Tau protein isoforms, phosphorylation and role in ...

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

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Tau protein isoforms, phosphorylation and role in neurodegenerative1disorders

a , ,1 c ,1 b a*´ ` ´ ´ ´Luc Buee , Thierry Bussiere , Valerie Buee-Scherrer , Andre Delacourte ,,c,d,e*Patrick R. Hof

aINSERM U422, Place de Verdun, 59045 Lille cedex, Franceb ´ ´ ´Universite d’Artois, Faculte Jean Perrin, Laboratoire de Biochimie Moleculaire et Cellulaire, 62307 Lens cedex, France

cKastor Neurobiology of Aging Laboratories and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York,NY 10029, USA

dDepartment of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, NY 10029, USAeDepartment of Ophthalmology, Mount Sinai School of Medicine, New York, NY 10029, USA

Accepted 16 February 2000

Abstract

Tau proteins belong to the family of microtubule-associated proteins. They are mainly expressed in neurons where they play animportant role in the assembly of tubulin monomers into microtubules to constitute the neuronal microtubules network. Microtubules areinvolved in maintaining the cell shape and serve as tracks for axonal transport. Tau proteins also establish some links betweenmicrotubules and other cytoskeletal elements or proteins. Tau proteins are translated from a single gene located on chromosome 17. Theirexpression 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 numerousneurodegenerative disorders referred to as ‘tauopathies’. Molecular analysis has revealed that an abnormal phosphorylation might be oneof the important events in the process leading to their aggregation. Moreover, a specific set of pathological tau proteins exhibiting atypical biochemical pattern, and a different regional and laminar distribution could characterize each of these disorders. Finally, a directcorrelation 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 mutationsin frontotemporal dementia with parkinsonism linked to chromosome 17 has reinforced the predominant role attributed to tau proteins inthe pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronalpopulations 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 bodies and neurofibrillary tangles (NFT). Most areargyrophilic and among them, NFT are the most common.

Neurodegenerative disorders are characterized by neuro- They are consistently found in Alzheimer’s disease (AD)nal loss and intraneuronal accumulations of fibrillary [38] amyotrophic lateral sclerosis /parkinsonism–dementiamaterials. Neuropathologists distinguish several intracellu- complex of Guam [189], corticobasal degeneration [314],lar inclusions such as Hirano bodies, Lewy bodies, Pick dementia pugilistica and head trauma [80,194], Down

syndrome [197,276], postencephalitic parkinsonism[126,198], progressive supranuclear palsy [179,200,219],

*Corresponding authors. Tel.: 133-320-622-074; fax: 133-320-622-and sometimes in Pick’s disease [196]. They have been079.

¨described in patients with Gerstmann–Straussler–´E-mail address: [email protected] (L. Buee).1These authors contributed equally to this work. Scheinker syndrome [129,130], Hallervordern–Spatz dis-

0165-0173/00/$ – see front matter 2000 Elsevier Science B.V. All rights reserved.PI I : S0165-0173( 00 )00019-9

´96 L. Buee et al. / Brain Research Reviews 33 (2000) 95 –130

ease [273], myotonic dystrophy [233], Niemann–Pick 2.2. Splicingdisease [267], subacute sclerosing panencephalitis [19,283]and in other rare conditions. They are also seen in normal The tau primary transcript contains 16 exons. However,aging [18,388]. Hyperphosphorylated microtubule-associ- three of them (exons 4A, 6 and 8) are never present in anyated tau proteins are the main components of the aggre- mRNA in human brain. They are specific to peripheral taugated filaments found in NFT in AD proteins. Exon 4A is found in bovine, human and rodent[44,87,88,116,144,154,160,238,255]. Similarly, tau im- peripheral tissues with a high degree of homology. Taumunoreactivity is observed in NFT in most neurodegenera- mRNA with either exons 6 or 8 have not been described intive disorders as well as in aging human. Some transcripts with exon 8 are found in bovine[34,56,57,59,113,132,321]. and rhesus monkey brains [186,299].

Most of our knowledge on tau proteins derives from Exon 21 is part of the promoter, and is transcribed butdata obtained from AD cases. In this review, we describe not translated. Exons 1, 4, 5, 7, 9, 11, 12 and 13 arefirst what is known about tau structure at the gene and constitutive exons. Exon 14 is found in messenger RNA,protein levels. Second, we review how some mechanisms but it is not translated into protein [5,144,145,345]. Exonslead to the pathological aggregation of tau proteins. Then 2, 3 and 10 are alternatively spliced and are adult brain-we discuss the involvement of aggregated tau isoforms in specific [5]. Exon 3 never appears independently of exon 2several neurodegenerative disorders. Finally, the detection [4]. Thus, alternative splicing of these three exons allowsof tau proteins as peripheral markers of AD and their use for six combinations (2232102; 2132102; 2131102;as a diagnostic tool is evoked. 2232101; 2132101; 2131101) [144,145,240]. In the

human brain, the tau primary transcript gives rise to sixmRNAs [144,145,186] (Fig. 1).

2. Tau proteins 2.3. Structure and roles

Tau proteins belong to the microtubule-associated pro- In the brain, tau proteins constitute a family of sixteins (MAP) family [410]. They are found in many animal isoforms which range from 352 to 441 amino acids. Theirspecies such as Caenorhabditis elegans [134,281], Dro- molecular weight is ranging from 45 to 65 kDa when runsophila [65,217], goldfish [265], bullfrog [423], rodents on polyacrylamide gel electrophoresis in presence of[237,249], bovines [185,186], goat [299], monkeys [299], sodium dodecyl sulfate (SDS–PAGE). The tau variantsand human [144,145]. differ from each other by the presence of either three or

In human, they are found in neurons (for review, see four repeat-regions in the carboxy-terminal (C-terminal)Refs. [347,393]), although non-neuronal cells usually have part of the molecule and the absence or presence of one ortrace amounts. For instance, tau proteins can be expressed two inserts (29 or 58 amino acids) in the amino-terminalin glial cells, mainly in pathological conditions [71], and it (N-terminal) part [144,145,186,239] (Fig. 1). Each of theseis possible to detect tau mRNA and proteins in several isoforms is likely to have particular physiological rolesperipheral tissues such as heart, kidney, lung, muscle, since they are differentially expressed during development.pancreas, testis, as well as in fibroblasts [162,216,396]. For instance, only one tau isoform, characterized by the

absence of N-terminal inserts and the presence of threeC-terminal repeats, is present during fetal stages, while the

2.1. Gene organization six isoforms (with one or two N-terminal inserts and threeor four C-terminal repeats) are expressed during adulthood

