**Phosphorylation of Tau Protein Associated as a Protective Mechanism in the Presence of Toxic, C-Terminally Truncated Tau in Alzheimer's Disease**

José Luna-Muñoz, Charles R. Harrington, Claude M. Wischik, Paola Flores-Rodríguez, Jesús Avila, Sergio R. Zamudio, Fidel De la Cruz, Raúl Mena, Marco A. Meraz-Ríos and Benjamin Floran-Garduño

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54228

**1. Introduction**

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Alzheimer's disease (AD) is the most common cause of dementia in the elderly and is char‐ acterized by progressive memory loss leading to a gradual and irreversible deterioration of cognitive function. The neuropathology of AD is characterized by the accumulation of fibril‐ lary lesions in the form of neuritic plaques (NPs, Fig. 1A), neurofibrillary tangles (NFTs, Fig. 1C,D; small arrow) and dystrophic neurites (DNs, Fig. 1; arrows) in neocortex, amygdala and hippocampus [1]. The density of the NPs and NFTs correlate with the degree of demen‐ tia in AD [2]. The accumulation of these lesions does not occur at random; the presence of NFTs is associated with vulnerability of the perforant pathway [3]. NPs are comprised of ex‐ tracellular deposits of amyloid-β peptide fibrils that are associated with DNs of dendritic and axonal origin (Fig. 1A; arrows). Intracellular NFTs selectively kill neurons in specific brain areas. In AD, the distribution of NFTs follows a stereotypical profile arising first in layer II of the entorhinal cortex, hippocampal region and CA1/subicular layer IV of the ento‐ rhinal cortex and then neocortex (mainly in fronto-temporal and parietal areas). This pattern of distribution was first described by Braak and Braak in 1991 [4], and provides the most im‐ portant neuropathological criteria for a definite diagnosis of AD (Fig. 2) [5]. Ultrastructural‐ ly, NFTs are composed of dense accumulations of structures known as paired helical

filaments (PHFs) [6, 7], which are mainly distributed in the perinuclear area of the neuron and in proximal processes (Fig. 1C). Tau protein is the major structural constituent of the PHF subunits [7-9]. Normally, tau protein exists as a family of microtubule-associated pro‐ tein (MAPs) that are found predominantly in axons. Through repeated domains located to‐ ward the carboxy-terminus of the protein, tau provides stability to the microtubule and this process can be regulated through a balance in the phosphorylation/dephosphorylation proc‐ ess of tau protein [10]. In AD, tau protein accumulates as PHFs in the somatodendritic com‐ partment, with consequent destabilization of axonal microtubules. Tau is further posttranslationally in AD, with modifications of ubiquitination [11, 12], glycation [13, 14], glycosylation [15], nitration [16], polyamination [17], hyperphosphorylation [18, 19] and proteolysis [7, 20-24]. The latter two changes occur throughout the tau molecule [25-27].

**Figure 2.** Braak stages of AD neuropathology base on the pattern of neurofibrillary change (NFT, Neuropil threads and plaques dystrofic neurites) [4], Although clinic-pathological correlations were not made, Braak and Braak did speculate that the entorhinal stage (I-II) represents clinically silent periods of the disease with NFT involvement con‐ fined to trans-entorhinal layer pre-alpha. Limbic stages (III/IV) correspond with clinically incipient AD, and NFT involve‐ ment of CA1, and neocortical stages (V/VI) represent fully developed AD, with NFT involvement of all areas of

Phosphorylation of Tau Protein Associated as a Protective Mechanism in the Presence of Toxic…

http://dx.doi.org/10.5772/54228

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Tau protein can be phosphorylated at multiple sites. While there is evidence that phosphor‐ ylation of tau protein promotes its assembly into PHFs [18, 19, 28, 29], the role of phosphory‐ lation in the genesis of PHFs has been limited to the analysis of "mature", intracellular NFTs (NFT-I). By this stage in the disease, tau protein will have been affected by many different pathological processes, several of which may be associated with the hyperphosphorylation

association cortex.

process [25, 26, 30].

**Figure 1.** Neuropathological hallmarks of Alzheimer´s disease. Double labelling with tau antibody (green channel) counterstained with thiazine red (red channel). A) A classical neuritic plaquein which an amyloid fibrillar plaque (Aβ), recognized by thiazine red, is associated with dystrophic neurites (arrows). B). Pre-tangle cells are characterized by dif‐ fuse granular deposits throughout the perinuclear area (small arrow) and proximal processes. C) A neurofibrillary tan‐ gle that is strongly labeled by tau antibody and colocalized with tiazine red. (A,B) projection of 20 and 9 confocal microscopy sections, respectively, each of 1.0 μm thickness.

Phosphorylation of Tau Protein Associated as a Protective Mechanism in the Presence of Toxic… http://dx.doi.org/10.5772/54228 91

filaments (PHFs) [6, 7], which are mainly distributed in the perinuclear area of the neuron and in proximal processes (Fig. 1C). Tau protein is the major structural constituent of the PHF subunits [7-9]. Normally, tau protein exists as a family of microtubule-associated pro‐ tein (MAPs) that are found predominantly in axons. Through repeated domains located to‐ ward the carboxy-terminus of the protein, tau provides stability to the microtubule and this process can be regulated through a balance in the phosphorylation/dephosphorylation proc‐ ess of tau protein [10]. In AD, tau protein accumulates as PHFs in the somatodendritic com‐ partment, with consequent destabilization of axonal microtubules. Tau is further posttranslationally in AD, with modifications of ubiquitination [11, 12], glycation [13, 14], glycosylation [15], nitration [16], polyamination [17], hyperphosphorylation [18, 19] and proteolysis [7, 20-24]. The latter two changes occur throughout the tau molecule [25-27].

90 Understanding Alzheimer's Disease

**Figure 1.** Neuropathological hallmarks of Alzheimer´s disease. Double labelling with tau antibody (green channel) counterstained with thiazine red (red channel). A) A classical neuritic plaquein which an amyloid fibrillar plaque (Aβ), recognized by thiazine red, is associated with dystrophic neurites (arrows). B). Pre-tangle cells are characterized by dif‐ fuse granular deposits throughout the perinuclear area (small arrow) and proximal processes. C) A neurofibrillary tan‐ gle that is strongly labeled by tau antibody and colocalized with tiazine red. (A,B) projection of 20 and 9 confocal

microscopy sections, respectively, each of 1.0 μm thickness.

**Figure 2.** Braak stages of AD neuropathology base on the pattern of neurofibrillary change (NFT, Neuropil threads and plaques dystrofic neurites) [4], Although clinic-pathological correlations were not made, Braak and Braak did speculate that the entorhinal stage (I-II) represents clinically silent periods of the disease with NFT involvement con‐ fined to trans-entorhinal layer pre-alpha. Limbic stages (III/IV) correspond with clinically incipient AD, and NFT involve‐ ment of CA1, and neocortical stages (V/VI) represent fully developed AD, with NFT involvement of all areas of association cortex.

Tau protein can be phosphorylated at multiple sites. While there is evidence that phosphor‐ ylation of tau protein promotes its assembly into PHFs [18, 19, 28, 29], the role of phosphory‐ lation in the genesis of PHFs has been limited to the analysis of "mature", intracellular NFTs (NFT-I). By this stage in the disease, tau protein will have been affected by many different pathological processes, several of which may be associated with the hyperphosphorylation process [25, 26, 30].

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

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