**2. Tau protein**

The cytoskeleton is formed by three types of filaments: microfilaments, intermediate fila‐ ments and microtubules [38]. The cytoskeleton provides a dynamic scaffold to proteins, vesicles and organelles, essential for proper cell function and changes in the state of its poly‐ merization, play an important role in neuronal process such as polarization, axonal trans‐ port, maintenance of neuronal extensions, synaptic plasticity and protein sorting [39]. Tau protein functions as a regulator of microtubule assembly [40]. Tau protein participates in mi‐ crotubule polymerization [41], regulation of axonal diameter [42], regulation of axonal trans‐ port [43], neurogenesis and the establishment of neuronal polarity in development [44]. Furthermore, tau participates in the regulation of signaling pathways by acting as a protein scaffold.

**Figure 3.** Schematic representation of the human *MAPT* (tau) gene, the primary tau transcript and the six CNS tau protein isoforms. The *MAPT* gene is located over 100kb of the long arm of chromosome 17 at position 17q21. It con‐ tains 16 exons, with exon −1 is a part of the promoter (upper panel). The tau primary transcript contains 13 exons. Exons −1 and 14 are transcribed but not translated. Exons 1, 4, 5, 7, 9, 11, 12, 13 are constitutive, and exons 2, 3, and 10 are alternatively spliced, giving rise to six different mRNAs, translated in six different CNS tau isoforms (lower pan‐ el). These isoforms differ by the absence or presence of one or two N-terminal inserts of 29 amino acids encoded by exon 2 (yellow box) and 3 (green box), in combination with either three (R1, R3 and R4) or four (R1–R4) C-terminal repeat-regions (black boxes). The additional microtubule-binding domain is encoded by exon 10 (pink box) (lower panel). Adult tau includes all six tau isoforms, including the largest isoform of 441-amino acids containing all inserts and other isoforms as indicated. The shortest 352-amino acids isoform is the only one found only in fetal brain.

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**Figure 4.** Schematic representation of the functional domains of the largest tau isoform (441 amino acids). The pro‐ jection domain, including an acidic and a proline-rich region, interacts with cytoskeletal elements to determine the spacing between microtubules in axons. The N-terminal part is also involved in signal transduction pathways by inter‐ acting with proteins such as PLC-γ and Src-kinases. The C-terminal part, referred to as the microtubule-binding do‐ main, regulates the rate of microtubules polymerization and is involved in binding with functional proteins such as

protein phosphatase 2A (PP2A) or presenilin 1(PS1).

The gene that encodes for tau consists of 16 exons and is located at the chromosomal locus 17q21 [45]. Through alternative splicing, six tau isoforms are generated in the CNS, varying from 352-441 amino acids in length (Fig. 3). Tau protein can be divided into three domains: an acidic region in the N-terminal projection, a proline-rich domain and a microtubule-bind‐ ing domain (Fig. 4) [46]. The alternative transcription of exons 2, 3 and 10 modifies the pres‐ ence of repeats in the N-terminus of tau (0-2N) and the number of microtubule-binding repeat domains (3R or 4R), respectively.

### **3. Tau protein metabolism**

The *MAPT* (tau) gene is transcribed mainly in neurons and a promoter that confers neu‐ ronal specificity has been described [47]. It has been reported that the presence of a tau promoter lacking neuronal specificity might account for the expression of tau in periph‐ eral tissue [48]. In both cases, sequences containing binding sites for transcription factors AP2 and Sp1 were described. Whereas tau protein synthesis is unaffected by microtu‐ bule polymerization or depolymerization, degradation of tau is stimulated by microtu‐ bule depolymerization [49].

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Another post-translational modification found in AD is the proteolytic truncation of the Cterminal portion of tau protein [7, 20, 21, 23, 31, 32]. It has been proposed that such trunca‐

In recent years, evidence from both *in vitro* and *in vivo* studies[36, 37], suggests that hyper‐ phosphorylation of tau protein has a protective role. In this review, we analyze the protec‐ tive effects of hyperphosphorylated species of tau protein and their relationship to toxicity,

The cytoskeleton is formed by three types of filaments: microfilaments, intermediate fila‐ ments and microtubules [38]. The cytoskeleton provides a dynamic scaffold to proteins, vesicles and organelles, essential for proper cell function and changes in the state of its poly‐ merization, play an important role in neuronal process such as polarization, axonal trans‐ port, maintenance of neuronal extensions, synaptic plasticity and protein sorting [39]. Tau protein functions as a regulator of microtubule assembly [40]. Tau protein participates in mi‐ crotubule polymerization [41], regulation of axonal diameter [42], regulation of axonal trans‐ port [43], neurogenesis and the establishment of neuronal polarity in development [44]. Furthermore, tau participates in the regulation of signaling pathways by acting as a protein

The gene that encodes for tau consists of 16 exons and is located at the chromosomal locus 17q21 [45]. Through alternative splicing, six tau isoforms are generated in the CNS, varying from 352-441 amino acids in length (Fig. 3). Tau protein can be divided into three domains: an acidic region in the N-terminal projection, a proline-rich domain and a microtubule-bind‐ ing domain (Fig. 4) [46]. The alternative transcription of exons 2, 3 and 10 modifies the pres‐ ence of repeats in the N-terminus of tau (0-2N) and the number of microtubule-binding

The *MAPT* (tau) gene is transcribed mainly in neurons and a promoter that confers neu‐ ronal specificity has been described [47]. It has been reported that the presence of a tau promoter lacking neuronal specificity might account for the expression of tau in periph‐ eral tissue [48]. In both cases, sequences containing binding sites for transcription factors AP2 and Sp1 were described. Whereas tau protein synthesis is unaffected by microtu‐ bule polymerization or depolymerization, degradation of tau is stimulated by microtu‐

tion unlike hyperphosphorylation, favours polymerisation of tau [33, 34][35].

and the participation of truncated species of tau in the formation of PHFs.

