Review Article

Tau and tauopathies

M. Robert, P. S. Mathuranath* Department of Neurology, Medical College, Trivandrum, Kerala and *Sree Chitra Thirunal Institute for Medical Sciences and Technol­ ogy, Trivandrum, Kerala - 695011, India

Tau protein is a neuronal microtubule-associated protein Chromosome 17 and their relationship to frontotemporal (MAP), which localizes primarily in the axon. It is one of the with (FTDP-17) enhanced the [1] major and most widely distributed MAPs in the central importance of tau protein in cognitive neurology. Tau nervous system. Its biochemistry and molecular pathology pathology is not restricted to the central nervous system is being increasingly studied. Tau is a key component of alone. Clusters (“tangles”) of paired-helical filaments neurofbrillary tangles in Alzheimer’s (AD). containing phosphorylated tau is one of the characteristic [2] Disorders with neuronal, oligodendroglial or astrocytic features of inclusion body myositis. Tau pathology has [3] filamentous tau inclusions are now grouped under the also been described in . Adult common rubric of tauopathies. The discovery of mutations patients with myotonic dystrophy Type 1 (DM1) frequently in the tau gene, located on Chromosome 17 and its develop a focal with aging, agreeing with recent relationship to with Parkinsonism studies documenting an abnormal tau-protein expression [4] (FTDP-17) has enhanced the importance of tau protein in in the brain.com). tissues of patients with DM1. A possible cognitive neurology. Aberrant aggregates of tau have been distinct subclass of peripheral tauopathy has been [5] documented in most of the neurodegenerative postulated based on immunoblot studies. This review, with filamentous inclusions. The role of cerebrospinal fluid however, will be focusing on the role of tau proteins in tau in the diagnosis of dementias is being investigated diseases where cognitive impairment is the predominant quite extensively. Recently, it has been shown that Abeta manifestation. immunotherapy leads to the clearance of early tau pathol- ogy. It is becoming clearer that understanding tau better.medknow Biochemistry and Molecular Pathology of Tau will lead to better understanding of many neurodegenerative diseases that may help develop inter- Microtubules are a major component of neuronal cell ventional strategies. (www processes involved in maintaining the cell shape and axonal transport.[6] It is probable that microtubule- Key words: Alzheimer’s disease, humans, tau proteins/ associated proteins (MAPs) play a major role in this metabolism, tauThis proteins/genetics PDFa site is hosted available by forMedknow freefunction. download Publications Tau protein fromis a neuronal MAP, which localizes primarily in the axon.[7] It is one of the major and most studied MAPs in the central nervous system.[8] The molecular weight is 50,000 to 64,000 Daltons. Tau protein Tau protein is a neuronal microtubule-associated protein purified from the brain has very little secondary (MAP), which localizes primarily in the axon. Ever since structure.[9] Because of their enormous molecular weights it was discovered to be a key component of neurofibrillary and poor tendency to form highly ordered 3D crystal tangles in Alzheimer’s disease (AD), it has been a focus of lattices, they have evaded high-resolution structure intense research. That a presumably neuronal protein was determination.[10] They play an important role in the also a component of glial lesions in a host of non Alzheimer assembly of tubulin monomers into microtubules to degenerative diseases was an unexpected finding and constitute the neuronal microtubules network, maintain offered an entirely new perspective on neurodegenerative structure[8] and establish links between microtubules and disorders. This group of disorders, with not only neuronal, other cytoskeletal elements or proteins.[6] It has been but also oligodendroglial and astrocytic filamentous tau proposed that, in vivo, tau induces the bundling and inclusions, has come to be known as the tauopathies. The stabilization of cellular microtubules, promotes neurite discovery of mutations in the tau gene located on outgrowth and establishes and maintains neuronal cell

