**3. Pathogenesis of tauopathy**

*2.2.2. Uniqueness of different tauopathies*

38 Cognitive Disorders

also be different [43, 46].

from the assault of tau aggregation [55, 56].

*2.2.3. Tau degradation*

unclear [61].

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

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

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

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 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 discussed separately in the sections below.