The human tau gene is unique and located over 100 kb [136,240]. Thus, tau isoforms are likely to have specificon the long arm of chromosome 17 at band position 17q21 functions related to the absence or presence of regions[300], and contains 16 exons [4,5] (Fig. 1). The restriction encoded by the cassette exons 2, 3 and 10. Furthermore,analysis and sequencing of the gene shows that it contains the six tau isoforms may not be equally expressed intwo CpG islands, one associated with the promoter region, neurons. For example, tau mRNAs containing exon 10 arethe other with exon 9 [4,5]. The CpG island in the putative not found in granular cells of the dentate gyrus [144].tau promoter region resembles to previously described Thus, tau isoforms may be differentially distributed inneuron-specific promoters. Two regions homologous to the neuronal subpopulations.mouse Alu-like sequence are present. The sequence of thepromoter region also reveals a TATA-less sequence that is 2.3.1. Structure and functions of the projection domainlikely to be related to the presence of multiple initiation The two 29 amino-acids sequences encoded by exons 2sites, typical of housekeeping genes. Three SP1-binding and 3 give different lengths to the N-terminal part of tausites that are important in directing transcription initiation proteins. These two additional inserts are highly acidic,in other TATA-less promoters, are also found in the and are following by a basic proline-rich region. Theproximity of the first transcription initiation site [6,341]. N-terminal part is referred to as the projection domain

´L. Buee et al. / Brain Research Reviews 33 (2000) 95 –130 97

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 islocated 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). Thetau 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 nottranslated. 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 insix 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 thelongest 441-amino acids component (2131101), the 410-amino acids component (2131102), the 412-amino acids component (2132101), the381-amino acids component (2132102) and the 383-amino acids component (2232101). The shortest 352-amino acids isoform (2232102) is foundonly in the fetal brain, and thus is referred as fetal tau isoform.

since it projects from the microtubule surface where it may [66,79,157,180,344,351]. Through these interactions, tauinteract with other cytoskeletal elements and plasma proteins may allow microtubules to interconnect with othermembrane [43,191] (Fig. 2). cytoskeletal components such as neurofilaments

In mice lacking the tau gene, an increase in microtubule- [2,257,285] and may restrict the flexibility of the micro-associated protein 1A which may compensate for the tubules [279]. There is also evidence that tau proteinsfunctions of tau proteins has been observed [171]. How- interact with cytoplasmic organelles. Such interactionsever, axonal diameter in some neurons is particularly may allow for binding between microtubules and mito-affected. This may be related to the particular length of the chondria [329]. The tau N-terminal projection domain alsoN-terminal domain (with or without sequences encoded by permits interactions with the neural plasma membraneexons 2 and 3) of tau proteins in specific axons. In fact, [43]. Thus, tau may act as a mediator between micro-projection domains of tau determine spacings between tubules and plasma membrane. More recently, this inter-microtubule in axon and may increase axonal diameter action has been defined as involving a binding between the[68]. It should be noted that in peripheral neurons which proline-rich sequence in the N-terminal part of tau proteinsoften project a very long axon with large diameter, an and the SH3 domains of src-family non-receptor tyrosineadditional N-terminal tau sequence encoded by exon 4A is kinases, such as fyn [252]. Lee and colleagues have shownpresent, generating a specific tau isoform called ‘big tau’ that the SH3 binding PXXP motif is located in the[5,127]. These results strongly suggest that N-terminal sequence Thr–Pro–Pro–Lys–Ser–Pro–Ser of tau231 237

regions of tau proteins are crucial in the stabilization and proteins (according to the numbering of the longestorganization of certain types of axons. isoform). Moreover, they described the colocalization of

Tau proteins bind to spectrin and actin filaments tau and fyn just beneath the plasma membrane, and an


Fig. 2. Schematic representation of the functional domains of the longest tau isoform (2131101). The projection domain, including an acidic and aproline-rich region, interacts with cytoskeletal elements to determine spacings between microtubules in axons. The N-terminal part is also involved insignal 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 presenilin1(PS1).

association between the tau–fyn complexes and the actin merization in vitro, and are involved in axonal transportcytoskeleton. These data are in favor of a role for tau [32,42,74,75,301,410]. They have been shown to increaseproteins in src-family tyrosine kinase signalling pathway the rate of microtubule polymerization, and to inhibit thethat may modify the cell shape by acting on the submem- rate of depolymerization [99]. The 18-amino acid repeatsbranous actin cytoskeleton [252]. The same proline-rich bind to microtubules through a flexible array of distributedregion of tau proteins is likely involved in the interaction weak sites [62,251]. It has been demonstrated that adult tauwith phospholipase C-g (PLC-g) isozymes [211]. Hwang isoforms with 4R (R1–R4) are more efficient at promotingand colleagues have demonstrated in vitro that tau proteins microtubule assembly than the fetal isoform with 3R (R1,complex specifically with the SH3 domain of PLC-g, and R3, R4) [62,136,164,253]. Interestingly, the most potentenhance its activity in the presence of unsaturated fatty part to induce microtubule polymerization is the inter-acids such as arachidonic acid. These results suggest that region between repeats 1 and 2 (R1–R2 inter-region) andin cells that express tau proteins, receptors coupled to more specifically peptide KVQIINKK within this274 281

cytosolic phospholipase A2 may activate PLC-g indirectly, sequence. This R1–R2 inter-region is unique to 4R tau,in the absence of the usual tyrosine phosphorylation, adult-specific and responsible for a 40-fold difference inthrough the hydrolysis of phosphatidylcholine to generate the binding affinities between 3R and 4R tau [148,309].arachidonic acid [211]. Finally, Jenkins and Johnson have The microtubule-binding region may be also involved inrecently shown that in situ, the association between tau and other functions than microtubule assembly. In mice, recentPLC-g exist even in the absence of arachidonic acid [222]. data have shown that there is a strong interaction betweenAltogether, these data indicate that tau proteins may also tau and Eed proteins suggesting that tau proteins may playplay a role in the signal transduction pathway involving an important role in development [250]. Eed is highlyPLC-g. homologous to the Drosophila Esc protein that is a long-

term repressor of homeotic genes [348,359]. It is possible2.3.2. Structure and functions of the microtubule that some Eed isoforms, resulting from an alternativeassembly domain splicing, are specifically transported to the nucleus. Inter-

Tau proteins bind microtubules through repetitive re- estingly, it has been shown that tau proteins are also foundgions in their C-terminal part (Fig. 2). These repetitive in the nucleus [40,385]. The nuclear tau isoforms areregions are the repeat domains (R1–R4) encoded by exons similar to cytoplasmic tau, but they show lower solubility,9–12 [251] (Fig. 1). The three (3R) or four copies (4R) are suggesting that they undergo specific modifications, eithermade of a highly conserved 18-amino acid repeat post-translational (phosphorylation) or through interactions[145,186,249,251] separated from each other by less with other proteins, which may involve Eed proteins. It isconserved 13- or 14-amino acid inter-repeat domains. Tau interesting to note that recent data have shown that tauproteins are known to act as promoter of tubulin poly- proteins bind RNA through their microtubule-binding


domain [229]. Prior to their addressing in the nucleus, tau Ser198, Ser199Pro, Ser202Pro, Thr205Pro, Ser208,proteins are phosphorylated in the cytoplasm [155]. The Ser210, Thr212Pro, Ser214, Thr217Pro, Thr231Pro,function of nuclear tau and how it may be regulated by Ser235Pro, Ser237, Ser241, Ser262, Ser285, Ser305,phosphorylation is still unknown. Ser324, Ser352, Ser356, Ser396Pro, Ser400, Thr403,