M. Robert Department of Neurology, Medical College, Trivandrum, Kerala - 695011, India. E-mail: [email protected]

Neurology India | January-March 2007 | Vol 55 | Issue 1 11 CMYK11 Robert et al.: Tau and tauopathies polarity. What is not clear is how tau’s ability to decrease developmentally regulated and fetal tau is more highly the dynamic instability of microtubules directly relates to phosphorylated in the embryonic compared to the adult these changes in microtubule organization and cell CNS. The degree of phosphorylation of the six adult tau morphology.[7] Tau proteins are expressed predominantly isoforms decreases with age. The tau phosphorylation in the axons of the central (CNS) and peripheral (PNS) sites are clustered in regions flanking the microtubule nervous system neurons, but are barely detectable in CNS binding repeats. While phosphorylation at these sites has astrocytes or oligodendrocytes.[11] been reported in normal tau, the phosphorylation Tau proteins are translated from a single gene located negatively regulates microtubule binding. Although the on Chromosome 17 (17q21). It is encoded by a single relative importance of individual sites for regulating the gene consisting of 16 exons (E) and is over a 100 binding of tau to microtubules is unclear, phosphorylation kilobases.[9] Their expression is developmentally regulated of some sites like Serine-262 and 396 has been reported by an alternative splicing mechanism and six different to play a dominant role in reducing the binding of tau to isoforms exist in the human adult brain.[6] The CNS microtubules. Both sites are phosphorylated in fetal tau isoforms are generated by alternative mRNA splicing of and they are hyperphosphorylated in all six adult human 11 exons. Alternative splicing of Exons 2 (E2), 3 (E3) and brain tau isoforms that form paired helical filaments (PHFs) 10 (E10) gives rise to six tau isoforms that range from 352 in Alzheimer’s disease (AD). Other potentially important to 441 amino acids. The isoforms differ in whether they phosphate acceptor sites also have been described and it contain three (tau-3L, tau-3S or tau-3: collectively 3R) or is possible that phosphorylation at multiple phosphate four (tau-4L, tau-4S or tau-4: collectively 4R) tubulin- acceptor sites regulates the binding of tau to binding domains/repeats (R) of 31 or 32 amino acids each microtubules.[11] Hyperphosporylation dislodges tau from at the C-terminal. They also differ on whether they have the microtubule surface, resulting in compromised axonal two (tau-3L, tau-4L), one (tau-3S, tau-4S) or no (tau-3, integrity and accumulation of toxic tau peptides.[13] tau-4) repeats of 29 amino acids each in the N-terminal A large number of Serine/Threonine protein kinases portion of the molecule. The terminal repeat sequences have been suggested to play a role in regulating tau are encoded by exons 9, 10, 11 or 12.[11] In the adult human functions in vivo, however, this aspect of tau biology brain, the proportion of 3R-tau to 4R-tau isoforms is about remains controversial..com). The major candidate tau kinases 50% each, but that of tau-3L (or 4L), tau-3S (or 4S), tau-3 include mitogen-activated protein kinase, glycogen (or 4) is about 54%, 37% and 9% respectively. As tau is synthase kinase 3β, cyclin-dependent kinase 2 (cdk2), developmentally regulated, only the shortest tau isoform cyclin-dependent kinase 5, cAMP-dependent protein (tau-3) is expressed in the fetal brain, but all six isoforms kinase, Ca2+/calmodulin-dependent protein kinase II, are seen in the adult human brain.[11] Tau’s interactions microtubule-affinity regulating kinase and stress-activated with microtubules are mediated by the tubulin-binding.medknow protein kinases.[11] The available evidence points to domains/repeat at the C-terminal region [Figure 1]. glycogen synthase kinase-3 being the predominant tau kinase in the brain, although other kinases also T au phosphorylation (www phosphorylate tau.[14] Protein phosphatases Tau is a phosphoprotein and its biological activity is counterbalance the effects of tau kinases, although their regulated by phosphorylation.[12] Tau phosphorylation is role in vivo is unclear. In vitro experiments showed that This PDFa site is hosted available by forMedknow freeinhibition download Publications of protein fromphosphatases 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.[11] 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.[15]

