Neurology India, Vol. 55, No. 1, January-March, 2007, pp. 11-16
Tau and Tauopathies
Robert M, Mathuranath PS
Department of Neurology, Medical College, Trivandrum, Kerala
Date of Acceptance: 18-Oct-2006
Code Number: ni07007
Tau protein is a neuronal microtubule-associated protein (MAP), which localizes primarily in the axon. It is one of the major and most widely distributed MAPs in the central nervous system. Its biochemistry and molecular pathology is being increasingly studied. Tau is a key component of neurofbrillary tangles in Alzheimer's disease (AD). Disorders with neuronal, oligodendroglial or astrocytic filamentous tau inclusions are now grouped under the common rubric of tauopathies. The discovery of mutations in the tau gene, located on Chromosome 17 and its relationship to frontotemporal dementia with Parkinsonism (FTDP-17) has enhanced the importance of tau protein in cognitive neurology. Aberrant aggregates of tau have been documented in most of the neurodegenerative diseases with filamentous inclusions. The role of cerebrospinal fluid tau in the diagnosis of dementias is being investigated quite extensively. Recently, it has been shown that Abeta immunotherapy leads to the clearance of early tau pathology. It is becoming clearer that understanding tau better will lead to better understanding of many neurodegenerative diseases that may help develop interventional strategies.
Keywords: Alzheimer's disease, humans, tau proteins/metabolism, tau proteins/genetics
Tau protein is a neuronal microtubule-associated protein (MAP), which localizes primarily in the axon. Ever since it was discovered to be a key component of neurofibrillary tangles in Alzheimer's disease (AD), it has been a focus of intense research. That a presumably neuronal protein was also a component of glial lesions in a host of non Alzheimer degenerative diseases was an unexpected finding and offered an entirely new perspective on neurodegenerative disorders. This group of disorders, with not only neuronal, but also oligodendroglial and astrocytic filamentous tau inclusions, has come to be known as the tauopathies. The discovery of mutations in the tau gene located on Chromosome 17 and their relationship to frontotemporal dementias with parkinsonism (FTDP-17) enhanced the importance of tau protein in cognitive neurology. Tau pathology is not restricted to the central nervous system alone. Clusters ("tangles") of paired-helical filaments containing phosphorylated tau is one of the characteristic features of inclusion body myositis. Tau pathology has also been described in myotonic dystrophy. Adult patients with myotonic dystrophy Type 1 (DM1) frequently develop a focal dementia with aging, agreeing with recent studies documenting an abnormal tau-protein expression in the brain tissues of patients with DM1. A possible distinct subclass of peripheral tauopathy has been postulated based on immunoblot studies. This review, however, will be focusing on the role of tau proteins in diseases where cognitive impairment is the predominant manifestation.
Biochemistry and Molecular Pathology of Tau
Microtubules are a major component of neuronal cell processes involved in maintaining the cell shape and axonal transport. It is probable that microtubule-associated proteins (MAPs) play a major role in this function. Tau protein is a neuronal MAP, which localizes primarily in the axon. It is one of the major and most studied MAPs in the central nervous system. The molecular weight is 50,000 to 64,000 Daltons. Tau protein purified from the brain has very little secondary structure. Because of their enormous molecular weights and poor tendency to form highly ordered 3D crystal lattices, they have evaded high-resolution structure determination. They play an important role in the assembly of tubulin monomers into microtubules to constitute the neuronal microtubules network, maintain structure and establish links between microtubules and other cytoskeletal elements or proteins. It has been proposed that, in vivo , tau induces the bundling and stabilization of cellular microtubules, promotes neurite outgrowth and establishes and maintains neuronal cell polarity. What is not clear is how tau's ability to decrease the dynamic instability of microtubules directly relates to these changes in microtubule organization and cell morphology. Tau proteins are expressed predominantly in the axons of the central (CNS) and peripheral (PNS) nervous system neurons, but are barely detectable in CNS astrocytes or oligodendrocytes.
