Tau protein isoforms, phosphorylation and role in neurodegenerative disorders1

Brain Research Reviews 33 (2000) 95–130 www.elsevier.com / locate / bres

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Tau protein isoforms, phosphorylation and role in neurodegenerative disorders 1 b ´ a ,* ,1 , Thierry Bussiere ` c ,1 , Valerie ´ Buee-Scherrer ´ Luc Buee , Andre´ Delacourte a , ,c,d,e Patrick R. Hof * a INSERM U422, Place de Verdun, 59045 Lille cedex, France ´ Universite´ d’ Artois, Faculte´ Jean Perrin, Laboratoire de Biochimie Moleculaire et Cellulaire, 62307 Lens cedex, France c Kastor Neurobiology of Aging Laboratories and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York, NY 10029, USA d Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, NY 10029, USA e Department of Ophthalmology, Mount Sinai School of Medicine, New York, NY 10029, USA b

Accepted 16 February 2000

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.  2000 Elsevier Science B.V. All rights reserved. Theme: Disorders of the nervous system Topic: Degenerative disease: Alzheimer’s — other Keywords: Alzheimer’s disease; Isoforms aggregation; Isoforms phosphorylation; Neurodegenerative disorder; Tau protein

1. 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 *Corresponding authors. Tel.: 133-320-622-074; fax: 133-320-622079. ´ E-mail address: [email protected] (L. Buee). 1 These authors contributed equally to this work.

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–Straussler– Scheinker syndrome [129,130], Hallervordern–Spatz dis-

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ease [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.

2.2. Splicing The tau primary transcript contains 16 exons. However, three of them (exons 4A, 6 and 8) are never present in any mRNA in human brain. They are specific to peripheral tau proteins. Exon 4A is found in bovine, human and rodent peripheral tissues with a high degree of homology. Tau mRNA with either exons 6 or 8 have not been described in human. Some transcripts with exon 8 are found in bovine and rhesus monkey brains [186,299]. Exon 21 is part of the promoter, and is transcribed but not translated. Exons 1, 4, 5, 7, 9, 11, 12 and 13 are constitutive exons. Exon 14 is found in messenger RNA, but it is not translated into protein [5,144,145,345]. Exons 2, 3 and 10 are alternatively spliced and are adult brainspecific [5]. Exon 3 never appears independently of exon 2 [4]. Thus, alternative splicing of these three exons allows for six combinations (2232102; 2132102; 2131102; 2232101; 2132101; 2131101) [144,145,240]. In the human brain, the tau primary transcript gives rise to six mRNAs [144,145,186] (Fig. 1).

2. Tau proteins

2.3. Structure and roles

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 cells, mainly in pathological conditions [71], and it is possible to detect tau mRNA and proteins in several peripheral tissues such as heart, kidney, lung, muscle, pancreas, testis, as well as in fibroblasts [162,216,396].

In the brain, tau proteins constitute a family of six isoforms which range from 352 to 441 amino acids. Their molecular weight is ranging from 45 to 65 kDa when run on polyacrylamide gel electrophoresis in presence of sodium dodecyl sulfate (SDS–PAGE). The tau variants differ from each other by the presence of either three or four repeat-regions in the carboxy-terminal (C-terminal) part of the molecule and the absence or presence of one or two inserts (29 or 58 amino acids) in the amino-terminal (N-terminal) part [144,145,186,239] (Fig. 1). Each of these isoforms is likely to have particular physiological roles since they are differentially expressed during development. For instance, only one tau isoform, characterized by the absence of N-terminal inserts and the presence of three C-terminal repeats, is present during fetal stages, while the six isoforms (with one or two N-terminal inserts and three or four C-terminal repeats) are expressed during adulthood [136,240]. Thus, tau isoforms are likely to have specific functions related to the absence or presence of regions encoded by the cassette exons 2, 3 and 10. Furthermore, the six tau isoforms may not be equally expressed in neurons. For example, tau mRNAs containing exon 10 are not found in granular cells of the dentate gyrus [144]. Thus, tau isoforms may be differentially distributed in neuronal subpopulations.

2.1. Gene organization The human tau gene is unique and located over 100 kb on the long arm of chromosome 17 at band position 17q21 [300], and contains 16 exons [4,5] (Fig. 1). The restriction analysis and sequencing of the gene shows that it contains two CpG islands, one associated with the promoter region, the other with exon 9 [4,5]. The CpG island in the putative tau promoter region resembles to previously described neuron-specific promoters. Two regions homologous to the mouse Alu-like sequence are present. The sequence of the promoter region also reveals a TATA-less sequence that is likely to be related to the presence of multiple initiation sites, typical of housekeeping genes. Three SP1-binding sites that are important in directing transcription initiation in other TATA-less promoters, are also found in the proximity of the first transcription initiation site [6,341].

2.3.1. Structure and functions of the projection domain The two 29 amino-acids sequences encoded by exons 2 and 3 give different lengths to the N-terminal part of tau proteins. These two additional inserts are highly acidic, and are following by a basic proline-rich region. The N-terminal part is referred to as the projection domain

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Fig. 1. Schematic representation of the human tau gene, the human tau primary transcript and the six human CNS tau isoforms. The human tau gene is located over 100kb on the long arm of chromosome 17 at position 17q21. It contains 16 exons, with exon 21 is a part of the promoter (upper panel). The tau primary transcript contains 13 exons, since exons 4A, 6 and 8 are not transcribed in human (middle panel). Exons 21 and 14 are transcribed but not translated. Exons 1, 4, 5, 7, 9, 11, 12, 13 are constitutive, and exons 2, 3, and 10 are alternatively spliced, giving rise to six different mRNAs, translated in six different CNS tau isoforms (lower panel). These isoforms differ by the absence or presence of one or two 29 amino acids inserts encoded by exon 2 (yellow box) and 3 (green box) in the amino-terminal part, in combination with either three (R1, R3 and R4) or four (R1–R4) repeat-regions (black boxes) in the carboxy-terminal part. The fourth microtubule-binding domain is encoded by exon 10 (slashed box) (lower panel). The adult tau isoforms include the longest 441-amino acids component (2131101), the 410-amino acids component (2131102), the 412-amino acids component (2132101), the 381-amino acids component (2132102) and the 383-amino acids component (2232101). The shortest 352-amino acids isoform (2232102) is found only in the fetal brain, and thus is referred as fetal tau isoform.

since it projects from the microtubule surface where it may interact with other cytoskeletal elements and plasma membrane [43,191] (Fig. 2). In mice lacking the tau gene, an increase in microtubuleassociated protein 1A which may compensate for the functions of tau proteins has been observed [171]. However, axonal diameter in some neurons is particularly affected. This may be related to the particular length of the N-terminal domain (with or without sequences encoded by exons 2 and 3) of tau proteins in specific axons. In fact, projection domains of tau determine spacings between microtubule in axon and may increase axonal diameter [68]. It should be noted that in peripheral neurons which often project a very long axon with large diameter, an additional N-terminal tau sequence encoded by exon 4A is present, generating a specific tau isoform called ‘big tau’ [5,127]. These results strongly suggest that N-terminal regions of tau proteins are crucial in the stabilization and organization of certain types of axons. Tau proteins bind to spectrin and actin filaments

[66,79,157,180,344,351]. Through these interactions, tau proteins may allow microtubules to interconnect with other cytoskeletal components such as neurofilaments [2,257,285] and may restrict the flexibility of the microtubules [279]. There is also evidence that tau proteins interact with cytoplasmic organelles. Such interactions may allow for binding between microtubules and mitochondria [329]. The tau N-terminal projection domain also permits interactions with the neural plasma membrane [43]. Thus, tau may act as a mediator between microtubules and plasma membrane. More recently, this interaction has been defined as involving a binding between the proline-rich sequence in the N-terminal part of tau proteins and the SH3 domains of src-family non-receptor tyrosine kinases, such as fyn [252]. Lee and colleagues have shown that the SH3 binding PXXP motif is located in the sequence 231 Thr–Pro–Pro–Lys–Ser–Pro–Ser 237 of tau proteins (according to the numbering of the longest isoform). Moreover, they described the colocalization of tau and fyn just beneath the plasma membrane, and an

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Fig. 2. Schematic representation of the functional domains of the longest tau isoform (2131101). The projection domain, including an acidic and a proline-rich region, interacts with cytoskeletal elements to determine spacings between microtubules in axons. The N-terminal part is also involved in signal transduction pathways by interacting with proteins as PLC-g and Src-kinases. The C-terminal part, referred to as microtubules binding domain, regulates the rate of microtubules polymerization. It is also involved in the binding with functional proteins as protein phosphatase 2A (PP2A) or presenilin 1(PS1).

association between the tau–fyn complexes and the actin cytoskeleton. These data are in favor of a role for tau proteins in src-family tyrosine kinase signalling pathway that may modify the cell shape by acting on the submembranous actin cytoskeleton [252]. The same proline-rich region of tau proteins is likely involved in the interaction with phospholipase C-g (PLC-g) isozymes [211]. Hwang and colleagues have demonstrated in vitro that tau proteins complex specifically with the SH3 domain of PLC-g, and enhance its activity in the presence of unsaturated fatty acids such as arachidonic acid. These results suggest that in cells that express tau proteins, receptors coupled to cytosolic phospholipase A2 may activate PLC-g indirectly, in the absence of the usual tyrosine phosphorylation, through the hydrolysis of phosphatidylcholine to generate arachidonic acid [211]. Finally, Jenkins and Johnson have recently shown that in situ, the association between tau and PLC-g exist even in the absence of arachidonic acid [222]. Altogether, these data indicate that tau proteins may also play a role in the signal transduction pathway involving PLC-g.

