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Tau and Tauopathies
R. Mathew, G. Srinivas, and P.S. Mathuranath
Abstract Tau protein is a neuronal microtubule associated protein, which localizes
primarily in the axon. It plays a major role in promoting microtubule assembly,
stabilizing microtubules and maintaining the normal morphology of the neurons.
Structurally tau is a heterogenous molecule due to several posttranslational modifi-
cations. Tauopathies are a group of disorders that are the consequence of abnormal
tau phosphorylation, abnormal levels of tau, abnormal tau splicing, or mutations
in the tau gene. These disorders are characterized not only by neuronal, but
also oligodendroglial and astrocytic filamentous tau inclusions. Tauopathies are
the commonest among the neurodegerative diseases with filamentous inclusions.
Tauopathies include frontotemporal dementia, Parkinsonism plus syndromes, neuro-
muscular disorders, and certain genetic and metabolic syndromes. The occurrence of
neurofibrillary tangles in a wide range of conditions, including Alzheimer’s disease,
initially led to the suggestion that tau deposition may be an incidental nonspecific
finding associated with cell death or cellular dysfunction. Later the discovery of
close to 20 different mutations in tau in frontotemporal dementia with Parkinsonism
linked to chromosome-17 (FTDP-17) clearly showed that dysfunction of tau protein
causes neurodegeneration and dementia. Among the tauopathies, the most studied is
Alzheimer’s disease. Frontotemporal dementia, progressive supranuclear palsy, and
corticobasal ganglionic degeneration are some of the other common tauopathies

that have been extensively studied. Overlap of clinical and histopathological fea-
tures occurs between various tauopathies. The role of CSF tau in the diagnosis of
dementias is under investigation. The measures of total tau as well as species of
phospho-tau detected by antibodies in CSF correlates best with a diagnosis of AD.
The discovery of a tau transgenic mouse model has paved the way for testing various
therapeutic models for targeting tau.
P.S. Mathuranath (B)
Cognition and Behavioural Neurology Section (CBNC), Department of Neurology, Sree Chitra
Tirunal Institute for Medical Sciences and Technology (SCTIMST), Thiruvananthapuram 695011,
Kerala, India
e-mail:
633
J.P. Blass (ed.), Neurochemical Mechanisms in Disease,
Advances in Neurobiology 1, DOI 10.1007/978-1-4419-7104-3_19,
C
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Springer Science+Business Media, LLC 2011
634 Mathew et al.
Keywords Tau · Tauopathy · Alzheimer’s disease · Frontotemporal dementia ·
Parkinsonism · Exon · Microtubule · Structural · Protein · Phosphorylation
Contents
1 Introduction 634
2 Biochemistry and Molecular Biology of Tau
635
2.1 Tau Gene
635
2.2 Structure, Cellular Localization, and Putative Functions of Tau Protein
636
2.3 Posttranslational Modifications of Tau
640

2.4 Turnover of Tau Protein
645
3 Tauopathies
646
3.1 Frontotemporal Dementia
647
3.2 Alzheimer’s Disease
649
3.3 Progressive Supranuclear Palsy
656
3.4 Corticobasalganglionic Degeneration
657
3.5 Multiple System Atrophy (MSA)
658
4 Future Direction
659
4.1 Tau as a Diagnostic Marker
659
4.2 Tau as a Therapeutic Target
660
4.3 Research Avenues
660
References
661
1 Introduction
Tau protein is a neuronal microtubule associated protein (MAP) that localizes pri-
marily in the axon (Leger et al., 1994). It is one of the major and most-studied MAPs
in the central nervous system (Alonso et al., 2001). Tau has been recognized to play
major roles in promoting microtubule assembly, stabilizing microtubules and main-
taining the normal morphology of the neurons. Tau has been the focus of intense

research for more than a decade after it was discovered to be a key component of
neurofibrillary tangles in Alzheimer’s disease (AD).
Tauopathies are a group of disorders that are the consequence of abnormal tau
phosphorylation, abnormal levels of tau, abnormal tau splicing, or mutations in the
tau gene. These disorders are characterized not only by neuronal, but also oligo-
dendroglial and astrocytic filamentous tau inclusions (Avila, 2000; Ulloa et al.,
1994).
In some tauopathies such as AD the tau pathology is associated with other cere-
bral changes (Avila et al., 2004). That a presumably neuronal protein was also a
component of glial lesions in a host of non-Alzheimer degenerative diseases was
unexpected and offered an entirely new perspective on neurodegenerative disorders.
The discovery of mutations in the tau gene on chromosome 17 in frontotempo-
ral dementias with Parkinsonism (FTDP-17) added to the importance of tauprotein
in cognitive neuroscience (Dickson, 1999). Tau pathology is not restricted to the