Tau proteins are translated from a single gene located on Chromosome 17 (17q21). It is encoded by a single gene consisting of 16 exons (E) and is over a 100 kilobases. Their expression is developmentally regulated by an alternative splicing mechanism and six different isoforms exist in the human adult brain. The CNS isoforms are generated by alternative mRNA splicing of 11 exons. Alternative splicing of Exons 2 (E2), 3 (E3) and 10 (E10) gives rise to six tau isoforms that range from 352 to 441 amino acids. The isoforms differ in whether they contain three (tau-3L, tau-3S or tau-3: collectively 3R) or four (tau-4L, tau-4S or tau-4: collectively 4R) tubulin-binding domains/repeats (R) of 31 or 32 amino acids each at the C-terminal. They also differ on whether they have two (tau-3L, tau-4L), one (tau-3S, tau-4S) or no (tau-3, tau-4) repeats of 29 amino acids each in the N-terminal portion of the molecule. The terminal repeat sequences are encoded by exons 9, 10, 11 or 12. In the adult human brain, the proportion of 3R-tau to 4R-tau isoforms is about 50% each, but that of tau-3L (or 4L), tau-3S (or 4S), tau-3 (or 4) is about 54%, 37% and 9% respectively. As tau is developmentally regulated, only the shortest tau isoform (tau-3) is expressed in the fetal brain, but all six isoforms are seen in the adult human brain. Tau's interactions with microtubules are mediated by the tubulin-binding domains/repeat at the C-terminal region [Figure - 1].
Tau is a phosphoprotein and its biological activity is regulated by phosphorylation. Tau phosphorylation is developmentally regulated and fetal tau is more highly phosphorylated in the embryonic compared to the adult CNS. The degree of phosphorylation of the six adult tau isoforms decreases with age. The tau phosphorylation sites are clustered in regions flanking the microtubule binding repeats. While phosphorylation at these sites has been reported in normal tau, the phosphorylation negatively regulates microtubule binding. Although the relative importance of individual sites for regulating the binding of tau to microtubules is unclear, phosphorylation of some sites like Serine-262 and 396 has been reported to play a dominant role in reducing the binding of tau to microtubules. Both sites are phosphorylated in fetal tau and they are hyperphosphorylated in all six adult human brain tau isoforms that form paired helical filaments (PHFs) in Alzheimer's disease (AD). Other potentially important phosphate acceptor sites also have been described and it is possible that phosphorylation at multiple phosphate acceptor sites regulates the binding of tau to microtubules. Hyperphosporylation dislodges tau from the microtubule surface, resulting in compromised axonal integrity and accumulation of toxic tau peptides.
A large number of Serine/Threonine protein kinases have been suggested to play a role in regulating tau functions in vivo , however, this aspect of tau biology remains controversial. The major candidate tau kinases include mitogen-activated protein kinase, glycogen synthase kinase 3b, cyclin-dependent kinase 2 (cdk2), cyclin-dependent kinase 5, cAMP-dependent protein kinase, Ca 2+sub /calmodulin-dependent protein kinase II, microtubule-affinity regulating kinase and stress-activated protein kinases. The available evidence points to glycogen synthase kinase-3 being the predominant tau kinase in the brain, although other kinases also phosphorylate tau. Protein phosphatases counterbalance the effects of tau kinases, although their role in vivo is unclear. In vitro experiments showed that inhibition of protein phosphatases by okadaic acid in cultured human neurons was followed by increased tau phosphorylation, decreased tau binding to microtubules, selective destruction of stable microtubules and rapid axonal degeneration.
In addition to phosphorylation, tau is also subject to ubiquitination, nitration, truncation, prolyl isomerization, association with heparan sulfate proteoglycan, glycosylation, glycation and modification by advanced glycation end-products.
In vitro and transgenic animal models have demonstrated that different mutations impair protein function, promote tau fibrilization or perturb tau gene splicing, leading to aberrant and distinct tau aggregates. The mutations in the autosomal dominant tauopathies are of two types - intronic mutations that disrupt the splicing of tau and missense mutations that alter the function of tau. The splicing of tau is tightly regulated so as to maintain the relative proportion of the 3R-tau and 4R-tau isoforms. Also the function of tau is normally tightly regulated through phosphorylation. It is likely that loss of this normal regulation somehow results in tau aggregation, although it should be noted that, in vitro , the mutations also increase tau aggregation itself. Transgenic mice carrying tau mutations have been shown to exhibit behavioral and neuropathological correlates of the disease process. This indicates that tau aggregates are a sign of primary pathology. Tau aggregation without amyloid pathology is sufficient to cause a dementia in mice and in humans and hence is likely to be a pathogenic protein.
Tau mutations have been well characterized in FTDP-17. The mutations described are missense, deletion or silent mutation in the coding region or intronic mutation located close to Exon 10. Coding region mutations are located in the microtubule binding repeat region or close to it. Mutation in Exon 10 affects only 4R isoforms whereas mutation in Exon 9, 12 and 13 affects all isoforms. Coding region mutations reduce the ability of tau to interact with microtubules. Intronic mutation leads to a net increase in 4R isoforms. This leads to filamentous tau pathology. Bird et al described three separate families with frontotemporal dementia, having the same molecular mutation in Exon 10 of tau gene (P301 L). However, differences were seen in clinical features as well as pathologic findings among diseased members of the family, in spite of the same mutation in all. This led to the suggestion that in addition to the mutation, there are other environmental and or genetic factors also influencing the phenotype.