Recent evidence supports a role for the microtubule- Ser404Pro, Ser409, Ser412, Ser413, Ser416 and Ser422Probinding domain in the modulation of the phosphorylation [176,268,290,313,338,380]. All of these sites are localizedstate of tau proteins. A direct and competitive binding has outside the microtubule-binding domains with the excep-been demonstrated between this part (residues 224–236 tion of Ser 262 (R1), Ser285 (R1–R2 inter-repeat), Ser305according to the numbering of the longest isoform) and (R2–R3 inter-repeat), Ser324 (R3), Ser352 (R4) andmicrotubules on one hand, and this part and protein Ser356 (R4) [144,338,356]. Most of these phosphorylationphosphatase 2A (PP2A) on the other hand [369]. As a sites are on Ser–Pro and Thr–Pro motives. A number ofconsequence, microtubules could inhibit PP2A activity by sites on non Ser /Thr–Pro sites have also been identifiedcompeting for binding to tau at the microtubule-binding [290]. The different states of tau phosphorylation resultdomains. Furthermore, a binding has been demonstrated from the activity of specific kinases and phosphatasesbetween the microtubule-binding domains and the residues towards these sites.250–298 of presenilin 1 (PS1) [381]. While this region ofPS1 is also involved in the binding of the kinase GSK-3b, 2.4.2.2. Kinases. Most of the kinases involved in tauPS1 may regulate the interaction between this enzyme and phosphorylation are part of the proline-directed proteintau proteins by bringing both into close proximity. kinases (PDPK), which include mitogen activated protein

kinase (MAP) [101,135,332,405], glycogen synthase ki-2.4. Post-translational modifications nase 3 (GSK3) [170], tau-tubulin kinase [380] and cyclin-

dependent kinases including cdc2 and cdk5 [21,264].2.4.1. O-glycosylation Stress-activated protein kinases (SAP kinases) have been

O-glycosylation is a dynamic and abundant post-transla- recently involved in tau phosphorylation [135,223,332].tional modification that is characterized by the addition of They may explain a number of observations. Thus, colda O-linked N-acetylglucosamine (O-GlcNAc) residue on water stress induces an immediate, i.e within 30–90 min, 2Ser or Thr in the proximity of Pro residues [166]. The to 3-fold increase in the phosphorylation of tau proteins inO-GlcNAc transferase was recently identified [242]. Al- rat brain, without direct involvement of the hypothalamic–though the functional significance of O-GlcNAc modi- pituitary–adrenal axis [236]. Similarly, heat–shock stressfication is not yet fully understood, it is implicated in also induces modifications of tau phosphorylation [310].transcriptional regulation, cell activation, cell cycle regula- Non Ser /Thr–Pro sites can be phosphorylated by manytion and the proper assembly of multimeric protein com- other protein kinases, including microtubule-affinity reg-

21plexes [174]. This modification is often reciprocal to ulating kinase (MARK) [100], Ca /calmodulin-depen-phosphorylation [72,165,206,256]. It occurs in neurofila- dent protein kinase II (CaMPK II) [20,227], cyclic-AMP-ments [97], microtubule-associated proteins including dependent kinase (PKA) [226,260] and casein kinase IIMAP2 [96] and tau proteins [13]. The number of O- [156]. Numerous kinases, proline-directed and non-prolineGlcNAcylated sites on tau proteins is lower than the directed, have to be used in tandem in order to observe anumber of phosphorylation sites. Site-specific or stoichio- complete phosphorylation of recombinant tau, and may bemetric changes in O-GlcNAcylation may modulate tau positively modulated at the substrate level by non-PDPK-function. In fact, phosphorylation and O-GlcNacylation catalyzed phosphorylations [360].may have opposite effects (see below for the role of tauphosphorylation). For instance, O-GlcNacylation of tau 2.4.2.3. Phosphatases. Tau proteins from brain tissue orproteins and other microtubule-associated proteins suggest neuroblastoma cells are rapidly dephosphorylated by en-a role for O-GlcNac in mediating their interactions with dogenous phosphatases [58,125,277,370]. Ser /Thr phos-tubulin. O-GlcNacylation may also play a role in subcellu- phatase proteins 1, 2A, 2B (calcineurin) and 2C are presentlar localization and degradation of tau proteins [13]. in the brain [76,215], and are developmentally regulated

[104,323]. Like kinases, phosphatases have many direct or2.4.2. Phosphorylation indirect physiological effects, and counterbalance the

action of kinases. They are associated directly or indirectly2.4.2.1. Sites of phosphorylation. There are seventy nine with microtubules [104,258,368,369]. Thus, tau proteinsputative Ser or Thr phosphorylation sites on the longest have been demonstrated to act as a link between PP1 andbrain tau isoform (441 amino-acids). Using phosphoryla- the tubulin [258], whereas PP2A is directly linked to thetion-dependent monoclonal antibodies against tau, mass microtubules by ionic interactions [369].spectrometry and sequencing, at least thirty phosphoryla- Purified phosphatase proteins 1, 2A and 2B can de-tion sites have been described, including Thr39, Ser46Pro, phosphorylate tau proteins in vitro [119,139,149,417,418].Thr50Pro, Thr69Pro, Thr153Pro, Thr175Pro, Thr 181Pro, For instance, in fetal rat primary cultured neurons, the use


of phosphatase 2A inhibitors induces phosphorylation of 2.5.2. Tau phosphorylation and cell sortingtau proteins on some sites, whereas phosphatase 2B Tau is a phosphoprotein, as was first demonstrated withinhibitors allow phosphorylation on other sites [306,342], the monoclonal antibody Tau-1 raised against a dephos-suggesting that phosphatases 2A and 2B are involved in phorylated site (Fig. 3). Since Tau-1 labels preferentiallydephosphorylation of different sites on tau proteins in axons, tau were tagged as ‘axonal proteins’ [28]. However,neurons. the state of phosphorylation of tau proteins is likely

different according to the cell compartments [333], andTau-1 immunoreactivity was observed in the somatoden-

2.5. Phosphorylation regulates different roles of tau dritic compartment of neurons after dephosphorylationproteins [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 compart-