Tau Mutation

In vitro and transgenic animal models have demonstrated that different mutations impair protein function, promote tau fibrilization or perturb tau gene Figure 1: Schematic representation of the human brain tau isoforms. splicing, leading to aberrant and distinct tau aggregates.[16] Alternatively spliced exons (2, 3 and 10) are shown in white bands. The tandem repeats (3 or 4) are shown in black bars. The number of amino The mutations in the autosomal dominant tauopathies acids is indicated on the right. (Modified from Spillantini et al[17]) are of two types - intronic mutations that disrupt the

12 Neurology India | January-March 2007 | Vol 55 | Issue 1 12 CMYK Robert et al.: Tau and tauopathies splicing of tau and missense mutations that alter the Table 1: Neurodegenerative disorders with abundant function of tau. The splicing of tau is tightly regulated so filamentous tau inclusions (modified from Tolnay and as to maintain the relative proportion of the 3R-tau and Probst, 1999[3] and Trojanowski and Lee, 2002[11]) 4R-tau isoforms. Also the function of tau is normally Dementia syndromes tightly regulated through phosphorylation. It is likely that Alzheimer’s disease Tangle only dementia loss of this normal regulation somehow results in tau Argyrophilic grain disease aggregation, although it should be noted that, in vitro, Pick’s disease the mutations also increase tau aggregation itself. Presenile dementia with tangles and calcification Transgenic mice carrying tau mutations have been shown Progressive subcortical gliosis Familial frontotemporal dementia and Parkinsonism linked to to exhibit behavioral and neuropathological correlates of chromosome 17 the disease process. This indicates that tau aggregates are Subacute sclerosing panencephalitis a sign of primary pathology. Tau aggregation without Gerstmann-straussler-scheinker disease with tangles amyloid pathology is sufficient to cause a dementia in Prion protein amyloid angiopathy Parkinsonism plus syndromes mice and in humans and hence is likely to be a pathogenic Corticobasal degeneration [14] protein. Progressive supranuclear palsy Tau mutations have been well characterized in FTDP- Multiple system atrophy 17. The mutations described are missense, deletion or Postencephalitic Parkinsonism Dementia pugilistica silent mutation in the coding region or intronic mutation Neuromuscular disorders located close to Exon 10. Coding region mutations are Amyotrophic lateral sclerosis with Parkinsonism located in the microtubule binding repeat region or close Dementia complex of Guam to it. Mutation in Exon 10 affects only 4R isoforms whereas Non-Guamanian motor neuron disease with neurofibrillary tangles mutation in Exon 9, 12 and 13 affects all isoforms. Coding Myotonic dystrophy region mutations reduce the ability of tau to interact with Inclusion body myositis microtubules. Intronic mutation leads to a net increase in Genetic/metabolic disorders 4R isoforms. This leads to filamentous tau pathology.[17] Down’s syndrome Hallervorden-spatz.com). disease Bird et al described three separate families with Niemann-pick disease type C 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 supranuclear palsy (PSP) and neuropil threads can be pathologic findings among diseased members of the seen in AD, Cortico basalganglionic degeneration (CBD), family, in spite of the same mutation in all. This led to FTDP-17 and PSP. Silver impregnation technique usually the suggestion that in addition to the mutation, there.medknow are detects most of the tau inclusions. However, other environmental and or genetic factors also influencing immunohistochemistry with monoclonal antibodies the phenotype.[18] against phosphorylated or nonphosphorylated epitopes Taupathies (www of tau are invaluable for the detection of the full extent of tau. Immunohistochemical studies have also revealed tau- Neurodegenerative diseases with filamentous inclusions positive glial inclusions in both oligodendrocytes and can be classifiedThis into four PDF agroups: site is (i) hosted tauopathies;available by (ii) forMedknowalfa- freeastrocytes download Publications in most but from not all taupathies.[3] Among the synucleinopathies; (iii) polyglutamine disorders; and (iv) taupathies, the most studied is AD. The analyses of other ubiquitin disorders. Taupathy is the commonest group.[3] types of dementia with tau pathology have usually been All these diseases have in common the presence of aberrant performed in comparison with AD.[17] Based on tau aggregates. Tau was first implicated as a protein electrophoretic pattern, four classes of tau aggregation are involved in the pathogenesis of AD when it was presently described. 1) AD and Parkinsonism dementia discovered to be a major component of the neurofibrillary complex (six tau isoforms); 2) PSP and CBD (the three tangle.[14] Subsequently, the occurrence of neurofibrillary isoforms with Exon 10 corresponding sequence); 3) Pick’s tangles in a wide range of conditions led to the suggestion disease (PiD) (the three isoforms without Exon 10) and 4) that tau deposition may be an incidental nonspecific myotonic dystrophy- the shortest tau isoform.[19] finding associated with cell death or cellular dysfunction. Later, the discovery of close to 20 different mutations in Tau in AD protein Tau in FTDP-17 clearly showed that dysfunction of tau protein causes neurodegeneration and dementia.[17] It is histopathologically characterized by beta-amyloid­ Table 1 gives a grouped under taupathies. containing plaques, tau-containing neurofibrillary A substantial overlap of clinical features exists between tangles, reduced synaptic density and neuronal loss in taupathies, with many cellular lesions encountered in selected brain areas. The two degenerative processes that more than one disease. For example, neurofibrillary tangles coexist in AD are amyloidosis and tau pathology. (NFT) can be seen in AD, FTDP-17, progressive Amyloidosis corresponds to the extracellular aggregation

