**2.2. Tau pathology**

Tauopathies feature a variety of pathological brain defects, such as neurites dystrophy, cell loss of certain brain regions, and brain shrinkage. The patients show associated symptoms like the decline of cognitive function, memory loss, and defects of the visual system. In the postmortem brains of most affected patients, tau aggregations are commonly found.

#### *2.2.1. Formation of fibrillar tangles*

The fibrillar tangle is the hallmark of tauopathy. The formation process of this aberrant salient could generally be categorized into several stages described as follow:

**Step 1.** Conformational change of tau: Certain sites phosphorylation and other posttranslational modifications or genetic mutation of MAPT rendering tau bind to tubulins with reduced affinity and detaches from microtubules no longer support the microtubule assemble, increasing the free tau protein pool [22, 36].

domains (0 N) or does not contain the second microtubule-binding domain (3R). Therefore, isoforms "1N4R", "0N4R", "2N3R", "1N3R," and "0N3R" are simply denoting the major functional domains of tau [22, 23]. The dominate forms found in human brain are 2N4R and 2N3R. Under physiological conditions, the ratio of isoforms with 4R and 3R is around 1 [24]. While in pathological conditions, the expression of tau isoforms could favor one form, especially 2N4R for most tauopathies. Researchers have long noticed the ratio alterations in disease conditions, but the exact meaning and the reason behind this change are still

Under physiological condition, tau exists in an unfolded state, and 80% of the proteins interact with microtubule in neurons [22, 26]. When tau is not interacting with other proteins, it may curl on its own, and this random curled state is believed important for preventing interactions with other tau proteins by masking the possible interacting sites [27, 28]. The protein itself is bipolar; the N-terminal side is highly negatively charged in normal physiology, while the proline-rich domain and C-terminal end are positively charged, allowing it to interact with the negatively charged C-terminal of tubulins [22, 29]. Various posttranslational modifications could alter its charge. Paired helical filaments (PHFs) are relatively acidic compared to normal full-length tau, which is believed due to the phosphorylation of the amino acid residues [30, 31]. Tau is also very hydrophilic, containing only a small portion of hydrophobic residues [27]. Both the net charge changes and a possible shift from being hydrophilic to hydrophobic are speculated of contributing to its aggregation behavior under pathological conditions [28, 31]. Also, normal tau proteins only exhibit transient secondary structures [27]. Phosphorylation of certain residues may prompt tau to form secondary structures, which is revealed by pseudophosphorylation of all the residues that could be recognized by phosphotau specific antibodies AT8, AT100, and PHF1 and are shown by the structural changes in nuclear magnetic resonance spectroscopy [32]. But how normal tau proteins are transformed

Given that tau may exist in various forms and structures, one shall be mindful not to overstate the possible role of tau based on data derived from truncated/engineered tau, which may only have the N terminal side or the C terminal side [18, 33–35]. Nevertheless, we have gained more understanding of tau and its function from previous works, but better manipulations are needed before we can be comfortable about applying those bench-side results to tauopa-

Tauopathies feature a variety of pathological brain defects, such as neurites dystrophy, cell loss of certain brain regions, and brain shrinkage. The patients show associated symptoms like the decline of cognitive function, memory loss, and defects of the visual system. In the

The fibrillar tangle is the hallmark of tauopathy. The formation process of this aberrant salient

postmortem brains of most affected patients, tau aggregations are commonly found.

could generally be categorized into several stages described as follow:

unknown [25].

36 Cognitive Disorders

to form aggregates remains a mystery.

thies treatment.