2.5.1. Tau phosphorylation and microtubule assembly ments of the nerve cells, and are not exclusively ‘axonalTau proteins bind microtubules through the microtubule- proteins’ [167]. However, compared to other MAPs, tau

binding domains. However, microtubule assembly depends proteins are preferentially axonal. Both phosphorylationpartially upon the phosphorylation state since phos- and transcription factors may be involved in tau traffickingphorylated tau proteins are less effective than non-phos- and cell sorting (nuclear, axonal or somatodendritic) [190].phorylated tau proteins on microtubule polymerization[26,41,74,75,102,259,418]. Phosphorylation of Ser262 2.5.3. Tau phosphorylation in developmentdramatically reduces the affinity of tau for microtubules in Phosphorylation of tau proteins is developmentallyvitro [26]. Nevertheless, this site alone, which is present in regulated [104,280,306,323,340,342]. It is high in fetal andfetal tau, adult tau as well as in hyperphosphorylated tau decreases with age due to phosphatases activationproteins found in NFT, is insufficient to eliminate tau [280,340]. Thus, the most precise analysis of the expres-binding to microtubules [356]. Recent data have indicated sion of phosphorylation sites during development and adultthat the heptapeptide KKVAVVR located in the life derives from immunohistochemical studies of the224 230

proline-rich region has a high microtubule binding activity nervous tissue in animals which had been fixed byin combination with the repeats regions [147], suggesting perfusion. This circumvents postmortem delays that de-intramolecular interactions between the both regions. Thus, stroy phosphorylation sites [58,280]. In fact, since at death,phosphorylation outside the microtubule-binding domains due to the lack of oxygen, ATP is no longer synthesized,can strongly influence tubulin assembly by modifying the and thus, kinases are not active. Conversely, phosphatasesaffinity between tau and microtubules. 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), andcorresponding specific antibodies. Hyperhosphorylated sites are grouped in two clusters located on both sides of the microtubules binding domain, with theexception of Ser262/Ser356. Phosphorylation-dependent antibodies (in italics) have been developed for each sites. AD-specific sites and correspondingantibodies are circled. Tau1 recognizes the dephosphorylated 189–207 amino acid sequence.


Thus, in anoxic conditions, most of the phosphorylation ability in the degree of phosphorylation is observed duringsites found on tau proteins are rapidly dephosphorylated development. Phosphorylation seems to affect simultan-(for review, see Ref. [85]). In addition, it is likely that an eously several sites. However, this has to be clarified,independent regulation of multiple phosphorylation sites using a panel of monoclonal antibodies against differenttakes place within subcellular domains of developing phosphorylation sites and following their fates duringneurons [141,274,327,379]. Other observations indicate development. Furthermore, the state of phosphorylation isthat tau proteins remain unpolarized at all stages in culture strongly modified during development, due to the expres-[98], or that they bind selectively to axonal microtubules at sion of several specific adult isoforms, and because theearly stages of development, as shown in cerebellar ratio between kinases and phosphatases is modifiedneurons [114]. [58,104,280,323]. Phosphorylation, in combination with

the type of isoform, can modulate the properties of tau2.5.4. Ischemia proteins. In turn, tau proteins provide the microtubule with

Many phosphorylated sites on aggregated tau proteins its own identity and physical characters (rigidity, length,are found on fetal and native adult tau as well [277,280]. stability, interactive capacity with other organelles). There-In particular, this has been verified in AD for Ser 202 and fore, by regulating microtubule assembly, tau proteins haveThr 205 [277], Ser 262 [356], Ser 396 and 404 [58,277] a role in modulating the functional organization of theand other Ser–Pro sites [205]. However, there is a rapid neuron, and particularly in axonal morphology, growth,endogeneous dephosphorylation of normal tau proteins and polarity.after death. In fact, using rat brain, we performed a kineticof dephosphorylation and observed that 80% of the tau-immunoreactivity, revealed by a phosphorylation-depen- 3. Pathological aggregation of tau proteinsdent monoclonal antibody raised against two phos-phorylated sites at Ser396 and 404 residues and named The most obvious pathological event in several neurode-AD2 [58], disappeared after a postmortem delay of 2 h at generative disorders is the aggregation of tau isoforms intoroom temperature [58]. Similar data were obtained for intraneuronal filamentous inclusions. Until recently, it wasnormal human brain [277,367]. During postmortem delays, thought that an abnormal phosphorylation of tau proteinsnormal tau proteins from autopsy-derived materials are was responsible for their aggregation in AD. However,dephosphorylated whereas PHF-tau are not, because of normal tau proteins are also phosphorylated in fetal andeither a poor accessibility of phosphorylated sites to adult brain, and they do not aggregate to form filamentousphosphatases or a decrease in phosphatase activity inclusions. Moreover, non-phosphorylated recombinant tau[146,243,277]. Under ischemic conditions, a similar phe- proteins form filamentous structures under physiologicalnomenon occurs, and no ATP is synthesized. Ischemia conditions in vitro, when sulfated glycosaminoglycans aredisrupts the neuronal cytoskeleton both by promoting or other polyanions present. These data suggest that, inproteolysis of its components and by affecting kinase and addition to phosphorylation, other mechanisms may bephosphatase activities that alter its assembly [50,94]. In a involved in the formation of pathological tau filaments.reversible model of spinal cord ischemia in rabbits, tau hasbeen found to be dephosphorylated in response to ischemia 3.1. Tau proteins phosphorylationwith a time course that closely matches the installation of

21permanent plegia. In a similar manner, Ca /calmodulin- In numerous neurodegenerative disorders, tau proteinsdependent kinase II activity is reduced only in the ischemic aggregate into intraneuronal filamentous inclusions. In AD,region. Thus, dephosphorylation of tau is an early marker these filaments are named paired helical filaments (PHF),

21of ischemia as is the rapid loss of Ca /calmodulin- and their constitutive proteins are referred to as PHF-taudependent kinase II activity [357]. In a canine model of proteins. Despite the fact that many phosphorylation sitescardiac arrest [339], the effects of global brain ischemia / are common to PHF-tau proteins and native tau, there arereperfusion on tau proteins were analyzed. Tau proteins are biochemical characteristics that differentiate them andcompletely dephosphorylated on Ser /Thr–Pro sites but support the concept of pathological tau proteins. First,after resuscitation and 2 h of reperfusion, there is a full two-dimensional immunoblot analysis reveals that PHF-taurestoration of phosphorylation [271]. Alterations in phos- proteins are more acidic than normal tau from biopsy-phorylation or degradation of tau may affect microtubule derived samples [352]. Second, insoluble polymers of taustability, possibly contributing to the disruption of axonal are present exclusively in AD brain extracts, where theytransport [50,93,272,357]. are visualized as ‘smears’ on Western blots. Therefore, the

main difference between biopsy and postmortem tissues is2.5.5. Summary that PHF-tau are aggregated, while tau from biopsies are

Altogether, these observations show that tau proteins are not (Fig. 4). Third, hyperphosphorylation generates differ-found in all cell compartments, but in different phos- ences that can be visualized by a few phosphorylation-phorylation states. Within the same compartment, vari- dependent antibodies such as AT100 [277], AP422 [175],


Fig. 4. Schematic representation of the modifications leading to tau proteins aggregation in Alzheimer’s disease. Phosphorylation state of normal tauproteins result from a balance between kinases and phosphatases activity. Tau proteins from biopsy-derived extracts are phosphorylated at several sites, andexhibit a higher molecular weight compared to dephosphorylated normal tau proteins from autopsy-derived brains (upper part). In this later case, there is nokinase activity, while the phosphatases are still active. Native tau proteins are detected as a triplet of bands ranging between 55 and 74 kDa by numerousphosphorylation-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 westernblotting 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 oftau variants with two cassette exons (2131102 and/or 2132101). Phosphorylation of the longest tau isoform (2131101) induces the formation of theadditional hyperphosphorylated tau74 variant. The phosphorylation of certain sites are AD-specific, as demonstrating with the antibody AT100. The colorcodes are similar to those used in Figs 1 and 3.