2.3.2. Structure and functions of the microtubule assembly domain Tau proteins bind microtubules through repetitive regions in their C-terminal part (Fig. 2). These repetitive regions are the repeat domains (R1–R4) encoded by exons 9–12 [251] (Fig. 1). The three (3R) or four copies (4R) are made of a highly conserved 18-amino acid repeat [145,186,249,251] separated from each other by less conserved 13- or 14-amino acid inter-repeat domains. Tau proteins are known to act as promoter of tubulin poly-

merization in vitro, and are involved in axonal transport [32,42,74,75,301,410]. They have been shown to increase the rate of microtubule polymerization, and to inhibit the rate of depolymerization [99]. The 18-amino acid repeats bind to microtubules through a flexible array of distributed weak sites [62,251]. It has been demonstrated that adult tau isoforms with 4R (R1–R4) are more efficient at promoting microtubule assembly than the fetal isoform with 3R (R1, R3, R4) [62,136,164,253]. Interestingly, the most potent part to induce microtubule polymerization is the interregion between repeats 1 and 2 (R1–R2 inter-region) and more specifically peptide 274 KVQIINKK 281 within this sequence. This R1–R2 inter-region is unique to 4R tau, adult-specific and responsible for a 40-fold difference in the binding affinities between 3R and 4R tau [148,309]. The microtubule-binding region may be also involved in other functions than microtubule assembly. In mice, recent data have shown that there is a strong interaction between tau and Eed proteins suggesting that tau proteins may play an important role in development [250]. Eed is highly homologous to the Drosophila Esc protein that is a longterm repressor of homeotic genes [348,359]. It is possible that some Eed isoforms, resulting from an alternative splicing, are specifically transported to the nucleus. Interestingly, it has been shown that tau proteins are also found in the nucleus [40,385]. The nuclear tau isoforms are similar to cytoplasmic tau, but they show lower solubility, suggesting that they undergo specific modifications, either post-translational (phosphorylation) or through interactions with other proteins, which may involve Eed proteins. It is interesting to note that recent data have shown that tau proteins bind RNA through their microtubule-binding

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domain [229]. Prior to their addressing in the nucleus, tau proteins are phosphorylated in the cytoplasm [155]. The function of nuclear tau and how it may be regulated by phosphorylation is still unknown. Recent evidence supports a role for the microtubulebinding domain in the modulation of the phosphorylation state of tau proteins. A direct and competitive binding has been demonstrated between this part (residues 224–236 according to the numbering of the longest isoform) and microtubules on one hand, and this part and protein phosphatase 2A (PP2A) on the other hand [369]. As a consequence, microtubules could inhibit PP2A activity by competing for binding to tau at the microtubule-binding domains. Furthermore, a binding has been demonstrated between the microtubule-binding domains and the residues 250–298 of presenilin 1 (PS1) [381]. While this region of PS1 is also involved in the binding of the kinase GSK-3b, PS1 may regulate the interaction between this enzyme and tau proteins by bringing both into close proximity.

2.4. Post-translational modifications 2.4.1. O-glycosylation O-glycosylation is a dynamic and abundant post-translational modification that is characterized by the addition of a O-linked N-acetylglucosamine (O-GlcNAc) residue on Ser or Thr in the proximity of Pro residues [166]. The O-GlcNAc transferase was recently identified [242]. Although the functional significance of O-GlcNAc modification is not yet fully understood, it is implicated in transcriptional regulation, cell activation, cell cycle regulation and the proper assembly of multimeric protein complexes [174]. This modification is often reciprocal to phosphorylation [72,165,206,256]. It occurs in neurofilaments [97], microtubule-associated proteins including MAP2 [96] and tau proteins [13]. The number of OGlcNAcylated sites on tau proteins is lower than the number of phosphorylation sites. Site-specific or stoichiometric changes in O-GlcNAcylation may modulate tau function. In fact, phosphorylation and O-GlcNacylation may have opposite effects (see below for the role of tau phosphorylation). For instance, O-GlcNacylation of tau proteins and other microtubule-associated proteins suggest a role for O-GlcNac in mediating their interactions with tubulin. O-GlcNacylation may also play a role in subcellular localization and degradation of tau proteins [13]. 2.4.2. Phosphorylation 2.4.2.1. Sites of phosphorylation. There are seventy nine putative Ser or Thr phosphorylation sites on the longest brain tau isoform (441 amino-acids). Using phosphorylation-dependent monoclonal antibodies against tau, mass spectrometry and sequencing, at least thirty phosphorylation sites have been described, including Thr39, Ser46Pro, Thr50Pro, Thr69Pro, Thr153Pro, Thr175Pro, Thr 181Pro,

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Ser198, Ser199Pro, Ser202Pro, Thr205Pro, Ser208, Ser210, Thr212Pro, Ser214, Thr217Pro, Thr231Pro, Ser235Pro, Ser237, Ser241, Ser262, Ser285, Ser305, Ser324, Ser352, Ser356, Ser396Pro, Ser400, Thr403, Ser404Pro, Ser409, Ser412, Ser413, Ser416 and Ser422Pro [176,268,290,313,338,380]. All of these sites are localized outside the microtubule-binding domains with the exception of Ser 262 (R1), Ser285 (R1–R2 inter-repeat), Ser305 (R2–R3 inter-repeat), Ser324 (R3), Ser352 (R4) and Ser356 (R4) [144,338,356]. Most of these phosphorylation sites are on Ser–Pro and Thr–Pro motives. A number of sites on non Ser / Thr–Pro sites have also been identified [290]. The different states of tau phosphorylation result from the activity of specific kinases and phosphatases towards these sites.

2.4.2.2. Kinases. Most of the kinases involved in tau phosphorylation are part of the proline-directed protein kinases (PDPK), which include mitogen activated protein kinase (MAP) [101,135,332,405], glycogen synthase kinase 3 (GSK3) [170], tau-tubulin kinase [380] and cyclindependent kinases including cdc2 and cdk5 [21,264]. Stress-activated protein kinases (SAP kinases) have been recently involved in tau phosphorylation [135,223,332]. They may explain a number of observations. Thus, cold water stress induces an immediate, i.e within 30–90 min, 2 to 3-fold increase in the phosphorylation of tau proteins in rat brain, without direct involvement of the hypothalamic– pituitary–adrenal axis [236]. Similarly, heat–shock stress also induces modifications of tau phosphorylation [310]. Non Ser / Thr–Pro sites can be phosphorylated by many other protein kinases, including microtubule-affinity regulating kinase (MARK) [100], Ca 21 / calmodulin-dependent protein kinase II (CaMPK II) [20,227], cyclic-AMPdependent kinase (PKA) [226,260] and casein kinase II [156]. Numerous kinases, proline-directed and non-proline directed, have to be used in tandem in order to observe a complete phosphorylation of recombinant tau, and may be positively modulated at the substrate level by non-PDPKcatalyzed phosphorylations [360]. 2.4.2.3. Phosphatases. Tau proteins from brain tissue or neuroblastoma cells are rapidly dephosphorylated by endogenous phosphatases [58,125,277,370]. Ser / Thr phosphatase proteins 1, 2A, 2B (calcineurin) and 2C are present in the brain [76,215], and are developmentally regulated [104,323]. Like kinases, phosphatases have many direct or indirect physiological effects, and counterbalance the action of kinases. They are associated directly or indirectly with microtubules [104,258,368,369]. Thus, tau proteins have been demonstrated to act as a link between PP1 and the tubulin [258], whereas PP2A is directly linked to the microtubules by ionic interactions [369]. Purified phosphatase proteins 1, 2A and 2B can dephosphorylate tau proteins in vitro [119,139,149,417,418]. For instance, in fetal rat primary cultured neurons, the use

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of phosphatase 2A inhibitors induces phosphorylation of tau proteins on some sites, whereas phosphatase 2B inhibitors allow phosphorylation on other sites [306,342], suggesting that phosphatases 2A and 2B are involved in dephosphorylation of different sites on tau proteins in neurons.

2.5. Phosphorylation regulates different roles of tau proteins

2.5.1. Tau phosphorylation and microtubule assembly Tau proteins bind microtubules through the microtubulebinding domains. However, microtubule assembly depends partially upon the phosphorylation state since phosphorylated tau proteins are less effective than non-phosphorylated tau proteins on microtubule polymerization [26,41,74,75,102,259,418]. Phosphorylation of Ser262 dramatically reduces the affinity of tau for microtubules in vitro [26]. Nevertheless, this site alone, which is present in fetal tau, adult tau as well as in hyperphosphorylated tau proteins found in NFT, is insufficient to eliminate tau binding to microtubules [356]. Recent data have indicated that the heptapeptide 224 KKVAVVR 230 located in the proline-rich region has a high microtubule binding activity in combination with the repeats regions [147], suggesting intramolecular interactions between the both regions. Thus, phosphorylation outside the microtubule-binding domains can strongly influence tubulin assembly by modifying the affinity between tau and microtubules.

2.5.2. Tau phosphorylation and cell sorting Tau is a phosphoprotein, as was first demonstrated with the monoclonal antibody Tau-1 raised against a dephosphorylated site (Fig. 3). Since Tau-1 labels preferentially axons, tau were tagged as ‘axonal proteins’ [28]. However, the state of phosphorylation of tau proteins is likely different according to the cell compartments [333], and Tau-1 immunoreactivity was observed in the somatodendritic compartment of neurons after dephosphorylation [311]. In fact, the labeling of cell bodies and dendrites with phosphorylation-independent antibodies such as Alz-50, demonstrates that these proteins are found in all compartments of the nerve cells, and are not exclusively ‘axonal proteins’ [167]. However, compared to other MAPs, tau proteins are preferentially axonal. Both phosphorylation and transcription factors may be involved in tau trafficking and cell sorting (nuclear, axonal or somatodendritic) [190]. 2.5.3. Tau phosphorylation in development Phosphorylation of tau proteins is developmentally regulated [104,280,306,323,340,342]. It is high in fetal and decreases with age due to phosphatases activation [280,340]. Thus, the most precise analysis of the expression of phosphorylation sites during development and adult life derives from immunohistochemical studies of the nervous tissue in animals which had been fixed by perfusion. This circumvents postmortem delays that destroy phosphorylation sites [58,280]. In fact, since at death, due to the lack of oxygen, ATP is no longer synthesized, and thus, kinases are not active. Conversely, phosphatases still are since they do not use ATP for dephosphorylation.

Fig. 3. Schematic representation of the hyperphosphorylation sites (indicated as peptidic sequence) of the longest tau isoform (2131101), and corresponding specific antibodies. Hyperhosphorylated sites are grouped in two clusters located on both sides of the microtubules binding domain, with the exception of Ser262 / Ser356. Phosphorylation-dependent antibodies (in italics) have been developed for each sites. AD-specific sites and corresponding antibodies are circled. Tau1 recognizes the dephosphorylated 189–207 amino acid sequence.

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Thus, in anoxic conditions, most of the phosphorylation sites found on tau proteins are rapidly dephosphorylated (for review, see Ref. [85]). In addition, it is likely that an independent regulation of multiple phosphorylation sites takes place within subcellular domains of developing neurons [141,274,327,379]. Other observations indicate that tau proteins remain unpolarized at all stages in culture [98], or that they bind selectively to axonal microtubules at early stages of development, as shown in cerebellar neurons [114].

