**1. Introduction**

Tauopathy is used to summarize all the diseases that the pathogenesis processes are related to tau protein. Tau is one of the most common proteins involved in neurodegenerative diseases. In many tauopathy cases, tau protein seeds and forms intracellular fibrillary tangles on itself, one of the pathological hallmarks of Alzheimer diseases [1]. The tangles formations are believed mostly due to altered posttranslational modifications of tau protein, which detaches from microtubules and binds each other forming aggregates. In several parkinsonism-associated movement disorders, including frontotemporal dementia with parkinsonism-17 (FTDP-17), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), mutations in tau have been identified, and those altered tau are prone to tangles formation [2]. The common

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involvement of tau protein in a range of neurological disorders makes it one of the most studied proteins. However, despite it has been studied for approximately 30 years since tau is coined as the major component of fibrillary tangles, concrete evidence that detail tauopathy in molecular and cellular levels is still limited [3], and most of the pathological data are obtained from studies using postmortem brain. Therefore, how tau protein and its dynamic changes affect the pathogenesis of various neurodegenerative diseases is still a mystery. Many outstanding questions are being stressed, including which posttranslational modifications are critical for it to gain toxicity, does other neurodegenerative diseases involved proteins interact with tau protein, which brain regions or cell types are most susceptive to the toxicity of tau and how the aggregates cause cellular dysfunction, and which forms of tau during the tangle formation process are toxic. In this process, some widely accepted concepts are being challenged. For example, traditionally, it is believed that hyperphosphorylation of tau induces it to detach from microtubule and increases its toxicity, but recent findings suggest some phosphorylations are protective instead [4, 5]. These findings will be emphasized in the following sections. Apparently, more efforts are needed before we can reach a definitive answer for these questions. Some exciting technological advances promise further exploration of some exist questions and more unexplored fields involving tau protein.

with photoactivatable green fluorescent protein (PAGFP), the interactions between tau and tubulins are viewed under total internal reflection fluorescence microscope (TIRF). With such high resolution and relatively short time frame, the live imaging revealed that tau moves on microtubule quickly without direction. In authors' words, it could "hops on and off" to another microtubule in milliseconds and moves along a microtubule with little dwindle time [14, 15]. In another study, under transmission electron microscope (TEM), it was found that tau could promote the microtubule assemble by laterally crosslinking protofilaments [13]. Moreover, tau showed a preference to bind GDP-tubulin over GTP-tubulin, but the reason

Tauopathy

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

Tau is encoded by the gene MAPT (microtubule-associated protein tau), which is located on chromosome 17q21. *MAPT* has 15 exons, and the alternative splicing of the mRNA resulted in six different isoforms. The longest one among these has 441 amino acids, which is often referred as full-length tau. In late 1980s, the basic protein structure of tau was defined [16, 17], and it was realized that the C-terminus of tau protein contains repeated domains responsible for the binding of microtubules [17]. The basic structure and functions of each functional

On the N terminal side (1–150), it has two N-terminal domains. Each has 29 amino acids, one from 45 to 74 and another from 75 to 103. The physiological functions of N terminal domain are largely unknown, and speculations on that including it could play roles in signal transduction as tau could co-immunoprecipitated with phospholipase C gamma through the bind-

The N terminal side is followed by two proline-rich domains, one from 151 to 198 followed by another from 199 to 243. Studies showed that this region interacts with src kinase family members, such as fyn serving for signal transductions [19, 20]. Furthermore, it was shown that tau could interact with beta and gamma actins, which are the subtypes of actins commonly seen in neurons [21]. A panel of different truncated and or mutated tau was generated to test the interactions of it with actins, and it was found that the proline-rich regions were responsible

The proline-rich region is followed by microtubule binding region (244–370), which is composed of four repeated domains and each one of them contains 18 highly conserved amino acids. The microtubule binding region directly binds to tubulin, which plays the most critical role in microtubule interaction [22]. Because the N terminal side does not bind to microtubule and was thought to interact with other proteins, the N terminal side plus the first proline-rich domain is often referred as projection domain of tau. The rest residues, including the second proline-rich domain and microtubule binding domains as well as the C terminal tail, are often

Because the full-length tau has all these N terminal regions (2 N) and C terminal repeats (4R), it is also referred as "2N4R" tau. The rest of other tau isoforms found in brain are the combinations of either lacks one (the second N terminal domain; 1 N) or two N terminal

behind it is not understood [13].

*2.1.2. Tau structures and functions*

region of it are summarized as follow:

ing sites within N terminus [18].

for this interaction [21].

referred as microtubule assembly domain [23].