988 [61], PHF-27 [205] or the TG/MC antibodies (i.e., AT100 on tau proteins is obtained in vitro after a complexTG3) [404] (Figs. 3 and 4). With the exception of Ser422, sequence of phosphorylation by GSK3 and PKA [425].these sites found in PHF-tau are conformation-dependent Mitotic protein kinases may also play a major role in tauepitopes. However, recently, it was also shown that TG3 phosphorylation since many mitosis-specific epitopes areepitope was selectively expressed in mitotic cells but not in found in NFT [235,404]. Stress-activated protein kinasesquiescent cells [404]. It does not recognize autopsy- and are also of interest [245,286,332] since all SAP kinasesbiopsy-derived normal tau proteins but binds PHF-tau and (JNK/SAPK1, p38/SAPK2, SAPK3) have been shown tomitotic epitopes. In fact, TG3 recognizes Thr231 and phosphorylate tau proteins [135,223]. Altogether, theseSer235 in a particular phosphorylated conformation [225], data suggest that SAPK family is an interesting candidatewhich may allow to better understand PHF formation. for the pathological phosphorylation of tau proteins. Con-

The hyperphosphorylation of tau proteins associated versely, tau hyperphosphorylation may be related to awith AD may be related to either an increase in kinase decrease in phosphatase activity. Recent data suggest thatactivity or a decrease in phosphatase activity [391]. phosphatase activities may be decreased in AD brainsAmong the numerous kinases that have been implicated [146,247]. Furthermore, phosphatase inhibition in cell(for review, see Ref. [268]), glycogen synthase kinase 3 models allows the formation of specific AD-type epitopes(GSK3) is still a controversial candidate. However, several such phosphorylation of Ser422 [64,270]. Finally, taupoints suggest that it may be involved in AD pathology. proteins hyperphosphorylation may only be a consequenceThe most striking one is that Alzheimer-specific epitope and occurs once tau proteins are already aggregated into


filaments. Others factors may be involved including 3.2.3. Neuronal redox potentialubiquitination, glycation and oxidation. Recombinant tau-derived constructs including the repeat

domains can aggregate into synthetic PHF. It has been3.2. Tau isoforms aggregation shown that the essential first step for this process is the

formation of antiparallel dimers linked by disulfide bridges3.2.1. Ubiquitination [413]. Moreover, this assembly could be inhibited by

Ubiquitin is a stress protein implicated in the ATP- blocking the SH group of the single Cys322 residue, or bydependent degradation of short-lived proteins or the re- mutating Cys for Ala, or by keeping tau in a reducingmoval of abnormal or damaged proteins [181]. The environment. Likewise, in the case of 4R-tau constructs,presence of a conjugated form of ubiquitin in PHF has repeats 2 and 3 may be linked via an intramolecularbeen suggested by the labeling of PHF with antibodies disulfide bridge involving the residues Cys291 and Cys322specific for conjugated ubiquitin [288]. It has been shown respectively. Thus, these constructs form compact mono-that the ubiquitin-targeted proteins in PHF are tau proteins, mers but cannot aggregate into synthetic PHF. This wouldand that the conjugation sites, including Lys254, 257, 311 explain the poor assembly of the 4R-tau isoform [349]. Inand 317, are localized on the microtubule-binding region. conclusion, the intermolecular disulfide bonds involvingThe analysis of tau proteins from an AD brain by Western the Cys322 residue of tau protein is probably important inblotting reveals the characteristic PHF-tau triplet and the polymerization into PHF, but cannot explain all theproteolytic products, and also smears that correspond to process. Furthermore, these data imply that the oxidativetau polymers. These smears consist largely of the C- redox potential in the neuron is crucial for PHF assembly,terminal portion of tau and ubiquitin. It is most likely that independently or in addition to pathological phosphoryla-abnormally phosphorylated full-length tau accumulates as tion reactions.PHF (PHF-tau), which is then gradually proteolyzed in itsN-terminal part and subsequently ubiquitinated in its C-terminal domain [289]. 3.2.4. N- and O-glycosylations

It has been reported that hyperphosphorylated tau pro-3.2.2. Glycation teins in AD brain are N-glycosylated and that the glycan(s)

Glycation is the reaction between the amino part of a maintains the helicity of PHF, but does not have anyside chain of an amino acid and the carboxyl part of apparent direct effect on the ability of tau to promote theglucose or other reducing sugars. This post-translational assembly of microtubules [409]. Conversely, tau proteinsmodification, also known as nonenzymatic glycosylation, are normally O-glycosylated [13]. However, O-GlcNAcleads to the formation of heterogeneous products called has been reported to be upregulated in AD. This increase isadvanced glycation end products (AGEs). PHF insolubility specific for proteins associated with the detergent insolublemay be related to glycation, since a cross-linking reaction cytoskeleton [158]. All of these data suggest thatleading to the formation of insoluble aggregates of proteins glycosylation may be implicated in PHF formation as wellis often described as a consequence of proteins glycation as stabilization in AD.[231,234,362]. Moreover, it has recently been demon-strated that AGEs can be detected immunohistochemicallyin senile plaques from AD, and also in NFT from AD, PSP 3.2.5. Transglutaminaseor ALS/PDC, and parts of the Pick’s bodies in Pick’s Tissue transglutaminase (TGase) is a calcium-activateddisease [343,363]. enzyme that catalyzes the formation of bonds between

Thirteen residues of lysine, the most suitable amino acid glutamine residues and primary amines included in pep-for glycation, have been identified as potential glycation tide-bound lysine residues or polyamines. TGase cross-sites in the longest human tau isoform [248,297]. Among links specific substrate proteins into insoluble and pro-the modified lysines, those located in the sequence com- tease-resistant high molecular weight complexes (for re-prising residues 318–336 (according to the numbering of view, see Ref. [69]). Due to this ability of cross-linkingthe longest human tau isoform) are found to be glycated, as activity, the involvement of TGase in tau aggregation intodetermined by the reaction with an antibody that recog- PHF was suggested. Thus, TGase-treated human recombi-nizes a glycated peptide containing this sequence. Because nant tau formed filamentous structures in vitro that arethose lysines are present in a tubulin binding motif of tau immunoreactive with antibodies to tau and TGase [10].protein, their modification could result in a decreased Likewise, PHF isolated from NFT from AD brain areinteraction of tau with tubulin [248]. Finally, AGE-tau immunoreactive to TGase antibody. These results indicategenerate oxygen free radicals that could activate transcrip- that tissue transglutaminase may play a role in the forma-tion via NF-kB, increase bPP and release 4 kDa amyloid tion of tau pathology associated with AD [103,284,302]. Apeptides similar to Ab. Therefore, glycated tau could transglutaminase-induced crosslinking of tau proteins lead-induce oxidative stress which may contribute to the ing to neurofibrillary tangle formation has also beenpathogenesis of AD [419]. suggested in progressive supranuclear palsy (PSP) [424].