2.5.4. Ischemia Many phosphorylated sites on aggregated tau proteins are found on fetal and native adult tau as well [277,280]. In particular, this has been verified in AD for Ser 202 and Thr 205 [277], Ser 262 [356], Ser 396 and 404 [58,277] and other Ser–Pro sites [205]. However, there is a rapid endogeneous dephosphorylation of normal tau proteins after death. In fact, using rat brain, we performed a kinetic of dephosphorylation and observed that 80% of the tauimmunoreactivity, revealed by a phosphorylation-dependent monoclonal antibody raised against two phosphorylated sites at Ser396 and 404 residues and named AD2 [58], disappeared after a postmortem delay of 2 h at room temperature [58]. Similar data were obtained for normal human brain [277,367]. During postmortem delays, normal tau proteins from autopsy-derived materials are dephosphorylated whereas PHF-tau are not, because of either a poor accessibility of phosphorylated sites to phosphatases or a decrease in phosphatase activity [146,243,277]. Under ischemic conditions, a similar phenomenon occurs, and no ATP is synthesized. Ischemia disrupts the neuronal cytoskeleton both by promoting proteolysis of its components and by affecting kinase and phosphatase activities that alter its assembly [50,94]. In a reversible model of spinal cord ischemia in rabbits, tau has been found to be dephosphorylated in response to ischemia with a time course that closely matches the installation of permanent plegia. In a similar manner, Ca 21 / calmodulindependent kinase II activity is reduced only in the ischemic region. Thus, dephosphorylation of tau is an early marker of ischemia as is the rapid loss of Ca 21 / calmodulindependent kinase II activity [357]. In a canine model of cardiac arrest [339], the effects of global brain ischemia / reperfusion on tau proteins were analyzed. Tau proteins are completely dephosphorylated on Ser / Thr–Pro sites but after resuscitation and 2 h of reperfusion, there is a full restoration of phosphorylation [271]. Alterations in phosphorylation or degradation of tau may affect microtubule stability, possibly contributing to the disruption of axonal transport [50,93,272,357]. 2.5.5. Summary Altogether, these observations show that tau proteins are found in all cell compartments, but in different phosphorylation states. Within the same compartment, vari-

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ability in the degree of phosphorylation is observed during development. Phosphorylation seems to affect simultaneously several sites. However, this has to be clarified, using a panel of monoclonal antibodies against different phosphorylation sites and following their fates during development. Furthermore, the state of phosphorylation is strongly modified during development, due to the expression of several specific adult isoforms, and because the ratio between kinases and phosphatases is modified [58,104,280,323]. Phosphorylation, in combination with the type of isoform, can modulate the properties of tau proteins. In turn, tau proteins provide the microtubule with its own identity and physical characters (rigidity, length, stability, interactive capacity with other organelles). Therefore, by regulating microtubule assembly, tau proteins have a role in modulating the functional organization of the neuron, and particularly in axonal morphology, growth, and polarity.

3. 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 under physiological conditions in vitro, when sulfated glycosaminoglycans are or other polyanions present. These data suggest that, in addition to phosphorylation, other mechanisms may be involved in the formation of pathological tau filaments.

3.1. Tau proteins phosphorylation In numerous neurodegenerative disorders, tau proteins aggregate into intraneuronal filamentous inclusions. In AD, these filaments are named paired helical filaments (PHF), and their constitutive proteins are referred to as PHF-tau proteins. Despite the fact that many phosphorylation sites are common to PHF-tau proteins and native tau, there are biochemical characteristics that differentiate them and support the concept of pathological tau proteins. First, two-dimensional immunoblot analysis reveals that PHF-tau proteins are more acidic than normal tau from biopsyderived samples [352]. Second, insoluble polymers of tau are present exclusively in AD brain extracts, where they are visualized as ‘smears’ on Western blots. Therefore, the main difference between biopsy and postmortem tissues is that PHF-tau are aggregated, while tau from biopsies are not (Fig. 4). Third, hyperphosphorylation generates differences that can be visualized by a few phosphorylationdependent antibodies such as AT100 [277], AP422 [175],

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Fig. 4. Schematic representation of the modifications leading to tau proteins aggregation in Alzheimer’s disease. Phosphorylation state of normal tau proteins result from a balance between kinases and phosphatases activity. Tau proteins from biopsy-derived extracts are phosphorylated at several sites, and exhibit a higher molecular weight compared to dephosphorylated normal tau proteins from autopsy-derived brains (upper part). In this later case, there is no kinase activity, while the phosphatases are still active. Native tau proteins are detected as a triplet of bands ranging between 55 and 74 kDa by numerous phosphorylation-dependent antibodies, except AT100 (upper right). In neurodegenerative disorders, several mechanisms (phosphorylation, ubiquitination, oxidation, glycation) are involved in the aggregation of tau proteins into PHF (lower part). These pathological tau proteins are visualized by western blotting as three major bands between 55 and 69 kDa, and a minor band at 74 kDa. Tau 55 results from the phosphorylation of the shortest isoform (2232102), tau 64 from the phosphorylation of tau variants with one cassette exon (2132102 and / or 2232101), tau 69 from the phosphorylation of tau variants with two cassette exons (2131102 and / or 2132101). Phosphorylation of the longest tau isoform (2131101) induces the formation of the additional hyperphosphorylated tau74 variant. The phosphorylation of certain sites are AD-specific, as demonstrating with the antibody AT100. The color codes are similar to those used in Figs 1 and 3.

988 [61], PHF-27 [205] or the TG / MC antibodies (i.e., TG3) [404] (Figs. 3 and 4). With the exception of Ser422, these sites found in PHF-tau are conformation-dependent epitopes. However, recently, it was also shown that TG3 epitope was selectively expressed in mitotic cells but not in quiescent cells [404]. It does not recognize autopsy- and biopsy-derived normal tau proteins but binds PHF-tau and mitotic epitopes. In fact, TG3 recognizes Thr231 and Ser235 in a particular phosphorylated conformation [225], which may allow to better understand PHF formation. The hyperphosphorylation of tau proteins associated with AD may be related to either an increase in kinase activity or a decrease in phosphatase activity [391]. Among the numerous kinases that have been implicated (for review, see Ref. [268]), glycogen synthase kinase 3 (GSK3) is still a controversial candidate. However, several points suggest that it may be involved in AD pathology. The most striking one is that Alzheimer-specific epitope

AT100 on tau proteins is obtained in vitro after a complex sequence of phosphorylation by GSK3 and PKA [425]. Mitotic protein kinases may also play a major role in tau phosphorylation since many mitosis-specific epitopes are found in NFT [235,404]. Stress-activated protein kinases are also of interest [245,286,332] since all SAP kinases (JNK / SAPK1, p38 / SAPK2, SAPK3) have been shown to phosphorylate tau proteins [135,223]. Altogether, these data suggest that SAPK family is an interesting candidate for the pathological phosphorylation of tau proteins. Conversely, tau hyperphosphorylation may be related to a decrease in phosphatase activity. Recent data suggest that phosphatase activities may be decreased in AD brains [146,247]. Furthermore, phosphatase inhibition in cell models allows the formation of specific AD-type epitopes such phosphorylation of Ser422 [64,270]. Finally, tau proteins hyperphosphorylation may only be a consequence and occurs once tau proteins are already aggregated into

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filaments. Others factors may be involved including ubiquitination, glycation and oxidation.

3.2. Tau isoforms aggregation 3.2.1. Ubiquitination Ubiquitin is a stress protein implicated in the ATPdependent degradation of short-lived proteins or the removal of abnormal or damaged proteins [181]. The presence of a conjugated form of ubiquitin in PHF has been suggested by the labeling of PHF with antibodies specific for conjugated ubiquitin [288]. It has been shown that the ubiquitin-targeted proteins in PHF are tau proteins, and that the conjugation sites, including Lys254, 257, 311 and 317, are localized on the microtubule-binding region. The analysis of tau proteins from an AD brain by Western blotting reveals the characteristic PHF-tau triplet and proteolytic products, and also smears that correspond to tau polymers. These smears consist largely of the Cterminal portion of tau and ubiquitin. It is most likely that abnormally phosphorylated full-length tau accumulates as PHF (PHF-tau), which is then gradually proteolyzed in its N-terminal part and subsequently ubiquitinated in its Cterminal domain [289]. 3.2.2. Glycation Glycation is the reaction between the amino part of a side chain of an amino acid and the carboxyl part of glucose or other reducing sugars. This post-translational modification, also known as nonenzymatic glycosylation, leads to the formation of heterogeneous products called advanced glycation end products (AGEs). PHF insolubility may be related to glycation, since a cross-linking reaction leading to the formation of insoluble aggregates of proteins is often described as a consequence of proteins glycation [231,234,362]. Moreover, it has recently been demonstrated that AGEs can be detected immunohistochemically in senile plaques from AD, and also in NFT from AD, PSP or ALS / PDC, and parts of the Pick’s bodies in Pick’s disease [343,363]. Thirteen residues of lysine, the most suitable amino acid for glycation, have been identified as potential glycation sites in the longest human tau isoform [248,297]. Among the modified lysines, those located in the sequence comprising residues 318–336 (according to the numbering of the longest human tau isoform) are found to be glycated, as determined by the reaction with an antibody that recognizes a glycated peptide containing this sequence. Because those lysines are present in a tubulin binding motif of tau protein, their modification could result in a decreased interaction of tau with tubulin [248]. Finally, AGE-tau generate oxygen free radicals that could activate transcription via NF-kB, increase bPP and release 4 kDa amyloid peptides similar to Ab. Therefore, glycated tau could induce oxidative stress which may contribute to the pathogenesis of AD [419].

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3.2.3. Neuronal redox potential Recombinant tau-derived constructs including the repeat domains can aggregate into synthetic PHF. It has been shown that the essential first step for this process is the formation of antiparallel dimers linked by disulfide bridges [413]. Moreover, this assembly could be inhibited by blocking the SH group of the single Cys322 residue, or by mutating Cys for Ala, or by keeping tau in a reducing environment. Likewise, in the case of 4R-tau constructs, repeats 2 and 3 may be linked via an intramolecular disulfide bridge involving the residues Cys291 and Cys322 respectively. Thus, these constructs form compact monomers but cannot aggregate into synthetic PHF. This would explain the poor assembly of the 4R-tau isoform [349]. In conclusion, the intermolecular disulfide bonds involving the Cys322 residue of tau protein is probably important in the polymerization into PHF, but cannot explain all the process. Furthermore, these data imply that the oxidative redox potential in the neuron is crucial for PHF assembly, independently or in addition to pathological phosphorylation reactions.