Neurology India | January-March 2007 | Vol 55 | Issue 1 13 CMYK13 Robert et al.: Tau and tauopathies of Aβ peptides into amyloid plaques. Tau pathology Tau Protein in Parkinsonian Disorders corresponds to the intraneuronal association of tau proteins into abnormal filaments. Amyloidosis is closely Parkinson’s syndrome is now viewed as being caused related to etiology and tau pathology is strongly by diseases characterized by either alpha-synuclein or correlated to the clinical expression of the disease. Little tau protein deposition although other conditions may is known about the relationship between amyloid-β also cause degenerative Parkinson’s syndromes. For precursor protein (APP) and tau pathologies, which is some of the autosomal dominant disorders, mutations one of the missing links in our fully understanding have been identified which link the genes encoding AD.[20] The quantification of Aβ in the different brain these proteins to the disease. Tau deposition has been areas demonstrates that the spreading pathway of tau described in a number of Parkinson’s syndrome pathology remains constant, whatever the cortical including PSP, CBD, postencephalitic and posttraumatic distribution of Aβ aggregates.[20] In the AD brain, tau is Parkinsonism, FTDP-17 and Parkinsonism dementia abnormally hyperphosphorylated and is present mostly complex of Guam. In addition, the original parkin as PHF. Unlike normal tau, which contains two or three mutation family has been shown to have tau phosphate groups, the cytosolic hyperphosphorylated neurofibrillary tangle pathology in a PD-like tau from the AD brain (AD P-tau) contains 5-9 mol of distribution. Tau deposition varies in topography, phosphate/mol of the protein.[8] The criteria for AD ultrastructure and protein chemistry in various diagnosis have been revised to include the presence of diseases. Progressive supranuclear palsy is the most tau pathology for diagnosing definite AD. extensively studied disease in this group. It is Neuropathologically, AD is now defined by the characterized by subcortical pathology of destruction accumulation of two types of insoluble fibrous material in globus pallidus, subthalamic nucleus and midbrain/ - extracellular amyloid protein in the form of senile pontine reticular formation and homogenous depletion plaques and intracellular neurofibrillary lesions (NFL) of substantia nigra pars reticulate. The brainstem made of abnormally and hyperphosphorylated tau involvement typically consists of damage to the protein. In addition to the neurofibrillary tangles (NFTs), supranuclear eye-movement control areas: the the NFL consists of neuropil threads and dystrophic interstitial.com). nucleus of cajal, the rostral interstitial neurites that are associated with senile plaques. nucleus of the medial longidudinal fasciculus and the Ultrastructurally NFL contains PHL as a major fibrous nucleus of Darkschewitsch. Similar propensity for component and straight filaments (SF) as a minor damage of globus pallidus as well as substantia nigra component. Both types are formed of the six brain tau has been demonstrated in CBD, Parkinsonism dementia isoforms in the hyperphosphorylated and abnormally complex of Guam and postencephalitic Parkinsonism. phosphorylated form. The mechanism of NFL formation.medknow The clinical observation that many of these diseases in AD is only now beginning to be understood. Tau is affect supranuclear control of gaze further suggests that first phosphorylated, accumulates in cytoplasm and then these diseases, all of which involve tau protein dimers form followed by polymers. Polymers(www form the deposition, share similarities in their topographic globular particles. As the concentration of globular pathology.The NFT in PSP is made of straight filaments particles increases, tau fibrils, PHFs and SFs appear. and predominantly 4R tau. In vitro experiments have While globular tauThis particles PDFa weresite is found hosted available in nonAD by brain, forMedknow freeconfirmed download Publications that 4R tau from forms into straight filament NFTs. their concentration was lower and there were no It remains unclear if these differences in tau protein filaments. This suggests that the trigger converting a non deposition reflect a topographically restricted pattern AD brain to an AD brain is the concentration of globular determined by tau gene expression. If true, then one tau particles. Unlike other taupathies, glial tau pathology could postulate that cortical neurons when damaged in is only a minor feature of AD.[3] AD express all six isoforms of the tau gene whereas substantia nigra neurons preferentially express 4R Tau in Pick’s Disease isoforms. Alternatively, the tau protein expression may represent a more fundamental aspect of the disease as Pick’s disease has distinctive molecular pathologic well. The isoform(s) of tau expressed in various diseases features involving the deposition of 3R tau protein. is shown in Table 2. Interestingly, the morphology of However, there may be further tau polymorphisms that tangles varies with the isoform. Thus when all six remain to be identified, outside the standard sequenced isoforms are expressed, as in AD, they are paired helical regions, which may have a role in the pathogenesis of filaments, while in 4R diseases they are either twisted PiD. Furthermore, PiD can be distinguished ribbon filaments (as in PiD) or straight filaments (as in immunohistochemically from other taupaties by the PSP).[22] Additionally, in many of these diseases, tau deposition of abnormally hyperphosphorylated tau and pathology has been described in glial cells as well. This by the absence of phosphorylation of tau Ser262, which contrasts with the findings in AD, where tau pathology is specifically recognized by the anti-tau antibody 12-E8.[21] is largely restricted to the neurons.[23]