TaupathiesNeurodegenerative diseases with filamentous inclusions can be classified into four groups: (i) tauopathies; (ii) alfa-synucleinopathies; (iii) polyglutamine disorders; and (iv) ubiquitin disorders. Taupathy is the commonest group. All these diseases have in common the presence of aberrant tau aggregates. Tau was first implicated as a protein involved in the pathogenesis of AD when it was discovered to be a major component of the neurofibrillary tangle. Subsequently, the occurrence of neurofibrillary tangles in a wide range of conditions 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 protein Tau in FTDP-17 clearly showed that dysfunction of tau protein causes neurodegeneration and dementia. [Table - 1] gives a list of diseases grouped under taupathies. A substantial overlap of clinical features exists between taupathies, with many cellular lesions encountered in more than one disease. For example, neurofibrillary tangles (NFT) can be seen in AD, FTDP-17, progressive supranuclear palsy (PSP) and neuropil threads can be seen in AD, Cortico basalganglionic degeneration (CBD), FTDP-17 and PSP. Silver impregnation technique usually detects most of the tau inclusions. However, immunohistochemistry with monoclonal antibodies against phosphorylated or nonphosphorylated epitopes of tau are invaluable for the detection of the full extent of tau. Immunohistochemical studies have also revealed tau-positive glial inclusions in both oligodendrocytes and astrocytes in most but not all taupathies. Among the taupathies, the most studied is AD. The analyses of other types of dementia with tau pathology have usually been performed in comparison with AD. Based on electrophoretic pattern, four classes of tau aggregation are presently described. 1) AD and Parkinsonism dementia complex (six tau isoforms); 2) PSP and CBD (the three isoforms with Exon 10 corresponding sequence); 3) Pick's disease (PiD) (the three isoforms without Exon 10) and 4) myotonic dystrophy- the shortest tau isoform.
Tau in ADIt is histopathologically characterized by beta-amyloid-containing plaques, tau-containing neurofibrillary tangles, reduced synaptic density and neuronal loss in selected brain areas. The two degenerative processes that coexist in AD are amyloidosis and tau pathology. Amyloidosis corresponds to the extracellular aggregation of Aβ peptides into amyloid plaques. Tau pathology corresponds to the intraneuronal association of tau proteins into abnormal filaments. Amyloidosis is closely related to etiology and tau pathology is strongly correlated to the clinical expression of the disease. Little is known about the relationship between amyloid-β precursor protein (APP) and tau pathologies, which is one of the missing links in our fully understanding AD. The quantification of Aβ in the different brain areas demonstrates that the spreading pathway of tau pathology remains constant, whatever the cortical distribution of Ab aggregates. In the AD brain, tau is abnormally hyperphosphorylated and is present mostly as PHF. Unlike normal tau, which contains two or three phosphate groups, the cytosolic hyperphosphorylated tau from the AD brain (AD P-tau) contains 5-9 mol of phosphate/mol of the protein. The criteria for AD diagnosis have been revised to include the presence of tau pathology for diagnosing definite AD. Neuropathologically, AD is now defined by the accumulation of two types of insoluble fibrous material - extracellular amyloid protein in the form of senile plaques and intracellular neurofibrillary lesions (NFL) made of abnormally and hyperphosphorylated tau protein. In addition to the neurofibrillary tangles (NFTs), the NFL consists of neuropil threads and dystrophic neurites that are associated with senile plaques. Ultrastructurally NFL contains PHL as a major fibrous component and straight filaments (SF) as a minor component. Both types are formed of the six brain tau isoforms in the hyperphosphorylated and abnormally phosphorylated form. The mechanism of NFL formation in AD is only now beginning to be understood. Tau is first phosphorylated, accumulates in cytoplasm and then dimers form followed by polymers. Polymers form the globular particles. As the concentration of globular particles increases, tau fibrils, PHFs and SFs appear. While globular tau particles were found in nonAD brain, their concentration was lower and there were no filaments. This suggests that the trigger converting a non AD brain to an AD brain is the concentration of globular tau particles. Unlike other taupathies, glial tau pathology is only a minor feature of AD.
Tau in Pick's DiseasePick's disease has distinctive molecular pathologic features involving the deposition of 3R tau protein. However, there may be further tau polymorphisms that remain to be identified, outside the standard sequenced regions, which may have a role in the pathogenesis of PiD. Furthermore, PiD can be distinguished immunohistochemically from other taupaties by the deposition of abnormally hyperphosphorylated tau and by the absence of phosphorylation of tau Ser262, which is specifically recognized by the anti-tau antibody 12-E8.