3.2.4. N- and O-glycosylations It has been reported that hyperphosphorylated tau proteins in AD brain are N-glycosylated and that the glycan(s) maintains the helicity of PHF, but does not have any apparent direct effect on the ability of tau to promote the assembly of microtubules [409]. Conversely, tau proteins are normally O-glycosylated [13]. However, O-GlcNAc has been reported to be upregulated in AD. This increase is specific for proteins associated with the detergent insoluble cytoskeleton [158]. All of these data suggest that glycosylation may be implicated in PHF formation as well as stabilization in AD.

3.2.5. Transglutaminase Tissue transglutaminase (TGase) is a calcium-activated enzyme that catalyzes the formation of bonds between glutamine residues and primary amines included in peptide-bound lysine residues or polyamines. TGase crosslinks specific substrate proteins into insoluble and protease-resistant high molecular weight complexes (for review, see Ref. [69]). Due to this ability of cross-linking activity, the involvement of TGase in tau aggregation into PHF was suggested. Thus, TGase-treated human recombinant tau formed filamentous structures in vitro that are immunoreactive with antibodies to tau and TGase [10]. Likewise, PHF isolated from NFT from AD brain are immunoreactive to TGase antibody. These results indicate that tissue transglutaminase may play a role in the formation of tau pathology associated with AD [103,284,302]. A transglutaminase-induced crosslinking of tau proteins leading to neurofibrillary tangle formation has also been suggested in progressive supranuclear palsy (PSP) [424].

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3.2.6. Proteolysis It has been suggested that truncation of tau proteins may precede their assembly into PHF, rather than reflecting proteolytic cleavage of full length tau assembled into extracellular tangles [110,303]. However, numerous studies have investigated the proteolysis of tau proteins by calpain, a calcium-dependent protease, and have demonstrated an increased resistance of PHF-tau proteins compared to normal tau proteins. Thus, normal tau proteins isolated from fetal or adult human brain are similarly and rapidly proteolyzed by calpain in vitro, and the formation of N-terminal tau fragments suggests that calpain-sensitive sites may be located in the C-terminal part of tau proteins. Conversely, PHF were extremely resistant to degradation, and only a partial proteolysis was obtained with a higher concentration of calpain, giving rise to a major C-terminal fragment of PHF-tau. These data suggest that the potential calpain-digestion sites buried in the core of filaments could become inaccessible to the protease, leading to the resistance of PHF to calpain-proteolysis, and subsequently to the accumulation of PHF in AD [421]. Finally, recent data indicate that the conformation of tau proteins into PHF, rather than hyperphosphorylation [260], is the major factor responsible for the resistance of abnormal filaments to calpain-mediated proteolysis [420]. In this context, tissue transglutaminase may play a crucial role in aggregation of tau proteins [392]. 3.2.7. Cofactors 3.2.7.1. Apolipoprotein E. Apolipoprotein E (ApoE), an heterogeneous protein with three major isoforms in humans (E2, E3, and E4 corresponding to three alleles ´2, ´3 and ´4), plays a critical role in lipid metabolism. It has been demonstrated that ApoE is a risk factor for AD, in that the ´4 allele frequency is increased in AD patients when compared to the normal population. Following that finding, it was shown that ApoE is bound to senile plaques and NFT [55,298], and could contribute to the formation of these lesions [320,378]. ApoE may play a secondary role in NFT formation or accumulates within the neurons in response to reparative processes induced by NFT-associated neuronal damage [23]. 3.2.7.2. Glycosaminoglycans. Glycosaminoglycans (GAGs) are the carbohydrate moiety of proteoglycans. They are polysaccharides containing hexuronic acid and hexosamine which may be further modified by sulfation and acetylation. There are four major classes of GAGs including chondroitin sulfate, dermatan sulfate, keratan sulfate, and heparan sulfate. Heparan sulfate is the most complex GAG, containing glucuronic acid linked to Nacetylglucosamine. Heparin (an analog of heparan sulfate) is more highly charged than heparan sulfate due to its high degree of sulfation. In AD, proteoglycans / GAGs are found in amyloid deposits and NFT [54,365,366]. There is a

strong interaction between the Ab amyloid peptide and GAG [52,53,364]. More recently, a strong binding of GAGs to the microtubule-binding domains of tau proteins has been shown suggesting that GAGs may enhance tau aggregation and disturb microtubule assembly [140,315,375]. Finally, GAGs may be responsible for PHF helicity [15].

3.2.7.3. Other polyanions ( RNA and lipids). Glycolipids have been reported to be associated with PHF [151,152]. Furthermore, phospholipids induce conformational changes of tau proteins that may facilitate their abnormal phosphorylation. Moreover, recent data have indicated that specific lipids including arachidonic acid may enhance the in vitro formation of straight filaments using tau proteins [414]. In the same manner, PHF assembly using recombinant tau proteins is strongly enhanced by ribonucleic acids [229]. It should be noted that RNAs have been found in NFT [133]. 3.2.7.4. Aluminum. Many metals have been involved in neurodegenerative disorders. Among them, aluminum has been directly implicated in tau aggregation and neurodegeneration (for review, see Ref. [358]). Aluminum has been reported in NFT not only in AD [317], but also in other neurodegenerative disorders including Guamanian amyotrophic lateral sclerosis / parkinsonism–dementia complex (for review, see Ref. [124]). It also facilitates tau aggregation in a phosphate-independent manner, without involving the formation of fibrils [350].

4. 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 the following sections, we review recent data on the characterization of aggregated tau proteins in different neurodegenerative disorders (for review, see Refs. [51,387]).

4.1. Alzheimer’ s disease 4.1.1. Description Alzheimer’s disease is a progressive neurodegenerative disorder that leads to dementia, and affects approximately 10% of the population older than 65 years of age [337]. Memory loss is the first sign of cognitive impairment, followed by aphasia, agnosia, apraxia and behavioral disturbances. The two main types of brain lesions observed

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in AD are senile plaques (SP) and neurofibrillary tangles (NFT). Senile plaques result from the extracellular accumulation of a peptide referred to as Ab into amyloid deposits. Ab derives from a precursor, the b-amyloid precursor protein (APP). In cases of familial AD, mutations have been found on APP gene, suggesting that it plays a central role in the etiopathogenesis [172]. SP are diffusely and variably distributed throughout the cerebral cortex and in subcortical structures. NFT correspond to the aggregation of abnormal fibrils into PHF [232], within certain vulnerable neuronal populations. At the microscopic level, NFT are preferentially observed in the large pyramidal cells of the hippocampus and the entorhinal cortex (Fig. 5A), and the supragranular (II–III) and infragranular (V–VI) layers of the association cortical areas (Fig. 5B and C), while primary sensory and motor cortices are relatively spared [14,39,91,107,195,201].

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Many cortical and subcortical areas, such as nucleus basalis of Meynert, amygdala, locus coeruleus and dorsal raphe, are also affected by NFT formation [37,330,415]. The demonstration of both SP and NFT within specific regions of the cerebral cortex is necessary to establish the diagnosis of definite AD, according to NINCDS–ADRDA criteria [212,282]. However, NFT lesions with a lower density are also present in entorhinal cortex and hippocampus of elderly normal brains (Fig. 5D and F), whereas neocortex exhibits only isolated NFT (Fig. 5E).

4.1.2. Tau phosphorylation in Alzheimer’ s disease The major antigenic components of PHF are tau proteins [44,87,144,160], and several groups have reported phosphorylation as the major modification of these proteins [116,154,161,213]. Their biochemical characterization by immunoblotting reveals the presence of a triplet of proteins

Fig. 5. Lesion distribution in an AD case (A–C) and in patient suffering very mild cognitive impairment and had a Clinical Dementia Rating score of 0.5 (D–F). The AD case displays high NFT and neurite densities, as well as some neuritic plaques (arrow), in the CA1 field of the hippocampus (A). These lesions are observed throughout the cortical layers in prefrontal area 46 (B, C). The arrow in C points to a neuritic plaque, the small arrows to NFT, and the arrow heads identify neuritic changes. The case with very mild cognitive changes shows involvement of neurons in layer II of the entorhinal cortex with a comparably minor neuritic involvement (D, F). The neocortex of this case displays only isolated NFT (arrow in E; most NFT were observed in Brodmann’s area 20 in the inferior temporal cortex). Materials were stained with antibody AD2. Arrowheads mark the boundaries of layers I, II, and III in B and E. Scale bar (on F)5400 mm (A, B, D, E) and 100 mm (C, F).

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(tau55, 64 and 69) also referred to as A68, or PHF-tau [88,138,154,255]. However, a 72–74 kDa component is also present in only very low amounts and corresponds to the longest tau isoform [45,142,293,353] (Figs 4,6). Using PHF-tau preparations, Goedert and colleagues showed that dephosphorylated PHF-tau proteins have a similar electrophoretic mobility than the six recombinant tau isoforms [142]. The following scheme is now well established: tau55 results from the phosphorylation of the fetal isoform (2232102), tau 64 from the phosphorylation of tau variants with one cassette exon (2132102 and / or 2232 101), tau69 from the phosphorylation of tau variants with two cassette exons (2131102 and / or 2132101). Phosphorylation of the longest tau isoform (2131101) induces the formation of the additional hyperphosphorylated tau74 variant [272,352,353] (Fig. 6). However, it is likely that both the size of tau isoforms and phosphorylation are responsible for variations in their electrophoretic mobility. For instance, phosphorylation of the longest tau isoform may lead to the formation of tau variants with molecular weights ranging from 68 to 72 kDa according to their degree of phosphorylation [293].

4.1.3. PHF-tau are reliable markers of NFT in aging and AD Using immunological probes specific of tau phosphoryl-

ation sites, it is possible to investigate biochemically NFT in postmortem brain materials. A strong correlation between the immunohistochemical detection of NFT and the presence of the tau triplet has been demonstrated, indicating that it is a reliable marker of the degenerating process. Therefore, the pathological tau proteins can be used to quantify neurofibrillary degeneration [115], and biochemical mappings using immunoblotting and / or ELISA have been performed in several cortical areas of the brain from patients with senile dementia of the Alzheimer type [207,401]. These analyses revealed that the detection of the pathological tau triplet is present in all studied areas, with the exception of regions such as primary motor and visual cortices (Brodmann’s areas 4 and 17, respectively). The detection is particularly strong in association cortex compared to primary sensory cortex, with the highest levels in temporal neocortical and limbic areas. However, for a given brain area, tau immunoreactivity varies among cases [207,401]. In a study of 130 cases with cognitive status ranging from normal aging to severe AD, PHF-tau were quantified by immunoblotting in different cortical areas, and these data were related to clinical and neuropathological data [86,90]. This study allowed to predict a sequential biochemical pathway of PHF-tau in cortical brain areas, referred to as the neurofibrillary degeneration pathway,

Fig. 6. Typical electrophoretic profiles of pathological tau proteins using the phosphorylation-dependent monoclonal antibody AD2 (in frame), with schematic representation of isoforms composition (right of each frame). The six tau isoforms are involved in the formation of the typical AD-triplet with the minor tau74 variant. This pattern is also described in Down syndrome (DS), post-encephalitic parkinsonism (PEP), ALS / PDC guamanian syndrome (ALS / PDC) and some families with FTDP-17 (left panel). The typical PSP/ CBD doublet tau64, 69 is related to the aggregation of hyperphosphorylated tau isoforms with exon 10. The FTDP-17 families with mutations in exon 10 or intron 10 exhibit the same profile (middle panel). Hyperphosphorylated tau proteins without exon 10 aggregated in Pick’s disease are detected as a tau55, 64 doublet (right panel). Color codes are similar to those used in Figs. 1 and 3.