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Table 2: Tau neurodegenerative diseases classified by the isoform of tau expressed (Modified from Morris et al[22]) All isoforms 4R tau 3R tau Familial Azheimer’s disease Frontotemporal dementia Myotonic dystrophy frontotemporal dementia Sporadic Azheimer’s disease Progressive supranuclear palsy Frontotemporal Parkinsonism dementia complex of guam Corticobasal degeneration dementia (Pick’s disease) Postencephalitic Parkinsonism

Cerebrospinal fluid Tau between tau protein and α-synneuclein and amyloid has to be delineated. This will further clarify the role of tau The role of cerebrospinal fluid (CSF) tau in the diagnosis protein in Parkinsonism as well as amyloidosis. of dementias is being studied quite extensively. The most commonly used assay for tau is the ELISA.[24] It has been References shown that elevated CSF tau levels are associated with AD pathology and can help discriminate AD from other 1. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, dementing disorders. Tau is one of the components of Wisniewski HM. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 1986;261:6084­ the core neuropathologic change in AD that can be 9. measured in CSF and has been frequently studied as a 2. Askanas V, Engel WK. Sporadic inclusion-body myositis and its candidate diagnostic biomarker. It has been shown in one similarities to Alzheimer disease brain. Recent approaches to of the studies that with the use of a cutoff value of 234 diagnosis and pathogenesis, and relation to aging. Scand J Rheumatol 1998;27:389-405. pg/ml, CSF tau demonstrated a sensitivity of 85%, 3. Tolnay M, Probst A. Review: Tau protein pathology in Alzheimer’s specificity of 84%, positive predictive value of 87% and disease and related disorders. Neuropathol Appl Neurobiol positive likelihood ratio of 5.3 in distinguishing patients 1999;25:171-87. with AD from cognitively normal controls. CSF tau was 4. Modoni A, Silvestri G, Pomponi MG, Mangiola F, Tonali PA, Marra C. Characterization of the pattern of cognitive impairment in also useful in distinguishing AD from Frontotemporal myotonic dystrophy type 1. Arch Neurol 2004;61:1943-7. dementia and Diffues Lewy body dementia, although the 5. Maurage.com). CA, Bussiere T, Sergeant N, Ghesteem A, Figarella­ positive likelihood ratio of correctly distinguishing was Branger D, Ruchoux MM, et al. Tau aggregates are abnormally only 3:1. It has been proposed that CSF tau may also be phosphorylated in inclusion body myositis and have an [25] immunoelectrophoretic profile distinct from other tauopathies. helpful in differentiating AD from . Neuropathol Appl Neurobiol 2004;30:624-34. Recently, phosphorylated tau level in CSF has been found 6. Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR. Tau to be useful as a biological marker of AD.[26,27] protein isoforms, phosphorylation and role in neurodegenerative The source of CSF tau remains unclear but most likely.medknow disorders. Brain Res Brain Res Rev 2000;33:95-130. 