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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: mathu@sctimst.ac.in 633 J.P. Blass (ed.), Neurochemical Mechanisms in Disease, Advances in Neurobiology 1, DOI 10.1007/978-1-4419-7104-3_19, C 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 . Bitan G, Budson AE, Sperling R, Selkoe DJ, Weiner HL (2003) Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest 112:415–422 Montgomery. 1000:32–39 Zhu X, Raina AK, Rottkamp CA, Aliev G, Perry G, Boux H, Smith MA (2001a) Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer’s. gonadotropin levels in patients with Alzheimer disease. Mayo Clin Proc 76:906–909 Smith MA (1998) Alzheimer disease. Int Rev Neurobiol 42:1–54 Smith MA, Atwood CS, Joseph JA, Perry G (2002a) Predicting