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comparable to the neurofibrillary degeneration stages previously described in neuropathologic studies [14,36,39,106]. In fact, PHF-tau were consistently detected in the entorhinal cortex of non-demented individuals aged over 75 years, and the hippocampus was also frequently affected. In these aged controls, PHF-tau were visualized as the characteristic tau triplet, similar to that found in AD brains but in lower amounts [86,90,398,400]. During the earliest stages of AD with moderate decline of cognitive functions, the neurofibrillary degeneration pathway is highly specific, spreading from the hippocampal formation to the anterior, inferior, and mid temporal cortex. Then, the disease progresses into association areas of the temporal (superior), parietal and frontal cortex. Lastly, primary motor or sensory areas such as the primary motor cortex or the primary visual cortex are affected. This study shows that neurofibrillary degeneration has to involve almost the entire temporal cortex to induce overt clinical manifestations [86,90]. Comparable data were obtained using a classical immunohistochemical approach on smaller populations with fewer brain regions investigated [25,34,35,106,202]. These studies also demonstrate that AD is a disease involving the long corticocortical connections. In fact, these are specifically affected with a well-defined pattern, involving subsets of pyramidal neurons that are found mainly in layers III and V of the neocortex [199,203].

4.2. Parkinsonism 4.2.1. Parkinsonism with dementia The most characteristic clinical features of Parkinson’s disease include resting tremor, expressionless face, rigidity, and slowness in initiating and performing voluntary movements. Neuropathologically, Parkinson’s disease is characterized by neuronal loss, especially in substantia nigra and locus coeruleus, and the presence of intracellular inclusions called Lewy bodies and Lewy neurites [120]. Recent studies suggest that a-synuclein is the major component of Lewy body filaments [374,406,407]. There is no data available about tau pathology in patients exhibiting cortical Lewy bodies. Thus, it should be noted that Parkinson’s disease is not considered as a real tauopathy. Nevertheless, in a subgroup of patients without any cortical Lewy bodies, a tau pathology has been described by Vermersch and colleagues using a Western blotting approach. A tau triplet similar to that described in AD is present in particularly large amounts in the prefrontal, temporal and entorhinal cortex of all Parkinson’s disease patients with dementia. Therefore, AD-type proteins are sometimes found in Parkinson’s disease with dementia, but the cortical distribution differs from the pattern seen in AD, with a significantly stronger involvement of prefrontal areas [399]. In cases without dementia, a tau pathology restricted to the hippocampal formation has been described in elderly individuals [400].

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Thus, a small group of patients presenting with Parkinson’s disease may also develop an AD-like tauopathy.

4.2.2. Postencephalitic parkinsonism Many patients who survived the influenza pandemic in the years 1916–1926 later developed postencephalitic parkinsonism (PEP) [57,126,198]. Extrapyramidal symptoms are the major clinical features and affected patients do not exhibit any cognitive changes and are usually neither aphasic nor apraxic. The immunohistochemical analysis of the brain of PEP cases demonstrated that NFT are found in variable densities in the hippocampus and entorhinal cortex, in neocortical areas 4, 9 and 20 and in subcortical regions (Fig. 7B and C). Higher NFT densities are observed in the hippocampus (CA1 and subiculum; Fig. 7A) and area 20, compared to areas 4 and 9, and the putamen, indicating that some regions are preferentially affected by the degenerative process. In addition, and contrasting with AD cases, NFT are more numerous in supragranular than in the infragranular layers [198]. Biochemical studies have shown that the PEP cases display the tau55, 64 and 69 triplet in cortical and subcortical brain regions, in contrast to AD cases where this triplet is mainly restricted to the hippocampal formation and association neocortex [57] (Fig. 6). Also, the tau triplet is found in brain areas usually spared in AD including primary motor cortex and basal ganglia. The regional distribution of the tau triplet differs among PEP cases, suggesting some heterogeneity in the neurodegenerative process [57]. 4.2.3. Guamanian ALS /PDC The amyotrophic lateral sclerosis / parkinsonism–dementia complex of Guam (ALS / PDC) is a chronic neurodegenerative disorder highly prevalent in the native Chamorro population of Guam in the Western Pacific [188]. Clinically, Guamanian amyotrophic lateral sclerosis (ALS) is indistinguishable from sporadic ALS and presents with fasciculations and lower and upper motor neuron signs. Parkinsonism–dementia is characterized by an insidious progressive mental decline and extrapyramidal signs including bradykinesia, rigidity and less often tremor [70,189]. Both aspects of the disease are frequently associated, but they are known to occur separately. The etiopathogenesis of this disorder is not yet elucidated, although environmental factors such as aluminum or neurotoxins might be involved [124]. The brain of Guamanian ALS / PDC patients exhibit a severe cortical atrophy and neuronal loss. The neuropathological hallmark is the widespread NFT formation, especially in the temporal and frontal isocortex, hippocampal formation and several subcortical structures [188,189] (Fig. 7D and F). Although NFT are numerous in both AD and ALS / PDC, these two conditions are distinguished by differential NFT laminar distribution patterns and densities in neocortex. NFT are preferentially distributed within

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Fig. 7. Lesion distribution in a PEP case (A–C) and in a Guamanian ALS / PDC case (D–F). In both conditions there are high NFT and neurite densities in the CA1 field of the hippocampus (A, D). The PEP case shows moderate densities of relatively small NFT throughout layers II and III of the frontopolar region (Brodmann’s area 10) and very high numbers of neurites (B). The neocortex of the Guamanian case displays the characteristic NFT distribution of ALS / PDC with most lesions localized in layer II and the superficial third of layer III (E; from Brodmann’s area 20 in the inferior temporal cortex). At higher magnification, NFT have a comparable morphology in PEP and Guamanian ALS / PDC (C, F; from layer III of area 20) In C and F, the large arrows point to NFT and the small arrows to neuritic alterations. Arrowheads mark the boundaries of layers I, II, and III in B and E. Materials were stained with antibody AD2. Scale bar (on F)5400 mm (A, B, D, E) and 100 mm (C, F).

layers II–III in the neocortical areas of Guamanian ALS / PDC cases and are relatively sparser in layers V–VI (Fig. 7E), whereas NFT are generally denser in layers V–VI in AD cases [202,204,307,308]. Immunohistochemical studies have also revealed that pathological tau proteins are present in NFT of ALS / PDC patients [56,61,202]. By using Western blotting and numerous phosphorylationdependent antibodies, these proteins can be visualized as a triplet tau55, 64, 69 [56] (Fig. 6). The ultrastructure of NFT consists of straight filaments and PHF [330], and PHF have been shown to be essentially similar to those observed in AD [187]. According to the neuropathological data, and in contrast to AD patients where the tau triplet is found mostly in cortical regions, the Guamanian tau triplet is detected in both cortical and subcortical areas. Finally, the pathologi-

cal tau proteins found in Guam ALS / PDC and AD share the same biochemical properties, but differ by their regional and laminar distribution in the brain of patients [56]. Since the etiology of Guamanian ALS / PDC is probably different from that of AD, this also demonstrates that neurofibrillary degeneration with a tau triplet 55, 64, 69 detected in both disorders most likely reflects a similar response to different types of neuronal insults. In this context, ALS / PDC of Guam and PEP have been linked to external factors such as viruses and toxins that may lead to similar neuropathology, characterized by the same tau electrophoretic profile. However, it is not known whether tau pathology in Guamanian ALS / PDC may be also related to mutations in tau gene in the Chamorro population. Recent linkage analyses and genetic studies do not support the involvement of tau gene mutation as a primary

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cause for the disease, although it does not rule out the possibility of tau proteins being important downstream in the process [316]. Unknown genetic factors may also play a major etiopathogenic role in Guamanian ALS / PDC.

and 24. Conversely, the other PSP studied cases with dementia contained large amounts of pathological tau proteins in the neocortex especially in Brodmann areas 4 and 6 and in subcortical structures.

4.2.4. Progressive supranuclear palsy Progressive supranuclear palsy (PSP) is a late-onset atypical parkinsonian disorder described by Steele, Richardson, and Olszewski in 1964 [377]. This neurodegenerative disorder is characterized by supranuclear vertical gaze paralysis, moderate or severe postural instability with falls during the first year after onset of symptoms, facial, nuchal and troncular dystonia. Dementia is also a common feature at the late stages of the disease [261–263]. Neuropathologically, PSP is characterized by neuronal loss, gliosis and NFT formation. Neurofibrillary tangles were first described in basal ganglia, brainstem, and cerebellum [377], and the subcortical localization of the neuropathological lesions initially led to the definition of PSP as a model of ‘subcortical dementias’ [3,81]. Later on, degenerative profiles have been described in the perirhinal, inferior temporal and prefrontal cortex, with variable densities of NFT among cases [24,179,200] (Fig. 8A and B). These studies also demonstrated that the primary motor cortex is more severely affected than neocortical association areas compared to AD [179,200] (Fig. 8C). Furthermore, glial fibrillary tangles have also been described [24,27,71,179,324]. Ultrastructural analyses further point to major differences between AD and PSP, since PHF are found in AD [232], while straight filaments are observed in PSP [384,389]. The electrophoretic profile of pathological tau proteins in PSP is substantially different from that in AD, as a characteristic doublet is found (tau64 and tau69) instead of the triplet found in AD [118,402]. A minor 74 kDa band is also detected (Fig. 6). In fact, hyperphosphorylated tau isoforms with sequence encoded by exon 10 are much more abundant and aggregate into filaments in PSP, whereas tau isoforms without exon 10 are not detected [272,355] (Fig. 6). However, most of the phosphorylation sites found in PHF-tau are also encountered in pathological tau proteins from PSP patients [346]. Biochemical mapping performed on several cortical and subcortical areas from PSP brain has revealed that the doublet of tau 64 and 69 is first detected in the subcortical regions where NFT are found, neocortical areas being affected later [402]. These results are in good agreement with previous neuropathological results that show a cortical involvement [179,200]. It is interesting to note that the presence of NFT in cortical areas is always correlated to dementia. We had the opportunity to analyze materials obtained from a nondemented very young (33-year-old) PSP patient. In this case, abnormally phosphorylated tau proteins were found in both basal ganglia and thalamus, whereas they were absent in all of the other areas studied including amygdala, hippocampus, and Brodmann’s areas 4, 9, 11, 17, 18, 20