3.2.6. Proteolysis strong interaction between the Ab amyloid peptide andIt has been suggested that truncation of tau proteins may GAG [52,53,364]. More recently, a strong binding of

precede their assembly into PHF, rather than reflecting GAGs to the microtubule-binding domains of tau proteinsproteolytic cleavage of full length tau assembled into has been shown suggesting that GAGs may enhance tauextracellular tangles [110,303]. However, numerous aggregation and disturb microtubule assemblystudies have investigated the proteolysis of tau proteins by [140,315,375]. Finally, GAGs may be responsible for PHFcalpain, a calcium-dependent protease, and have demon- helicity [15].strated an increased resistance of PHF-tau proteins com-pared to normal tau proteins. Thus, normal tau proteins 3.2.7.3. Other polyanions (RNA and lipids). Glycolipidsisolated from fetal or adult human brain are similarly and have been reported to be associated with PHF [151,152].rapidly proteolyzed by calpain in vitro, and the formation Furthermore, phospholipids induce conformational changesof N-terminal tau fragments suggests that calpain-sensitive of tau proteins that may facilitate their abnormal phos-sites may be located in the C-terminal part of tau proteins. phorylation. Moreover, recent data have indicated thatConversely, PHF were extremely resistant to degradation, specific lipids including arachidonic acid may enhance theand only a partial proteolysis was obtained with a higher in vitro formation of straight filaments using tau proteinsconcentration of calpain, giving rise to a major C-terminal [414]. In the same manner, PHF assembly using recombi-fragment of PHF-tau. These data suggest that the potential nant tau proteins is strongly enhanced by ribonucleic acidscalpain-digestion sites buried in the core of filaments could [229]. It should be noted that RNAs have been found inbecome inaccessible to the protease, leading to the resist- NFT [133].ance of PHF to calpain-proteolysis, and subsequently tothe accumulation of PHF in AD [421]. Finally, recent data 3.2.7.4. Aluminum. Many metals have been involved inindicate that the conformation of tau proteins into PHF, neurodegenerative disorders. Among them, aluminum hasrather than hyperphosphorylation [260], is the major factor been directly implicated in tau aggregation and neurode-responsible for the resistance of abnormal filaments to generation (for review, see Ref. [358]). Aluminum hascalpain-mediated proteolysis [420]. In this context, tissue been reported in NFT not only in AD [317], but also intransglutaminase may play a crucial role in aggregation of other neurodegenerative disorders including Guamaniantau proteins [392]. amyotrophic lateral sclerosis /parkinsonism–dementia

complex (for review, see Ref. [124]). It also facilitates tau3.2.7. Cofactors aggregation in a phosphate-independent manner, without

involving the formation of fibrils [350].3.2.7.1. Apolipoprotein E. Apolipoprotein E (ApoE), anheterogeneous protein with three major isoforms inhumans (E2, E3, and E4 corresponding to three alleles ´2, 4. Tau isoforms and neurodegenerative disorders´3 and ´4), plays a critical role in lipid metabolism. It hasbeen demonstrated that ApoE is a risk factor for AD, in The data described above indicate that the main featurethat the ´4 allele frequency is increased in AD patients of pathological tau proteins is their aggregation intowhen compared to the normal population. Following that polymers that constitute the neurofibrillary lesions in AD.finding, it was shown that ApoE is bound to senile plaques In addition, and possibly in association with the aggrega-and NFT [55,298], and could contribute to the formation of tion process, specific phosphorylation sites are also presentthese lesions [320,378]. ApoE may play a secondary role on PHF-tau. However, tau aggregation is not specific toin NFT formation or accumulates within the neurons in AD, and has also been described in many other neurode-response to reparative processes induced by NFT-associ- generative disorders. Interestingly, the tau electrophoreticated neuronal damage [23]. profile is often disease-specific. In the following sections,

we review recent data on the characterization of aggre-3.2.7.2. Glycosaminoglycans. Glycosaminoglycans (GA- gated tau proteins in different neurodegenerative disordersGs) are the carbohydrate moiety of proteoglycans. They (for review, see Refs. [51,387]).are polysaccharides containing hexuronic acid and hex-osamine which may be further modified by sulfation and 4.1. Alzheimer’s diseaseacetylation. There are four major classes of GAGs includ-ing chondroitin sulfate, dermatan sulfate, keratan sulfate, 4.1.1. Descriptionand heparan sulfate. Heparan sulfate is the most complex Alzheimer’s disease is a progressive neurodegenerativeGAG, containing glucuronic acid linked to N- disorder that leads to dementia, and affects approximatelyacetylglucosamine. Heparin (an analog of heparan sulfate) 10% of the population older than 65 years of age [337].is more highly charged than heparan sulfate due to its high Memory loss is the first sign of cognitive impairment,degree of sulfation. In AD, proteoglycans /GAGs are found followed by aphasia, agnosia, apraxia and behavioralin amyloid deposits and NFT [54,365,366]. There is a disturbances. The two main types of brain lesions observed


in AD are senile plaques (SP) and neurofibrillary tangles Many cortical and subcortical areas, such as nucleus(NFT). Senile plaques result from the extracellular ac- basalis of Meynert, amygdala, locus coeruleus and dorsalcumulation of a peptide referred to as Ab into amyloid raphe, are also affected by NFT formation [37,330,415].deposits. Ab derives from a precursor, the b-amyloid The demonstration of both SP and NFT within specificprecursor protein (APP). In cases of familial AD, muta- regions of the cerebral cortex is necessary to establish thetions have been found on APP gene, suggesting that it diagnosis of definite AD, according to NINCDS–ADRDAplays a central role in the etiopathogenesis [172]. SP are criteria [212,282]. However, NFT lesions with a lowerdiffusely and variably distributed throughout the cerebral density are also present in entorhinal cortex and hippocam-cortex and in subcortical structures. NFT correspond to the pus of elderly normal brains (Fig. 5D and F), whereasaggregation of abnormal fibrils into PHF [232], within neocortex exhibits only isolated NFT (Fig. 5E).certain vulnerable neuronal populations. At the micro-scopic level, NFT are preferentially observed in the large 4.1.2. Tau phosphorylation in Alzheimer’s diseasepyramidal cells of the hippocampus and the entorhinal The major antigenic components of PHF are tau proteinscortex (Fig. 5A), and the supragranular (II–III) and [44,87,144,160], and several groups have reported phos-infragranular (V–VI) layers of the association cortical phorylation as the major modification of these proteinsareas (Fig. 5B and C), while primary sensory and motor [116,154,161,213]. Their biochemical characterization bycortices are relatively spared [14,39,91,107,195,201]. 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). Theselesions 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 thearrow heads identify neuritic changes. The case with very mild cognitive changes shows involvement of neurons in layer II of the entorhinal cortex with acomparably minor neuritic involvement (D, F). The neocortex of this case displays only isolated NFT (arrow in E; most NFT were observed in Brodmann’sarea 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).