7. Leger JG, Brandt R, Lee G. Identification of tau protein regions is related to the degeneration of neurofibrillary tangle- required for process formation in PC12 cells. J Cell Sci laden neurons. The protein has not been well 1994;107:3403-12. characterized in the CSF and may exist in(www fragmented 8. Alonso AD, Zaidi T, Novak M, Barra HS, Grundke-Iqbal I, Iqbal K. forms. A report has indicated that it may require three to Interaction of tau isoforms with Alzheimer’s disease abnormally hyperphosphorylated tau and in vitro phosphorylation into the five months for elevated CSF tau levels to return to normal disease-like protein. J Biol Chem 2001;276:37967-73. after an acute stroke.This The PDF arate site of clearanceis hosted available of tau by from forMedknow the free9. Kdownloadosik PublicationsKS. The molecular from and cellular biology of tau. Brain Pathol CSF in patients with neurodegenerative dementia, 1993;3:39-43. however, remains unknown. Elevated CSF tau has also 10. Margittai M, Langen R. Template-assisted filament growth by parallel stacking of tau. Proc Natl Acad Sci USA 2004;101:10278­ been reported in CBD, FTD and in many patients with 83. Creutzfeldt-Jakob disease (CJD).[28] It has been shown that 11. Trojanowski JQ, Lee VM. The role of tau in Alzheimer’s disease. higher amounts of phosphorylated tau in the CSF in Med Clin North Am 2002;86:615-27. sporadic CJD is associated with a rapid progression of 12. Feijoo C, Campbell DG, Jakes R, Goedert M, Cuenda A. Evidence [29] that phosphorylation of the microtubule-associated protein Tau by the disease to akinetic mutism. SAPK4/p38delta at Thr50 promotes microtubule assembly. J Cell Sci 2005;118:397-408. Future Direction 13. Drewes G. MARKing tau for tangles and toxicity. Trends Biochem Sci 2004;29:548-55. 14. Lovestone S, McLoughlin DM. Protein aggregates and dementia: Recently, using a triple transgenic model it has been Is there a common toxicity? J Neurol Neurosurg Psychiatry β 2002;72:152-61. shown that A immunotherapy leads to the clearance of 15. Chen F, David D, Ferrari A, Gotz J. Posttranslational modifications early tau pathology. The clearance of the tau pathology is of tau-role in human tauopathies and modeling in transgenic mediated by the proteasome and is dependent on the animals. Curr Drug Targets 2004;5:503-15. phosphorylation state of tau, as hyperphosphorylated tau 16. Cairns NJ, Lee VM, Trojanowski JQ. The cytoskeleton in β [30] neurodegenerative diseases. J Pathol 2004;204:438-49. aggregates are unaffected by the A antibody treatment. 17. Spillantini MG, Goedert M. Tau mutations in familial It has been shown that the inhibition of the proteasome frontotemporal dementia. Brain 2000;123:857-9. led to a bidirectional degradation of Tau.[31] The relation 18. Bird TD, Nochlin D, Poorkaj P, Cherrier M, Kaye J, Payami H, et