**2.2. Tau pathology**

*2.2.1. Formation of fibrillar tangles*

**Step 2.** Oligomer formation: The detached tau proteins form globular oligomers, which are composed of 40 monomers in vitro in the presence of heparin [37]. The mainstream opinion speculates that the detached/modified tau proteins, especially the hyperphosphorylated types, are prone to interact with each other. The phosphorylation on the residues of C-terminal and proline-rich domains neutralizes the charges of the region and reduces the net charge of the protein by which it may contribute to losing the natively unfolded property and prohibit the intramolecular interactions of tau protein [22, 38, 39]. On the other hand, it was reported that the two cysteine residues on tau, cysteine-291 and cysteine-322, play a pivotal role in the tau dimerization [40] because oxidation of the residues may lead to the disulfide bond formation between tau monomers, which potentially seeds for the oligomerization process. This theory is supported by the frequent observation of oxidative stress in tauopathies [41]. Moreover, a recent study showed a compound which could effectively inhibit heparin-induced tau oligomerization was through its interaction with the cysteine residues [37]. However, tau can also form cysteine-independent oligomers [40]. Another recent study adopted tau fragment (aa. 297–391), which is the core of PHF, to study the role of cysteine in the polymerization of tau in the absence of heparin [42]. The results showed that replacement of the cysteine residue or in the presence of reducing agents, the polymerization process was accelerated rather than decelerated [42].

It is noteworthy that most of these studies used anionic agents like heparin to induce the oligomerization of different recombinant tau isoforms or fragments to test the intrinsic properties and the effects of the modifications in vitro. But to what extent could this artificially induced tau oligomerization reflects the real pathological process is questionable. A recent study showed that heparin-induced recombinant tau tangles have little seeding ability in the wild-type mouse. In contrast, tau tangles isolated from patients have a strong seeding ability, and the pathology could spread quickly to different brain regions, shedding lights on the difference between in vitro generated tau tangles and in situ harvested tau tangles [43].

**Step 3.** PHF formation: Tau oligomers may further develop into more complex structures like PHF or straight filaments (SF) [44]. It has been shown that in different tauopathies, the ratio of PHF/SF and their sizes may vary [45, 46]. For example, in Alzheimer's disease, PHF is more commonly observed than SF [45]. On the other hand, in progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and pick's disease (PiD), SF is predominately found [46]. In certain cell types beyond neurons, tau inclusions may exhibit different morphologies and have been given different names to describe their shapes [47]. With the help of Cryo-Electron Microscopy (Cryo-EM), we are now able to identify the structures with high resolutions [48]. It becomes clear that the cores of the filaments are composed of eight β-sheets which requires some hydrophobic interactions between individual peptides; the difference between PHF and SF is due to the lateral interactions between the sheets. However, disulfide bonds formed in the structures remain to be determined [48]. The β-sheets formed in tau oligomers and PHF could be detected with thioflavin T or S staining [28].

#### *2.2.2. Uniqueness of different tauopathies*

As mentioned above, tau inclusions are found in different types of cells in different tauopathies. In Alzheimer's disease (AD), tau inclusions are found in neurons as neurofibrillary tangles (NFT). While in many other tauopathies, the inclusions are found both in neurons and glia cells. Also, the compositions of the inclusions are different. In many tauopathies, the inclusions are mainly composed by 4R tau, while in PiD, 3R tau is the dominant form in the inclusions. In AD, the ratio of 3R/4R is close to 1 albeit the expression favors 2N4R [46]. How the different tau tangles are constructed and what the chemical and physical factors attributing the assembled pattern are still an enigma. Moreover, the locations where the aggregates are first found are also different, following different transmission pathways [46]. Together these indicate that although tau aggregate is the hallmark for all tauopathies, the properties of the inclusions are different and the factors that trigger various pathological changes may also be different [43, 46].

or autolysosomes. These observations imply a significant upregulation of autophagy activities preceded by certain stimuli like cytoskeletal dysregulation or oxidative stress, likely causing the neurons to initiate apoptosis and contribute to neurites dystrophy [55, 56, 62]. Dense lysosome proteases staining results in AD brains also indicate defective degradation of major intracellular protein aggregates. Moreover, in the familial AD, presenilin 1 mutation is one of the most common mutations causing the disease. Traditionally, it is believed the pathogenic mechanism is that the expression of presenilin 1 mutations results in the generation of Amyloid-beta, as this molecule constitutes the active domain of γ-Secretase. However, presenilin 1 also plays a critical role in autophagy that functions as an ER chaperon transporting enzyme subunit critical for lysosome protease activation. Deletion of presenilin 1 could abolish autophagy [56]. All these results support the notion that tau aggregation may cause

Tauopathy

39

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

There are two forms of tauopathy, familial and sporadic. Familial tauopathy is linked with genetic mutations of tau, and sporadic tauopathy is often associated with altered posttranslational modifications. Since the pathogenesis of the two forms is different, so they are dis-