(tau55, 64 and 69) also referred to as A68, or PHF-tau ation sites, it is possible to investigate biochemically NFT[88,138,154,255]. However, a 72–74 kDa component is in postmortem brain materials. A strong correlation be-also present in only very low amounts and corresponds to tween the immunohistochemical detection of NFT and thethe longest tau isoform [45,142,293,353] (Figs 4,6). Using presence of the tau triplet has been demonstrated, indicat-PHF-tau preparations, Goedert and colleagues showed that ing that it is a reliable marker of the degenerating process.dephosphorylated PHF-tau proteins have a similar electro- Therefore, the pathological tau proteins can be used tophoretic mobility than the six recombinant tau isoforms quantify neurofibrillary degeneration [115], and biochemi-[142]. The following scheme is now well established: cal mappings using immunoblotting and/or ELISA havetau55 results from the phosphorylation of the fetal isoform been performed in several cortical areas of the brain from(2232102), tau 64 from the phosphorylation of tau patients with senile dementia of the Alzheimer typevariants with one cassette exon (2132102 and/or 2232 [207,401]. These analyses revealed that the detection of the101), tau69 from the phosphorylation of tau variants with pathological tau triplet is present in all studied areas, withtwo cassette exons (2131102 and/or 2132101). Phos- the exception of regions such as primary motor and visualphorylation of the longest tau isoform (2131101) in- cortices (Brodmann’s areas 4 and 17, respectively). Theduces the formation of the additional hyperphosphorylated detection is particularly strong in association cortex com-tau74 variant [272,352,353] (Fig. 6). However, it is likely pared to primary sensory cortex, with the highest levels inthat both the size of tau isoforms and phosphorylation are temporal neocortical and limbic areas. However, for aresponsible for variations in their electrophoretic mobility. given brain area, tau immunoreactivity varies among casesFor instance, phosphorylation of the longest tau isoform [207,401].may lead to the formation of tau variants with molecular In a study of 130 cases with cognitive status rangingweights ranging from 68 to 72 kDa according to their from normal aging to severe AD, PHF-tau were quantifieddegree of phosphorylation [293]. by immunoblotting in different cortical areas, and these

data were related to clinical and neuropathological data4.1.3. PHF-tau are reliable markers of NFT in aging [86,90]. This study allowed to predict a sequential bio-and AD chemical pathway of PHF-tau in cortical brain areas,

Using immunological probes specific of tau phosphoryl- 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), withschematic representation of isoforms composition (right of each frame). The six tau isoforms are involved in the formation of the typical AD-triplet withthe 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 hyperphosphorylatedtau isoforms with exon 10. The FTDP-17 families with mutations in exon 10 or intron 10 exhibit the same profile (middle panel). Hyperphosphorylated tauproteins 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 and3.


comparable to the neurofibrillary degeneration stages Thus, a small group of patients presenting with Parkin-previously described in neuropathologic studies son’s disease may also develop an AD-like tauopathy.[14,36,39,106]. In fact, PHF-tau were consistently detectedin the entorhinal cortex of non-demented individuals aged 4.2.2. Postencephalitic parkinsonismover 75 years, and the hippocampus was also frequently Many patients who survived the influenza pandemic inaffected. In these aged controls, PHF-tau were visualized the years 1916–1926 later developed postencephaliticas the characteristic tau triplet, similar to that found in AD parkinsonism (PEP) [57,126,198]. Extrapyramidal symp-brains but in lower amounts [86,90,398,400]. During the toms are the major clinical features and affected patientsearliest stages of AD with moderate decline of cognitive do not exhibit any cognitive changes and are usuallyfunctions, the neurofibrillary degeneration pathway is neither aphasic nor apraxic. The immunohistochemicalhighly specific, spreading from the hippocampal formation analysis of the brain of PEP cases demonstrated that NFTto the anterior, inferior, and mid temporal cortex. Then, the are found in variable densities in the hippocampus anddisease progresses into association areas of the temporal entorhinal cortex, in neocortical areas 4, 9 and 20 and in(superior), parietal and frontal cortex. Lastly, primary subcortical regions (Fig. 7B and C). Higher NFT densitiesmotor or sensory areas such as the primary motor cortex or are observed in the hippocampus (CA1 and subiculum;the primary visual cortex are affected. This study shows Fig. 7A) and area 20, compared to areas 4 and 9, and thethat neurofibrillary degeneration has to involve almost the putamen, indicating that some regions are preferentiallyentire temporal cortex to induce overt clinical mani- affected by the degenerative process. In addition, andfestations [86,90]. Comparable data were obtained using a contrasting with AD cases, NFT are more numerous inclassical immunohistochemical approach on smaller popu- supragranular than in the infragranular layers [198].lations with fewer brain regions investigated Biochemical studies have shown that the PEP cases[25,34,35,106,202]. These studies also demonstrate that display the tau55, 64 and 69 triplet in cortical andAD is a disease involving the long corticocortical con- subcortical brain regions, in contrast to AD cases wherenections. In fact, these are specifically affected with a this triplet is mainly restricted to the hippocampal forma-well-defined pattern, involving subsets of pyramidal neu- tion and association neocortex [57] (Fig. 6). Also, the taurons that are found mainly in layers III and V of the triplet is found in brain areas usually spared in ADneocortex [199,203]. including primary motor cortex and basal ganglia. The

regional distribution of the tau triplet differs among PEP4.2. Parkinsonism cases, suggesting some heterogeneity in the neurode-

generative process [57].4.2.1. Parkinsonism with dementia

The most characteristic clinical features of Parkinson’s 4.2.3. Guamanian ALS /PDCdisease include resting tremor, expressionless face, rigidi- The amyotrophic lateral sclerosis /parkinsonism–demen-ty, and slowness in initiating and performing voluntary tia complex of Guam (ALS/PDC) is a chronic neurode-movements. Neuropathologically, Parkinson’s disease is generative disorder highly prevalent in the native Chamor-characterized by neuronal loss, especially in substantia ro population of Guam in the Western Pacific [188].nigra and locus coeruleus, and the presence of intracellular Clinically, Guamanian amyotrophic lateral sclerosis (ALS)inclusions called Lewy bodies and Lewy neurites [120]. is indistinguishable from sporadic ALS and presents withRecent studies suggest that a-synuclein is the major fasciculations and lower and upper motor neuron signs.component of Lewy body filaments [374,406,407]. There Parkinsonism–dementia is characterized by an insidiousis no data available about tau pathology in patients progressive mental decline and extrapyramidal signs in-exhibiting cortical Lewy bodies. Thus, it should be noted cluding bradykinesia, rigidity and less often tremorthat Parkinson’s disease is not considered as a real [70,189]. Both aspects of the disease are frequentlytauopathy. Nevertheless, in a subgroup of patients without associated, but they are known to occur separately. Theany cortical Lewy bodies, a tau pathology has been etiopathogenesis of this disorder is not yet elucidated,described by Vermersch and colleagues using a Western although environmental factors such as aluminum orblotting approach. A tau triplet similar to that described in neurotoxins might be involved [124].AD is present in particularly large amounts in the prefron- The brain of Guamanian ALS/PDC patients exhibit atal, temporal and entorhinal cortex of all Parkinson’s severe cortical atrophy and neuronal loss. The neuro-disease patients with dementia. Therefore, AD-type pro- pathological hallmark is the widespread NFT formation,teins are sometimes found in Parkinson’s disease with especially in the temporal and frontal isocortex, hippocam-dementia, but the cortical distribution differs from the pal formation and several subcortical structures [188,189]pattern seen in AD, with a significantly stronger in- (Fig. 7D and F). Although NFT are numerous in both ADvolvement of prefrontal areas [399]. In cases without and ALS/PDC, these two conditions are distinguished bydementia, a tau pathology restricted to the hippocampal differential NFT laminar distribution patterns and densitiesformation has been described in elderly individuals [400]. in neocortex. NFT are preferentially distributed within