Tau Protein in Parkinsonian DisordersParkinson's syndrome is now viewed as being caused by diseases characterized by either alpha-synuclein or tau protein deposition although other conditions may also cause degenerative Parkinson's syndromes. For some of the autosomal dominant disorders, mutations have been identified which link the genes encoding these proteins to the disease. Tau deposition has been described in a number of Parkinson's syndrome including PSP, CBD, postencephalitic and posttraumatic Parkinsonism, FTDP-17 and Parkinsonism dementia complex of Guam. In addition, the original parkin mutation family has been shown to have tau neurofibrillary tangle pathology in a PD-like distribution. Tau deposition varies in topography, ultrastructure and protein chemistry in various diseases. Progressive supranuclear palsy is the most extensively studied disease in this group. It is characterized by subcortical pathology of destruction in globus pallidus, subthalamic nucleus and midbrain/pontine reticular formation and homogenous depletion of substantia nigra pars reticulate. The brainstem involvement typically consists of damage to the supranuclear eye-movement control areas: the interstitial nucleus of cajal, the rostral interstitial nucleus of the medial longidudinal fasciculus and the nucleus of Darkschewitsch. Similar propensity for damage of globus pallidus as well as substantia nigra has been demonstrated in CBD, Parkinsonism dementia complex of Guam and postencephalitic Parkinsonism. The clinical observation that many of these diseases affect supranuclear control of gaze further suggests that these diseases, all of which involve tau protein deposition, share similarities in their topographic pathology. The NFT in PSP is made of straight filaments and predominantly 4R tau. In vitro experiments have confirmed that 4R tau forms into straight filament NFTs. It remains unclear if these differences in tau protein deposition reflect a topographically restricted pattern determined by tau gene expression. If true, then one could postulate that cortical neurons when damaged in AD express all six isoforms of the tau gene whereas substantia nigra neurons preferentially express 4R isoforms. Alternatively, the tau protein expression may represent a more fundamental aspect of the disease as well. The isoform(s) of tau expressed in various diseases is shown in [Table - 2]. Interestingly, the morphology of tangles varies with the isoform. Thus when all six isoforms are expressed, as in AD, they are paired helical filaments, while in 4R diseases they are either twisted ribbon filaments (as in PiD) or straight filaments (as in PSP). Additionally, in many of these diseases, tau pathology has been described in glial cells as well. This contrasts with the findings in AD, where tau pathology is largely restricted to the neurons.
Cerebrospinal fluid Tau
The role of cerebrospinal fluid (CSF) tau in the diagnosis of dementias is being studied quite extensively. The most commonly used assay for tau is the ELISA. It has been shown that elevated CSF tau levels are associated with AD pathology and can help discriminate AD from other dementing disorders. Tau is one of the components of the core neuropathologic change in AD that can be measured in CSF and has been frequently studied as a candidate diagnostic biomarker. It has been shown in one of the studies that with the use of a cutoff value of 234 pg/ml, CSF tau demonstrated a sensitivity of 85%, specificity of 84%, positive predictive value of 87% and positive likelihood ratio of 5.3 in distinguishing patients with AD from cognitively normal controls. CSF tau was also useful in distinguishing AD from Frontotemporal dementia and Diffues Lewy body dementia, although the positive likelihood ratio of correctly distinguishing was only 3:1. It has been proposed that CSF tau may also be helpful in differentiating AD from vascular dementia. Recently, phosphorylated tau level in CSF has been found to be useful as a biological marker of AD.,
The source of CSF tau remains unclear but most likely is related to the degeneration of neurofibrillary tangle-laden neurons. The protein has not been well characterized in the CSF and may exist in fragmented forms. A report has indicated that it may require three to five months for elevated CSF tau levels to return to normal after an acute stroke. The rate of clearance of tau from the CSF in patients with neurodegenerative dementia, however, remains unknown. Elevated CSF tau has also been reported in CBD, FTD and in many patients with Creutzfeldt-Jakob disease (CJD). It has been shown that higher amounts of phosphorylated tau in the CSF in sporadic CJD is associated with a rapid progression of the disease to akinetic mutism.
Future DirectionRecently, using a triple transgenic model it has been shown that Aβ immunotherapy leads to the clearance of early tau pathology. The clearance of the tau pathology is mediated by the proteasome and is dependent on the phosphorylation state of tau, as hyperphosphorylated tau aggregates are unaffected by the Aβ antibody treatment. It has been shown that the inhibition of the proteasome led to a bidirectional degradation of Tau. The relation between tau protein and α-synneuclein and amyloid has to be delineated. This will further clarify the role of tau protein in Parkinsonism as well as amyloidosis.
Copyright 2007 - Neurology India
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