4.2.5. Corticobasal degeneration Corticobasal degeneration (CBD) is a rare, sporadic and slowly progressive neurodegenerative disorder. It is clinically characterized by cognitive disturbances like aphasia and apraxia, and extrapyramidal motor dysfunction, like rigidity, limb dystonia, akinesia and action tremor [326]. Moderate dementia emerges sometimes late in the course of the disease [335]. There is a clinical and pathological overlap between PSP and CBD [113,261,263], and it would be most helpful to distinguish these two pathologies on a neuropathological or immunochemical basis. Neuropathological examination reveals a frontoparietal atrophy of the brain [408], and also glial and neuronal abnormalities. Thus, the glial pathology is dominated by the description of astrocytic plaques, and numerous tau-immunoreactive inclusions in the white matter [111,113,278]. The presence of achromatic ballooned neurons has been shown in cortex, brainstem and subcortical structures, as well as neuritic changes and NFT. These lesions can be visualized with phosphorylation-dependent anti-tau antibodies [59,111,244,314] (Fig. 8D and F). The electrophoretic profile of tau pathological proteins in CBD is similar to that of PSP [59,244], and is described as a tau64, 69 doublet (Fig. 6). However, the components may be different since this doublet is not detected in CBD using antibodies raised against the region encoded by exon 3 [244]. These data have been confirmed by immunohistochemistry [112]. Moreover, in a recent study, tau isoforms with sequence encoded by exon 10 were found in CBD, whereas tau isoforms without exon 10 were not detected (Fig. 6). These data suggested that mainly isoforms with four microtubule-binding domains aggregate into filaments in CBD [272,355]. In this respect, the only isoform with sequence encoded by both exons 3 and 10 is the longest tau isoform. Since the longest tau isoform is found in very low amounts in the human brain, it may explain why some investigators did not find any immunoreactivity for the sequence encoded by exon 3 [112,244]. Thus, hyperphosphorylation of different tau isoforms (with or without exon 10) may lead to similar electrophoretic profiles. These data confirm the observation that both size and phosphorylation of tau isoforms are responsible for the observed differences in tau electrophoretic mobility. 4.3. Frontotemporal dementia 4.3.1. Pick’ s disease Pick’s disease is a rare form of neurodegenerative disorder characterized by a distinct progressive dementing process. Early in the clinical course, patients show signs of frontal disinhibition including mood disturbances and

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Fig. 8. Lesion distribution in PSP (A–C), CBD (D–F), and Pick’s disease (G–I). The CA1 field of the hippocampus (A, D) contains an intense neuritic degeneration in PSP and CBD, as well as NFT (arrow) and some swollen neurons. A comparable severity of pathologic alterations is observed in the prefrontal cortex of the PSP case (B; Brodmann’s area 46), and in the inferior temporal cortex of the CBD case (E). In both conditions, the primary motor cortex is dramatically affected and shows a very high density of neuritic changes, NFTs (arrow), and swollen neurons (arrowhead) as well as coiled bodies (small arrow) (C, F). In Pick’s disease, the granule cell layer of the dentate gyrus displays the characteristic distribution and very high densities of Pick bodies (G). Pick bodies are preferentially distributed in layers II and V–VI of the frontopolar neocortex, where they coexist with immunolabeled swollen cells (arrow), neuritic changes, glial tangles (arrowhead) and NFTs (small arrow) (H, I). Arrowheads mark the boundaries of cortical layers in B, E and H. Materials were stained with antibody AD2. Scale bar (on F)5400 mm (A, B, D, E, G, H) and 100 mm (C, F, I).

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progressive language impoverishment leading to mutism [78]. Neuropathologically, Pick’s disease is characterized by prominent frontotemporal lobar atrophy, gliosis, severe neuronal loss, ballooned neurons and the presence of neuronal inclusions called Pick bodies in both cortical and subcortical structures [47,386]. Pick bodies are labeled by anti-PHF-tau antibodies, with a higher density in the hippocampus than in the neocortex [59,89,196] (Fig. 8G and I). In the hippocampus, Pick bodies are numerous in the granule cells of the dentate gyrus (Fig. 8G), in the CA1 field, the subiculum and the entorhinal cortex, whereas in the neocortex, they are mainly found in layers II and VI of the anterior segment of temporal and frontal lobes (Fig. 8H and I). Some NFT may be also found in the hippocampus and are usually considered as part of aging. The biochemical analysis using a quantitative Western blot approach with phosphorylation-dependent anti-tau antibodies has revealed that in all studied cases of Pick’s disease, a major 55 and 64 kDa tau doublet is observed in the isocortex, in the limbic areas and in subcortical nuclei [59,89] (Fig. 6). In addition, a very faint band is observed at 69 kDa. In the neocortex, all Brodmann areas of the prefrontal and temporal cortices are affected. The parietal cortex is sometimes involved while the occipital cortex is spared. In subcortical structures, the doublet of pathological tau is found in the striatum, substantia nigra, locus coeruleus, and brainstem. The 55 and 64 kDa doublet is characteristic of Pick’s disease because it is different from the tau triplet of AD or the doublet tau55, 64 in CBD and PSP [59,272] (Fig. 6). Moreover, pathological tau proteins in Pick’s disease can not be detected by the monoclonal antibody 12E8 raised against the phosphorylated residue Ser262 [325]. This result indicates that this site is not phosphorylated in tau proteins aggregated in Pick bodies. Finally, the characteristic electrophoretic pattern of pathological tau in Pick’s disease is well correlated with the presence of Pick bodies [89]. Pick bodies are commonly encountered in granule neurons of the dentate gyrus of the hippocampus [89,196], and these neuronal cells do not contain tau isoforms with exon 10 [145]. As expected, Pick bodies and the tau doublet tau 55 and 64 are not labeled with immunological probes directed against the sequence encoded by exon 10 [354]. Thus, particular sets of tau isoforms that aggregate in subpopulations of neurons may lead to a specific electrophoretic tau profile [90,272].

4.3.2. Non-Alzheimer non-Pick frontal lobe degeneration Frontal lobe degeneration (FLD) is a common neurological disorder that leads to dementia [163]. The first symptoms appear in the presenium and the onset is usually slow and insidious. The clinical characteristics are quite similar to that of Pick’s disease, with disturbances of behavior and speech. A ‘frontal’ distribution of morphologic changes is defined, since neuronal cell loss, spongiosis and gliosis are mainly described in the superfi-

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cial cortical layers of the frontal and temporal cortex [49]. However, while Pick’s disease is easy to diagnose neuropathologically, using the characteristic Pick bodies immunostained with antibodies against phosphorylated tau proteins such as AD2 [59,89,196], FLD has no specific neuropathological hallmarks although a classification in subgroups has been proposed [131]. To date, no tau pathology has been described by common biochemical or immunohistochemical methods.

4.4. Genetic disorders with tau pathology 4.4.1. Familial frontotemporal dementia and chromosome 17 -linked pathologies 4.4.1.1. Introduction. Historically, frontotemporal dementia (FTD) were often classified as a form of Pick’s disease, even when Pick cells or Pick bodies were not found [78]. However, this denomination may involve different subgroups of pathologies (see above), and the Lund and Manchester groups published in 1994 a consensus on Clinical and Neuropathological Criteria for Frontotemporal Dementia [49]. This publication clarified the position of Pick’s disease within FTD, and several of the reported cases of familial Pick’s disease were probably cases of familial FTD. Indeed it is difficult to ascertain families which have the classic pathological features of Pick’s disease from the literature [48], because they often have unusual clinical features. In 1994, Wilhelmsen and colleagues have described an autosomal dominantly-inherited disease related to familial FTD, characterized by adult-onset behavioral disturbances, frontal lobe dementia, parkinsonism and amyotrophy [412]. They demonstrated a genetic linkage between this pathology, denominated disinhibition–dementia–parkinsonism–amyotrophy complex (DDPAC), and chromosome 17q21-22 [269,412]. Since then, several families sharing strong clinical and pathological features and for which there is a linkage with chromosome 17q22-22 have been described [29,182,295,411]. They have been included in a group of pathologies referred to as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) [121]. 4.4.1.2. FTDP-17. Although a clinical heterogeneity could be described between and within the families with FTDP-17, usual symptoms include behavioral changes, loss of frontal executive functions, language deficit and hyperorality. Parkinsonism and amyotrophy are described in some families, but are not consistent features. Neuropathologically, brains of FTD patients exhibit an atrophy of frontal and temporal lobes, a severe neuronal cell loss, a grey and white matter gliosis, and a superficial laminar spongiosis. One of the main important characteristic is the filamentous pathology affecting the neuronal cells, or the

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both neuronal and glial cells in some cases. The absence of amyloid aggregates is usually established [121,371]. FTDP-17 has been related to mutations on the tau gene [210,322,372,373]. Tau mutations always segregate with the pathology and are not found in the control subjects, suggesting their pathogenic role. To date, 17 mutations have been described in the tau gene among the different families with cases diagnosed as FTDP-17 (Table 1). Ten missense mutations in coding regions K257T [319], I260V (M. Hutton, personal communication), G272V [210,372], N279K [73,82,92], P301L [105,182,210,371], P301S [60], S305N [178,214], V337M [177,322], G389R [296,319], R406W [210,328], one silent mutation L284L [82], one single amino acid deletion (DK280) [82,336], and four

intronic mutations in the splicing region following exon 10 at position 13 [373], 113 [210], 114 [210] and 116 [143] have been reported. A fifth intronic mutation with a likely pathogenic effect was recently described at position 133 [336] (Table 1). Depending on their functional effects, mutations on tau proteins may be divided into two groups: the mutations affecting the alternative splicing of exon 10, and leading to changes in the proportion of 4R- and 3R-tau isoforms, and the mutations modifying tau interactions with microtubules. The first group includes intronic mutations (13, 113, 114, 116) and some missense mutations. Intronic mutations disturb a stem loop structure in the 59 splice site of exon 10 that stabilizes this region of the pre-mRNA

Table 1 Tau gene mutations and FTDP-17 a Tau gene Mutation K257T

Location

missense

Exon 9 R1

Effects

Tau Pathology

Filamentous inclusions

References

tau mRNAs

tau proteins

ND

ND

Pick doublet?