Genetic mutations of tau can cause familial tauopathies, which are commonly found in frontal temporal dementia (FTD), including a range of clinical conditions like Pick's disease, corticobasal dementia, and progressive supranuclear palsy [63, 64]. Mutations of tau were first discovered in the late 1990s in inherited FTD families [65], and it was the first known monogenic mutations that could cause FTD [63, 64]. Epidemiological surveys showed MAPT mutations are responsible for 5–20% FTD cases [63]. Since MAPT is localized to chromosome 17 and the subject showed FTD with parkinsonism syndrome, it was named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) to refer tau mutations-associated FTD [66]. More than a hundred tau mutations have been identified, and not all of them are pathogenic. A detailed mutations list and their associated impacts can be found online at Alzforum. org [67]. Tau mutations are rarely found in Alzheimer's disease (AD) and normally are not considered as a major genetic risk factor for the disease's familial form. But certain mutations could contribute to the pathogenesis of AD, and some found that mutations' pathogenicity

Pathogenic tau mutations typically result in either RNA splicing variation causing the ratio change of 3R/4R or a structure change, which will further affect its binding affinity with

upregulation of autophagy activity.

**3. Pathogenesis of tauopathy**

cussed separately in the sections below.

*3.1.1. Tau mutations in neurodegenerative disorders*

**3.1. Genetic mutations of tau**

has not been integrated yet [67, 68].

*3.1.2. Tauopathy animal models*

#### *2.2.3. Tau degradation*

Normally, the lifetime of tau is short. It was tested in cultured cells that the lifetime of tau is within 24 hours [49, 50]. It is presumed that tau proteolysis is mainly controlled by proteasomes degradation and in vitro studies also support this notion [51]. Since many endogenous proteolytic enzymes can cleave tau proteins, it is likely there is some coordination which may exist among them and also with the proteasomes [51]. Nevertheless, in tau pathology, the turnover time for tau significantly increased. It has been reported that tau phosphorylation inhibits the protein degradation [52], which could explain its pathogenic link. Recently, studies showed autophagy is involved in the digestion of tau, especially for those bulky inclusions that are probably hard to be digested by the proteasome [53]. It was found hyperphosphorylated tau co-localized with LC3 positive vesicles, a critical autophagy adaptor protein, in postmortem brains of different tauopathies [54]. More importantly, many evidence directly shows that both proteasome and autophagy systems are impaired in tauopathies, likely resulting from the assault of tau aggregation [55, 56].

For proteasome-mediated degradation of tau, different studies have shown that proteasome activities are decreased in tauopathies. Both in a tauopathy animal model or AD brains, isolated tau of sarkosyl-insoluble fraction was co-immunoprecipitated with proteasome subunits [57, 58]. Furthermore, incubating proteasome with fibrillar tau or tau oligomers decreased the activities of the proteasome, whereas when it was incubated with monomer tau, the activities were not affected, demonstrating that pathological tau might cause proteasome dysfunction [57]. It was observed that the ubiquitinated protein levels are increased in a tauopathy model, and PHF tau was also ubiquitinated in both animal models and AD brains [57, 59, 60]. While these results demonstrate a nice correlation between proteasome function and tau degradation, whether the turnover of normal or pathological tau depends on proteasome or not is still unclear [61].

For autophagy, it was observed that the dystrophic neuritis of postmortem AD brains contains huge amounts of autophagic-like vacuoles, which are presumably to be autophagosome or autolysosomes. These observations imply a significant upregulation of autophagy activities preceded by certain stimuli like cytoskeletal dysregulation or oxidative stress, likely causing the neurons to initiate apoptosis and contribute to neurites dystrophy [55, 56, 62]. Dense lysosome proteases staining results in AD brains also indicate defective degradation of major intracellular protein aggregates. Moreover, in the familial AD, presenilin 1 mutation is one of the most common mutations causing the disease. Traditionally, it is believed the pathogenic mechanism is that the expression of presenilin 1 mutations results in the generation of Amyloid-beta, as this molecule constitutes the active domain of γ-Secretase. However, presenilin 1 also plays a critical role in autophagy that functions as an ER chaperon transporting enzyme subunit critical for lysosome protease activation. Deletion of presenilin 1 could abolish autophagy [56]. All these results support the notion that tau aggregation may cause upregulation of autophagy activity.
