Elsevier

Brain Research Reviews

Volume 33, Issue 1, August 2000, Pages 95-130
Brain Research Reviews

Interactive report
Tau protein isoforms, phosphorylation and role in neurodegenerative disorders1

https://doi.org/10.1016/S0165-0173(00)00019-9Get rights and content

Abstract

Tau proteins belong to the family of microtubule-associated proteins. They are mainly expressed in neurons where they play an important role in the assembly of tubulin monomers into microtubules to constitute the neuronal microtubules network. Microtubules are involved in maintaining the cell shape and serve as tracks for axonal transport. Tau proteins also establish some links between microtubules and other cytoskeletal elements or proteins. Tau proteins are translated from a single gene located on chromosome 17. Their expression is developmentally regulated by an alternative splicing mechanism and six different isoforms exist in the human adult brain. Tau proteins are the major constituents of intraneuronal and glial fibrillar lesions described in Alzheimer’s disease and numerous neurodegenerative disorders referred to as ‘tauopathies’. Molecular analysis has revealed that an abnormal phosphorylation might be one of the important events in the process leading to their aggregation. Moreover, a specific set of pathological tau proteins exhibiting a typical biochemical pattern, and a different regional and laminar distribution could characterize each of these disorders. Finally, a direct correlation has been established between the progressive involvement of the neocortical areas and the increasing severity of dementia, suggesting that pathological tau proteins are reliable marker of the neurodegenerative process. The recent discovery of tau gene mutations in frontotemporal dementia with parkinsonism linked to chromosome 17 has reinforced the predominant role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies.

Introduction

Neurodegenerative disorders are characterized by neuronal loss and intraneuronal accumulations of fibrillary materials. Neuropathologists distinguish several intracellular inclusions such as Hirano bodies, Lewy bodies, Pick bodies and neurofibrillary tangles (NFT). Most are argyrophilic and among them, NFT are the most common. They are consistently found in Alzheimer’s disease (AD) [38] amyotrophic lateral sclerosis/parkinsonism–dementia complex of Guam [189], corticobasal degeneration [314], dementia pugilistica and head trauma [80], [194], Down syndrome [197], [276], postencephalitic parkinsonism [126], [198], progressive supranuclear palsy [179], [200], [219], and sometimes in Pick’s disease [196]. They have been described in patients with Gerstmann–Sträussler–Scheinker syndrome [129], [130], Hallervordern–Spatz disease [273], myotonic dystrophy [233], Niemann–Pick disease [267], subacute sclerosing panencephalitis [19], [283] and in other rare conditions. They are also seen in normal aging [18], [388]. Hyperphosphorylated microtubule-associated tau proteins are the main components of the aggregated filaments found in NFT in AD [44], [87], [88], [116], [144], [154], [160], [238], [255]. Similarly, tau immunoreactivity is observed in NFT in most neurodegenerative disorders as well as in aging [34], [56], [57], [59], [113], [132], [321].

Most of our knowledge on tau proteins derives from data obtained from AD cases. In this review, we describe first what is known about tau structure at the gene and protein levels. Second, we review how some mechanisms lead to the pathological aggregation of tau proteins. Then we discuss the involvement of aggregated tau isoforms in several neurodegenerative disorders. Finally, the detection of tau proteins as peripheral markers of AD and their use as a diagnostic tool is evoked.

Section snippets

Tau proteins

Tau proteins belong to the microtubule-associated proteins (MAP) family [410]. They are found in many animal species such as Caenorhabditis elegans [134], [281], Drosophila [65], [217], goldfish [265], bullfrog [423], rodents [237], [249], bovines [185], [186], goat [299], monkeys [299], and human [144], [145].

In human, they are found in neurons (for review, see Refs. [347], [393]), although non-neuronal cells usually have trace amounts. For instance, tau proteins can be expressed in glial

Pathological aggregation of tau proteins

The most obvious pathological event in several neurodegenerative disorders is the aggregation of tau isoforms into intraneuronal filamentous inclusions. Until recently, it was thought that an abnormal phosphorylation of tau proteins was responsible for their aggregation in AD. However, normal tau proteins are also phosphorylated in fetal and adult brain, and they do not aggregate to form filamentous inclusions. Moreover, non-phosphorylated recombinant tau proteins form filamentous structures

Tau isoforms and neurodegenerative disorders

The data described above indicate that the main feature of pathological tau proteins is their aggregation into polymers that constitute the neurofibrillary lesions in AD. In addition, and possibly in association with the aggregation process, specific phosphorylation sites are also present on PHF-tau. However, tau aggregation is not specific to AD, and has also been described in many other neurodegenerative disorders. Interestingly, the tau electrophoretic profile is often disease-specific. In

Tau proteins as peripheral markers

Aggregated tau proteins are the major constituent of NFT, and their biochemical or immunohistochemical detection in the central nervous system of AD patients is well-correlated with the severity of dementia. Therefore, their presence has been investigated in peripheral tissues and biological fluids, in the hope to define an ideal marker of AD that could be used as a diagnostic tool.

Recently, a consensus report on the molecular and biochemical markers of AD has defined the criteria of such a

Animal models

The development of experimental animal models that reproduce the features of neurodegenerative diseases is useful in order to elucidate their pathogenic mechanisms, and to investigate potential therapeutic interventions. In the field of the tauopathies, several models of transgenic mice expressing either the longest tau isoform (4R-tau) or the shortest one (3R-tau) have been recently described [46], [150], [218], [376]. Previous data reported by Götz and colleagues indicated that in transgenic

Concluding remarks

Aggregation of tau proteins in filamentous inclusions is a common feature of numerous neurodegenerative disorders. The laminar and regional distribution of NFT or other inclusions are different among dementing conditions. Likewise, a specific electrophoretic profile of tau proteins could discriminate among these disorders, even though an important overlap has been described for some of them. These different biochemical signatures may be related to the expression of different tau isoforms,

Acknowledgements

We thank Drs C. Bouras, J.P. David, M.B. Delisle, A. Destée, C. DiMenza, D. Gauvreau, P. Giannakopoulos, V. Haroutunian, D. Leys, F. Pasquier, D.P. Perl, H. Petit, Y. Robitaille, M.M. Ruchoux, and P. Vermersch for providing human materials as well as clinical and neuropathological evaluation of the cases, Dr J.H. Morrison for his constant support and interest, and C. Brown, G.I. Lin, B. Wicinski, W.G.M. Janssen and A.P. Leonard for expert technical assistance. This work was supported by the

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    These authors contributed equally to this work.

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