**2. Tau protein**

92 Understanding Alzheimer's Disease

scaffold.

repeat domains (3R or 4R), respectively.

**3. Tau protein metabolism**

bule depolymerization [49].

**Figure 3.** Schematic representation of the human *MAPT* (tau) gene, the primary tau transcript and the six CNS tau protein isoforms. The *MAPT* gene is located over 100kb of the long arm of chromosome 17 at position 17q21. It con‐ tains 16 exons, with exon −1 is a part of the promoter (upper panel). The tau primary transcript contains 13 exons. Exons −1 and 14 are transcribed but not translated. Exons 1, 4, 5, 7, 9, 11, 12, 13 are constitutive, and exons 2, 3, and 10 are alternatively spliced, giving rise to six different mRNAs, translated in six different CNS tau isoforms (lower pan‐ el). These isoforms differ by the absence or presence of one or two N-terminal inserts of 29 amino acids encoded by exon 2 (yellow box) and 3 (green box), in combination with either three (R1, R3 and R4) or four (R1–R4) C-terminal repeat-regions (black boxes). The additional microtubule-binding domain is encoded by exon 10 (pink box) (lower panel). Adult tau includes all six tau isoforms, including the largest isoform of 441-amino acids containing all inserts and other isoforms as indicated. The shortest 352-amino acids isoform is the only one found only in fetal brain.

**Figure 4.** Schematic representation of the functional domains of the largest tau isoform (441 amino acids). The pro‐ jection domain, including an acidic and a proline-rich region, interacts with cytoskeletal elements to determine the spacing between microtubules in axons. The N-terminal part is also involved in signal transduction pathways by inter‐ acting with proteins such as PLC-γ and Src-kinases. The C-terminal part, referred to as the microtubule-binding do‐ main, regulates the rate of microtubules polymerization and is involved in binding with functional proteins such as protein phosphatase 2A (PP2A) or presenilin 1(PS1).

It is technically difficult to determine the half life of the different tau isoforms and several factors may regulate tau degradation such as, for example, the extent of phosphorylation and acetylation of tau (see below). The half life of tau decreases in rats by neonatal period P20 and there is less demand for tau in non-dividing, mature neurons [50].

of tau into insoluble forms may help to account for the different dementias in which both

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**Figure 5.** tau protein, which forms part of a microtubule. The microtubule helps transpot nutrients and other impor‐ tant substances from one part of the nerve cells to another. Axon are long threadlike extensions that conduct nerve impulses away from the nerve cells; dendrites are short branched threadlike extensions that conduct nerve impulses toward the verve cell body. In Alzheimer´s disease the tau protein is abnormal and the microtubule structures col‐

In 1988, Wischik et al, [7, 22] identified tau protein as the major constituent of Pronase-resist‐ ant PHFs and tau was characterized by a specific C-terminal truncation of the protein at Glu-391. This truncation is identified by the monoclonal antibody (mAb) 423 [23, 31], and the acid-reversible occlusion of the intact core tau domain. PHFs are labeled by the fluores‐ cent dye, thiazin-red, a dye which can be used to differentiate between amorphous and fi‐ brillar states of tau and amyloid proteins in AD. The minimum tau fragment in the PHF [20, 24] corresponds to the tandem repeat region in the C-terminal domain of tau protein, a spe‐ cies having a molecular weight of 12.5 kDa. Characteristically, this fragment is highly stable to proteolysis, insoluble and toxic and is referred to as PHF-core tau [22, 57, 58]. PHF-core

**5. C-terminal truncation of tau protein in AD**

clinical symptoms and age of onset differ.

lapse.

**5.1. PHF-core concept**

Two main mechanisms for tau protein degradation have been documented: 1) the proteaso‐ mal ubiquitin pathway and 2) the lysosomal autophagic pathway. Proteasomal degradation of tau protein has been described by 20S proteasomal processing [51], although there have also been reports suggesting that tau is not normally degraded by the proteasome [52]. Tau, modified by phosphorylation, can be ubiquitinated by the CHIP-hsc70 complex and degrad‐ ed by the proteasome [53]. Furthermore, acetylation of tau can regulate its proteasomal deg‐ radation by modifying those lysine residues needed for ubiquitination. In this way, acetylation of tau inhibits its degradation through a competition between ubiquitination and acetylation [54].

On the other hand, tau may get processed through a lysosomal autophagic mechanism. It has been reported that tau can be degraded by lysosomal proteases [55] and, more recently, it was shown that tau fragmentation and clearance can occur by lysosomal processing [56].

Tau protein is a microtubule-associated protein. It's mostly abundant in neurons in the Cen‐ tral Nervous System (CNS). The main function of Tau protein is to interact with tubulin to stabilize microtubules and promote tubulin assembly into microtubules. Tau protein con‐ trols microtubule stability in two different ways : isoforms and phosphorylation.

Normally, the tau protein is very important, as it manages the transport of materials within soma and other cellular regions through the myelin sheaths. Once it spotted something sus‐ picious or irrelevant, it stops the information sending process automatically. However, in Alzheimer's disease, the tau proteins started to perform uncommon reaction, where it trans‐ mitting the information to the brain simultaneously, regardless of its validity.

Once the above problem happening, it causes the brain overloading with information and might lead to inflammation, clumps or tangles, which kill most of the brain cells (Fig. 5).
