation [160]. Multiple different antibodies or vaccines aiming at different tau epitopes have been developed since then, and some

Molecular chaperones play important roles in protein homeostasis. It was reported that inhibiting heat shock protein 90 (Hsp90) could inhibit tau toxicity in tauopathy model [160]. The mechanism behind could involve Hsp90 stabilize p35, the activator of CDK5, GSK3β, and tau, inhibiting their degradation [160, 161]. On the other hand, Hsp70 could facilitate protein ubiquitination and degradation by the proteasome [162]. Overexpression of Hsp70 in cells could decrease tau aggregation in vitro [163]. Recently, it is also suggested that targeting co-

Several traditional Chinese medicines have been suggested that might be useful for treating tauopathies [150, 165]. Huannao Yicong Decotion was shown to improve learning and memory in rat AD model. Immunolabeling showed the expression levels of GSK3β, CDK5, and TTBK1 in CA1 region of the hippocampus are downregulated in the drug treatment groups [150]. Interestingly, it was also suggested that some traditional Chinese medicines, including Huperzine A and Tianma, could induce upregulation of ubiquitin ligases, indicating that they

chaperones of Hsp90 could offer another approach to ameliorate tauopathy [164].

might facilitate protein degradation through ubiquitin-proteasome pathway [166].

decline in AD patients [155].

waiting to be discovered [151, 156].

have entered the early phases of clinical trials [157].

**4.2. Novel treatment approaches**

*4.1.2. Tau immunotherapy*