Pick bodies

[319] Spillantini (pers. comm)

6 mRNAs mutated

Reduced binding to microtubules

AD triplet

PHF1SF Neurons only

[210,372]

Create an exon splicing enhancer ⇒Increased E101mRNAs

Increased 4R-tau isoforms

PSP doublet

Twisted ribbon filaments Neurons and glia

[73,82,92]

I260V G272V

missense

N279K

missense

DK280

deletion

⇒No E101mRNAs (mechanism unknown)

Increased 3R-tau 1 reduced binding to microtubules

ND

ND

[82,336]

L284L

silent

Destroy an exon splicing silencing element ⇒Increased E101 mRNAs

Increased 4R-tau isoforms

PSP doublet

Ultrastructure: ND Neurons and glia

[92]

P301L P301S

missense

Exon 10 R2

E101 mRNAs mutated

Reduced binding to microtubules

PSP doublet minor 72–74kDa variant

Twisted ribbon filaments Neurons and glia

[105,182,210,371] [60]

S305N

missense

Exon 10 R2–R3 IR

Create an exon splicing enhancer ⇒Increased E101mRNAs

Increased 4 R-tau isoforms?

PSP Doublet

SF Neurons and glia

[178,214,247]

13 113 114 116 133

intronic

Intron 10

Disturbance of stem loop structure ⇒Increased E101mRNAs

Increased 4R-tau isoforms

PSP doublet minor 72–74kDa variant

Twisted ribbon filaments filaments Neurons and glia

[373] [143,159,210]

Inhibition of splicing?

ND

ND

ND

[336]

V337M

missense

6 mRNAs mutated

Reduced binding to microtubules

PHF1SF Neurons only

[322]

AD triplet

ND

Pick doublet?

Pick bodies-like

[296,319]

Reduced binding to microtubules

AD triplet

PHF1SF Neurons only

[210,328]

G389R R406W a

missense

Exon 10 R1–R2 IR

Exon 12 R3–R4 IR Exon 13

Twisted ribbons refer to filaments with a longer periodicity than PHF; ND, not determined; AD triplet, tau 55, 64, 69; PSP doublet, tau 64, 69; Pick doublet, tau 55, 64; SF, straight filaments; IR, inter-repeat.

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[159,210,373,397] (Fig. 9). Sequence analysis of this splicing region in different animals indicates that the lack of the stem loop structure is associated with an increase in tau mRNAs containing exon 10 [159]. Indeed, without this stem loop, access of U1snRNP to this site may be facilitated, increasing the formation of exon 101 tau mRNAs and thus the 4R-tau isoform [82,159,397] (Fig. 6). Interestingly, in these families, abnormally phosphorylated 4R-tau isoforms aggregate into filaments and display a tau electrophoretic profile similar to the major tau doublet at 64 and 69 kDa found in PSP and CBD [59,118,244,372,373]. Some missense mutations (N279K and S305N) also modify the splicing of exon 10 [82,123]. For instance, the change in nucleotide for N279K and S305N mutations also creates an exon-splicing enhancer sequence [82]. The silent mutation L284L increases the formation of tau mRNAs containing exon 10, presumably by destroying an exon splicing silencing element [82]. Families with one of these three missense mutations display the same electrophoretic tau pattern than those having intronic mutations, namely a tau doublet at 64 and

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69 kDa (Fig. 6) [82,208,328]. Finally, the twisted ribbon filaments described in neurons and glial cells are a common neuropathological feature in all of the neurodegenerative disorders belonging to this first group. The second group of tau mutations found in FTDP-17 includes several missense mutations. The effects of mutations G272V, P301L, P301S, V337M and R406W in an in vitro system of microtubule assembly were reported by Goedert and colleagues. These authors showed that mutated tau isoforms bind microtubules to a lesser extent than wild type isoforms. They suggest that the mutated isoforms may induce microtubule disassembly [137,177]. These data are now confirmed by a number of studies [82,208]. When missense mutations are located in tau regions common to all isoforms, outside exon 10 (V272G, V337M, R406W), the six tau isoforms do not bind properly to microtubules. These proteins aggregate into PHF and straight filaments similar to those described in AD, and are present in neuronal cells. Their biochemical characterization shows a tau electrophoretic profile similar to the AD tau-triplet (tau55, 64 and 69; Fig. 6). Conversely, when missense

Fig. 9. Schematic representation of the tau gene mutations involved in FTDP-17. Tau gene mutations located either in exon 10 and outside the repeat domain R2 (N279K, L284L, S305N) (slashed frame), or in intron 10 (E1013,113, 114, 116) (dotted line) affect the alternative splicing of exon 10. They modify the regulatory elements of the splice site or disturb the stem loop structure in the 59 end of the site, respectively. The final effect is a modification of the 4R-tau / 3R-tau proportion. Mutations located in tau region common to all six isoforms, outside exon 10 (V272G, V337M, G389R, R406W), affect the binding of the six tau proteins to microtubules. The missense mutations located in the sequence of exon 10 corresponding to the R2 domain (P301L, P301S) (black box) affect only the 4R-tau binding. The DK280 mutation modifies the ration 4R-tau / 3R-tau and also affects the interaction with the microtubules. Mutations located in exons are indicated as peptidic sequence (framed part) and intronic mutations are indicated as nucleotidic sequence (dotted part).

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mutations are located in exon 10 (P301L, P301S), 4R-tau isoforms are affected, do not bind to microtubules, and aggregate into twisted ribbon filaments. This type of filamentous inclusions is described in both neurons and glial cells. The biochemical characterization shows a tau electrophoretic profile similar to the major tau doublet encountered in PSP and CBD (tau64 and 69; Fig. 6). The DK280 mutation is particular, since it modifies the ratio 4R-tau / 3R-tau and could also affect the interaction between tau and microtubules. This mutation may decrease the formation of tau mRNAs containing exon 10 and thus, enhancing the formation of 3R-tau isoforms. Moreover, this deletion mutation is also responsible for a considerably reduced ability of tau to promote microtubule assembly, and is stronger than the effect of the P301L mutation. No data are currently available on the biochemistry of tau aggregates in this family [82,336]. Mutations of the tau gene and their involvement in FTDP-17 emphasize the fact that abnormal tau proteins may play a central role in the etiopathogenesis of neurodegenerative disorders, without any implication of the amyloid cascade. The functional effects of the mutations suggest that a reduced ability of tau to interact with microtubules may be upstream of hyperphosphorylation and aggregation. These mutations may also lead to an increase in free cytoplasmic tau (especially 4R-tau isoforms), and therefore facilitating their aggregation into filaments [422]. In this respect, it is interesting to note that overexpression of tau was reported to block dynein-mediated axonal transport [108].

4.4.2. PSP polymorphism Although most cases of PSP are usually considered to be sporadic, De Yebenes and colleagues reported a family with autosomal dominant PSP, and mentioned six other families previously described [84]. Nevertheless, the typical missense or 59 splice site mutations described in exon 10 of the tau gene in FTDP-17 cases were not found in PSP cases [183,210]. However, Conrad and colleagues identified a polymorphic dinucleotide repeat sequence in the intron 9 of the tau gene, in a Caucasian population with PSP [77]. These authors described a significant overrepresentation of the A0 allele, characterized by the presence of 11 TG repeat, and of the homozygous genotype A0 /A0 in the PSP cohort (95.5%), compared to normal controls (57.4%) or patients with AD (49.7%). Recently, these data were confirmed by several studies and extended to a haplotype, including numerous single nucleotide polymorphisms spread out along the entire tau gene and one intronic 238bp deletion [17,22,33,109,183,184,291,304]. The deletion of 218 bp was described in the intron flanking exon 10, but its significance remains unclear [17]. It could influenced the exon 10 splicing and, thus, the proportion of tau-4R isoform. Finally, even though these recent data indicate that the dinucleotide polymorphism in the tau gene is

probably important in the pathogenesis of PSP, it remains to be determined whether it represents a primary event leading to the development of PSP. It should be noted that this polymorphism was also recently described in other pathologies including CBD and Parkinson’s disease [95,312].

4.4.3. Myotonic dystrophy Myotonic dystrophy is an autosomal dominant and slowly progressive multisystemic disorder characterized principally by myotonia, muscular atrophy, cataract and endocrine dysfunction [173]. Affected individuals present with a highly variable phenotype, ranging from an asymptomatic condition to a severe congenital form. Impairment of intellectual and cognitive function in myotonic dystrophy has been reported [221]. The molecular basis of the defect is an unstable CTG trinucleotide repeat in the 39 untranslated region of a gene encoding a putative Ser / Thr protein kinase (myotonic dystrophy protein kinase) (DMPK) located on chromosome 19 [63]. Expanded repeat shows particular effect on DMPK transcripts. In fact, these DMPK transcripts are retained within the nucleus and are absent from the cytoplasm [83,168]. Typically, neuropathological observations in myotonic dystrophy show reduced brain weight and minor abnormalities in gyral architecture. Microscopically, a disordered cortical cellular arrangement is described with neurons present in subcortical white matter, and intracytoplasmic inclusion bodies in cortical and subcortical structures [305]. The presence of abnormally frequent NFT has also been reported in the temporal lobe, especially in the parahippocampal gyrus from patients with myotonic dystrophy [233]. By immunoblotting, PHF-tau are also detected in the hippocampus, the entorhinal cortex and in most of the temporal areas. The amounts of pathological tau proteins are higher in the most severely affected myotonic dystrophy cases but always lower than in AD brain. Their profile differs from the characteristic triplet of AD, with no or low amounts of the tau69 variant but high amounts of the tau55 variant [403]. Interestingly, this pathology emphasizes the possible link between the genetic dysfunction of the Ser / Thr protein kinase and the presence of pathological tau proteins. These observations demonstrate that changes in kinase expression can induce a cascade of pathological events, including the formation of NFT in specific brain areas [403]. 4.4.4. Prion disorders with NFT ¨ Gerstmann–Straussler–Scheinker disease (GSS) is an autosomal dominant neurodegenerative disorder with a wide spectrum of clinical presentations including ataxia, spastic paraparesis, extrapyramidal signs, and dementia [128]. Neuropathologically, prion plaques are observed in many brain areas, associated with a severe neuronal loss and spongiosis. Exceptionally, NFT with tau proteins

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similar to PHF-tau of AD have also been described in GSS [129,130]. One patient from a large French GSS family with the mutation (A117V) in codon 117 of the prion gene developed NFT, especially around prion plaques, while other members of this family did not. The tau profile from the patient with GSS and NFT displayed some common features with AD, but also many differences. The three PHF-tau components (tau55, 64, 69) were present in extremely low levels, as well as their catabolic products. Most of the tau were highly aggregated and immunodetected as ‘smears’ intensely stained from the top to the bottom of the Western blot. The tau profile of the other members of the GSS family, whose brain did not contain NFT, is normal. The reason why some patients with GSS develop NFT remains unknown [390].