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al. A clinical pathological comparison of three families with 26. Hampel H, Buerger K, Zinkowski R, Teipel SJ, Goernitz A, frontotemporal dementia and identical mutations in the tau gene Andreasen N, et al. Measurement of phosphorylated tau epitopes (P301L). Brain 1999;122:741-56. in the differential diagnosis of Alzheimer disease: A comparative 19. Caparros-Lefebvre D, Sergeant N, Lees A, Camuzat A, Daniel S, cerebrospinal fluid study. Arch Gen Psychiatry 2004;61:95-102. Lannuzel A, et al. Guadeloupean parkinsonism: A cluster of 27. de Jong D, Jansen RW, Kremer BP, Verbeek MM. Cerebrospinal progressive supranuclear palsy-like tauopathy. Brain 2002;125:801- fluid amyloid beta42/phosphorylated tau ratio discriminates 11. between Alzheimer’s disease and vascular dementia. J Gerontol A 20. Delacourte A, Sergeant N, Champain D, Wattez A, Maurage CA, Biol Sci Med Sci 2006;61:755-8. Lebert F, et al. Nonoverlapping but synergetic tau and APP 28. Clark CM, Xie S, Chittams J, Ewbank D, Peskind E, Galasko D, et pathologies in sporadic Alzheimer’s disease. Neurology al. Cerebrospinal fluid tau and beta-amyloid: How well do these 2002;59:398-407. biomarkers reflect autopsy-confirmed dementia diagnoses? Arch 21. Morris HR, Baker M, Yasojima K, Houlden H, Khan MN, Wood Neurol 2003;60:1696-702. NW, et al. Analysis of tau haplotypes in Pick’s disease. Neurology 29. Van Everbroeck B, Green AJ, Vanmechelen E, Vanderstichele H, 2002;59:443-5. Pals P, Sanchez-Valle R, et al. Phosphorylated tau in cerebrospinal 22. Morris HR, Lees AJ, Wood NW. Neurofibrillary tangle parkinsonian fluid as a marker for Creutzfeldt-Jakob disease. J Neurol Neurosurg disorders—tau pathology and tau genetics. Mov Disord Psychiatry 2002;73:79-81. 1999;14:731-6. 30. Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM. Abeta 23. Komori T. Tau-positive glial inclusions in progressive supranuclear immunotherapy leads to clearance of early, but not late, palsy, corticobasal degeneration and Pick’s disease. Brain Pathol hyperphosphorylated tau aggregates via the proteasome. Neuron 1999;9:663-79. 2004;43:321-32. 24. Schooneboom N HH, Scheltens P, Leon M. Cerebrospinal fluid 31. Delobel P, Leroy O, Hamdane M, Sambo AV, Delacourte A, Buee markers for the diagnosis of Alzheimer’s disease. In: Gauthier SS, L. Proteasome inhibition and Tau proteolysis: An unexpected Cummings JL, editor. Alzheimer’s Disese and related Disorders regulation. FEBS Lett 2005;579:1-5. Annual. Special pharma edition ed. 2 Park square. Taylor and Francis: United Kingdom; 2006. p. 17-33. 25. Leszek J, Malyszczak K, Janicka B, Kiejna A, Wiak A. Total tau in Accepted on 18-10-2006 cerebrospinal fluid differentiates Alzheimer’s disease from vascular Source of Support: Nil, Conflict of Interest: None declared. dementia. Med Sci Monit 2003;9:CR484-8.

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