*4.1.2. Tau immunotherapy*

*3.2.4. Other posttranslational modifications*

tauopathy [146].

46 Cognitive Disorders

**4. Tauopathy treatment**

*4.1.1. Tau aggregation inhibitors*

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

To date, no drug targeting tauopathies has entered the market [147]. Over the past two decades, a dozen representative drugs have been pursued in the clinical trials [148], and these drugs represented the major therapeutic approaches in tauopathy treatment, including tau aggregation inhibitors, tau phosphorylation-related kinase inhibitors, microtubule stabilizers, and immunotherapy against tau. However, since these strategies have yet to show significant benefit, new approaches are being probed, among which a scheme to enhancing protein homeostasis is an intriguing approach [147, 149]. Other alternative approaches including

Five treatment approaches mentioned above have been scrutinized in clinical trials, and only microtubule stabilization and immunotherapy against tau are still active tau aggregation inhibitors, and phosphorylation kinase inhibitors, including GSK3β inhibitors and CDK5

The direct inhibition of tau aggregation was the major therapeutic strategy being developed and had entered the clinical trials [151]. The development of tau aggregation inhibitor was initiated in the mid-1990s. The first platform to screen the drugs was reported in 1996 with the discovery of phenothiazine, a relatively potent tau aggregation inhibitor in vitro [152]. In this platform, recombinant PHF core tau fragment was incubated in wells, by reciprocal treating the wells with recombinant full-length tau, the protease-resistant tau aggregation could form [152]. By incubating the wells with compounds, the goal was to identify inhibitors that could effectively disrupt tau aggregation through the high-throughput assay, and phenothiazine showed a strong potency [152]. Unfortunately, phenothiazine was found no efficacy in clinical trials, and it was blamed for its poor absorption and was difficult to be transported into the brain [153]. Years later, a renewed platform was designed [153]. In this platform, fibroblasts

inhibitors, were once favored, but they showed little efficacy in clinical trials [151].

using traditional Chinese medicine are also being pursued [150].

**4.1. Treatment approaches target features of tauopathy**

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