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childhood, adolescence or, occasionally, in adulthood. Common neurological manifestations are clumsiness, ataxia, supranuclear gaze paresis, seizures and psychomotor retardation [394]. Neuropathologically, brains from NPC patients show neuronal distension in cortex and swollen axons in brainstem. In NPC cases with a chronic progressive course, NFT with PHF are present in many parts of the brain, including hippocampus, neocortex and several subcortical structures [267]. PHF-tau in tangle-rich NPC brains are indistinguishable from PHF-tau in AD brains [16]. Recent data suggest that this cholesterol storage may be related to genetic defects in intracellular LDL-derived cholesterol trafficking linked to a gene referred to as NPC1 located on chromosome18 [67,266].

5. Tau proteins as peripheral markers

4.4.5. Down syndrome Due to the trisomy of chromosome 21, Down syndrome (DS) patients have numerous somatic dysfunctions that occur during development. In particular, a deficit of growth and maturation of the brain is consistently described, and the patients develop a variable degree of cognitive impairment, usually leading to dementia after 50 years of age [195]. Neuropathologically, a severe neuronal loss is described in the hippocampal formation and neocortex as well as in subcortical structures. The formation of NFT and amyloid deposits occurs prior to neuronal loss. A high density of diffuse amyloid deposits is observed after 15 years, followed by the massive deposition of senile plaques in the next decade of life. Neurofibrillary degeneration with tau accumulation appears later [197,275]. The hippocampal formation, including the entorhinal cortex, contains the highest number of NFTs, with layer II of entorhinal cortex involved in all the DS cases older than 35, followed by the subiculum and CA1–CA3 sectors in cases older than 45, and the perirhinal cortex in the oldest cases [195] (Fig. 10D and F). The laminar distribution of NFTs and SPs is similar to that in AD [197]. Using an immunoblot approach, it has been demonstrated that DS brain extracts contain significant amount of insoluble tau. This insolubility is correlated to an abnormal phosphorylation, as demonstrated by the detection of the typical AD triplet of pathological tau proteins in the isocortex of DS older than 35 years [117,169] (Fig. 6), indicating that biochemical dysfunctions linked to tau pathology during DS are very similar to those found in AD. 4.4.6. Niemann–Pick Type C disease Niemann–Pick Type C disease (NPC) is a cholesterol storage disease with defects of the intracellular trafficking of exogenous cholesterol derived from low density lipoproteins. NPC includes juvenile dystonic lipidosis, ophthalmoplegic lipidosis, neurovisceral storage disease with vertical supranuclear ophthalmolegia, and juvenile Niemann–Pick disease. The onset may be in infancy, early

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 test, emphasizing that the proposed marker should have a sensitivity of at least 80% for detecting AD and a specificity of at least 80% for discriminating other dementias, and should be reliable, non-invasive, simple to use and inexpensive [1]. Moreover, these biomarkers should be able to diagnose the disease at an early asymptomatic stage, thus increasing the efficiency of a hypothetical preventive treatment.

5.1. Olfactory system In 1989, Talamo and colleagues reported that neurons in the human olfactory epithelium taken at autopsy may express AD-type epitopes, such as phosphorylated neurofilaments or tau proteins [383]. Other reports also indicated a pathology of olfactory mucosa or olfactory cortex in AD patients [318]. In fact, tau antibodies revealed dystrophic neurites and NFT in autopsic or biopsic samples from olfactory epithelium of AD patients [241,254,331,382,416]. However, it has been shown that the detection of pathological tau proteins may be related to aging of the olfactory system [416], or may appear predominantly in the latest stages of AD [192]. Thus, the usefulness of a biopsy sample from the olfactory epithelium as an early and specific diagnostic tool is illusory.

5.2. Cerebrospinal fluid The presence of tau proteins in the cerebrospinal fluid

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Fig. 10. Lesion distribution in a FTDP-17 case (A–C) and in a 64-year-old Down syndrome case (D–F). The FTDP-17 case show low NFT densities and high numbers of neuritic lesions in the CA1 field of the hippocampus (A), and a few NFT (arrow) in the superficial layers of the inferior temporal neocortex (B, C). The Down syndrome case is characterized by a high degree of pathologic changes in the hippocampus (D), and a notable involvement of the inferior temporal cortex (E, F). Note the presence of NFT (arrowhead), neuritic plaques (arrow) and considerable neuritic changes (small arrows) in the Down syndrome brain (D–F). Materials were stained with antibody AD2. Arrowheads mark the boundaries of layer I, II, and III in B and E. Scale bar (on F)5400 mm (A, B, D, E) and 100 mm (C, F).

have been reported by numerous studies. Most of these use a sandwich ELISA method, that allows the quantitation of total tau proteins (PHF-tau and normal tau) [395]. A significant increase in tau concentration has been shown in CSF of AD patients and the sensitivity of this test depends on the control population used, ranging to 50–60% to 85–100% [9,11,12,30,31,122,193,220,224,246,287,292,294,334]. A high variability of the CSF-tau level exists among the different studies with concentration ranging from 40 to 820 pg / ml in AD cases, and from 27 to 380 pg / ml in control cases (for review, see Ref. [9]). Specificity of the assay seems to be low when studied populations include AD patients and patients with other neurodegenerative disorders exhibiting some similar clinical features like vascular dementia [9,31,361] or FTD [153]. The origin and the nature of intrathecal tau proteins

remain unclear. Tau antigens could derive from PHF, a specific lesion, or could be released following neuronal cell death, an aspecific feature of neurological disorders. Concerning the biochemical characterization of the CSFtau proteins, Johnson and colleagues have shown that tau-immunoreactive materials in CSF are mostly made of dephosphorylated and truncated N-terminal tau fragments [228]. Overall, an increase in tau proteins concentration in CSF has been described in AD, but several issues remain unclear. Extensive and accurate analysis of CSF could be helpful to define tau proteins species present in physiological conditions, or released during the progression of a given neurodegenerative disease. Thus, determining the isoform content of tau should add specificity to the biological test, because many neurodegenerative disorders can be distinguished by their set of tau isoforms that

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accumulate in neurons (see Section 4). Finally, recent studies suggest that a combined assessment of the two basic components of AD lesions, Ab1-42 which is significantly decreased and tau proteins significantly increased, improves the specificity and sensitivity of the biological test [7,8,209,230].

6. 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 ¨ and [46,150,218,376]. Previous data reported by Gotz colleagues indicated that in transgenic mice expressing the longest human brain tau isoform under the control of the human Thy-1 promoter, transgenic human tau proteins are present in nerve cell bodies, axons and dendrites. These proteins are phosphorylated at sites that are hyperphosphorylated in AD PHF, and their somatodendritic pattern is homogeneous or granular, but not fibrillar as described in AD neurofibrillary lesions [150]. Likewise, Spitteals and colleagues have described a similar transgenic model and reported that the induced intraneuronal excess of tau proteins caused an axonopathy, which is related to the level of expression of the transgene. A two- to three-fold increase in tau protein in the brain and spinal cord of homozygous transgenic mice resulted in somatodendritic redistribution, which is presumably a pretangle stage, and conformational alterations of the transgenic proteins [376]. Furthermore, transgenic mice expressing the shortest human tau isoform have been extensively described in two recent studies [46,218]. Results indicate that the transgenic tau expressed in these mice accumulate in the somatodendritic compartment, but are also detected in many axons. A substantial fraction of these proteins are insoluble, and the amount of these proteins progressively accumulates with age and disease progression, as in AD and other tauopathies. Thus, transgenic mice models of tauopathies exhibit similarities with the pathological mechanisms involved in AD, especially in regard to the aberrant intracellular targeting of tau proteins. Nevertheless, and like most of the animal models, they do not fully reproduce all of the features leading to the onset of tauopathies.

7. 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.

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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, according to the presence or absence of the peptidic sequence encoded by exon 10. Moreover, the presence of a pathologic tau triplet, as in AD, or doublet, as in PSP or CBD, may be specific of a subtype of neurons. For instance, only isoforms without exon 10 aggregate in granule cells of the dentate gyrus that exhibit Pick bodies in Pick’s disease. These data suggest that different tau isoforms (with or without exon 10) are expressed in subsets of neurons that exhibit differential vulnerability, in addition to possibly variable sets of enzymes (e.g. kinases, phosphatases). Notwithstanding the regional or laminar distribution or the electrophoretic pattern of tau proteins, their aggregation is always correlated to dementia when association neocortical areas are involved. The recent discovery of mutations on the tau gene, resulting in an abnormal aggregation of tau isoforms into filamentous inclusions in FTDP-17, demonstrates that abnormal tau metabolism is sufficient to induce nerve cell degeneration. Finally, an aberrant cell trafficking of tau proteins can be considered, since in neurodegenerative disorders, hyperphosphorylated tau proteins accumulate in somatodendritic compartments, instead of being located predominantly in axons. Since tau trafficking is phosphorylation-dependent, an abnormal phosphorylation of tau proteins may lead to aberrant cell trafficking and tau aggregation. Altogether, these data indicate that numerous mechanisms including cell vulnerability, regulation of many enzymes, tau mutations or aberrant cell trafficking could interact to disturb tau metabolism, and result in the disorganization of the cytoskeleton commonly observed in all of these neurodegenerative illnesses. But the key event is always the disorganization of the cytoskeleton leading to nerve cell degeneration.

Acknowledgements We thank Drs C. Bouras, J.P. David, M.B. Delisle, A. ´ C. DiMenza, D. Gauvreau, P. Giannakopoulos, V. Destee, 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 Institut de la ´ Sante´ et de la Recherche Medicale, the Centre National de ´ la Recherche Scientifique, Aventis, Conseil Regional Nord ˆ Pas-de-Calais (Pole Neurosciences), NIH Grants AG02219, AG05138 and AG14382, and the Brookdale

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Foundation. T.B. is the recipient of a fellowship from the Philippe Foundation. [17]

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