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 inthe CA1 field of the hippocampus (A, D). The PEP case shows moderate densities of relatively small NFT throughout layers II and III of the frontopolarregion (Brodmann’s area 10) and very high numbers of neurites (B). The neocortex of the Guamanian case displays the characteristic NFT distribution ofALS/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). Athigher 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 arrowspoint 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 withantibody 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/ cal tau proteins found in Guam ALS/PDC and AD sharePDC cases and are relatively sparser in layers V–VI (Fig. the same biochemical properties, but differ by their7E), whereas NFT are generally denser in layers V–VI in regional and laminar distribution in the brain of patientsAD cases [202,204,307,308]. Immunohistochemical [56]. Since the etiology of Guamanian ALS/PDC isstudies have also revealed that pathological tau proteins are probably different from that of AD, this also demonstratespresent in NFT of ALS/PDC patients [56,61,202]. By that neurofibrillary degeneration with a tau triplet 55, 64,using Western blotting and numerous phosphorylation- 69 detected in both disorders most likely reflects a similardependent antibodies, these proteins can be visualized as a response to different types of neuronal insults. In thistriplet tau55, 64, 69 [56] (Fig. 6). The ultrastructure of context, ALS/PDC of Guam and PEP have been linked toNFT consists of straight filaments and PHF [330], and external factors such as viruses and toxins that may lead toPHF have been shown to be essentially similar to those similar neuropathology, characterized by the same tauobserved in AD [187]. electrophoretic profile. However, it is not known whether

According to the neuropathological data, and in contrast tau pathology in Guamanian ALS/PDC may be alsoto AD patients where the tau triplet is found mostly in related to mutations in tau gene in the Chamorro popula-cortical regions, the Guamanian tau triplet is detected in tion. Recent linkage analyses and genetic studies do notboth cortical and subcortical areas. Finally, the pathologi- support the involvement of tau gene mutation as a primary


cause for the disease, although it does not rule out the and 24. Conversely, the other PSP studied cases withpossibility of tau proteins being important downstream in dementia contained large amounts of pathological tauthe process [316]. Unknown genetic factors may also play proteins in the neocortex especially in Brodmann areas 4a major etiopathogenic role in Guamanian ALS/PDC. and 6 and in subcortical structures.

4.2.4. Progressive supranuclear palsy 4.2.5. Corticobasal degenerationProgressive supranuclear palsy (PSP) is a late-onset Corticobasal degeneration (CBD) is a rare, sporadic and

atypical parkinsonian disorder described by Steele, Richar- slowly progressive neurodegenerative disorder. It is clini-dson, and Olszewski in 1964 [377]. This neurodegenera- cally characterized by cognitive disturbances like aphasiative disorder is characterized by supranuclear vertical gaze and apraxia, and extrapyramidal motor dysfunction, likeparalysis, moderate or severe postural instability with falls rigidity, limb dystonia, akinesia and action tremor [326].during the first year after onset of symptoms, facial, nuchal Moderate dementia emerges sometimes late in the courseand troncular dystonia. Dementia is also a common feature of the disease [335]. There is a clinical and pathologicalat the late stages of the disease [261–263]. Neuro- overlap between PSP and CBD [113,261,263], and itpathologically, PSP is characterized by neuronal loss, would be most helpful to distinguish these two pathologiesgliosis and NFT formation. Neurofibrillary tangles were on a neuropathological or immunochemical basis. Neuro-first described in basal ganglia, brainstem, and cerebellum pathological examination reveals a frontoparietal atrophy[377], and the subcortical localization of the neuro- of the brain [408], and also glial and neuronal abnor-pathological lesions initially led to the definition of PSP as malities. Thus, the glial pathology is dominated by thea model of ‘subcortical dementias’ [3,81]. Later on, description of astrocytic plaques, and numerous tau-im-degenerative profiles have been described in the perirhinal, munoreactive inclusions in the white matter [111,113,278].inferior temporal and prefrontal cortex, with variable The presence of achromatic ballooned neurons has beendensities of NFT among cases [24,179,200] (Fig. 8A and shown in cortex, brainstem and subcortical structures, asB). These studies also demonstrated that the primary motor well as neuritic changes and NFT. These lesions can becortex is more severely affected than neocortical associa- visualized with phosphorylation-dependent anti-tau anti-tion areas compared to AD [179,200] (Fig. 8C). Further- bodies [59,111,244,314] (Fig. 8D and F).more, glial fibrillary tangles have also been described The electrophoretic profile of tau pathological proteins[24,27,71,179,324]. Ultrastructural analyses further point in CBD is similar to that of PSP [59,244], and is describedto major differences between AD and PSP, since PHF are as a tau64, 69 doublet (Fig. 6). However, the componentsfound in AD [232], while straight filaments are observed in may be different since this doublet is not detected in CBDPSP [384,389]. using antibodies raised against the region encoded by exon

The electrophoretic profile of pathological tau proteins 3 [244]. These data have been confirmed by immuno-in PSP is substantially different from that in AD, as a histochemistry [112]. Moreover, in a recent study, taucharacteristic doublet is found (tau64 and tau69) instead of isoforms with sequence encoded by exon 10 were found inthe triplet found in AD [118,402]. A minor 74 kDa band is CBD, whereas tau isoforms without exon 10 were notalso detected (Fig. 6). In fact, hyperphosphorylated tau detected (Fig. 6). These data suggested that mainly iso-isoforms with sequence encoded by exon 10 are much forms with four microtubule-binding domains aggregatemore abundant and aggregate into filaments in PSP, into filaments in CBD [272,355]. In this respect, the onlywhereas tau isoforms without exon 10 are not detected isoform with sequence encoded by both exons 3 and 10 is[272,355] (Fig. 6). However, most of the phosphorylation the longest tau isoform. Since the longest tau isoform issites found in PHF-tau are also encountered in pathological found in very low amounts in the human brain, it maytau proteins from PSP patients [346]. Biochemical map- explain why some investigators did not find any immuno-ping performed on several cortical and subcortical areas reactivity for the sequence encoded by exon 3 [112,244].from PSP brain has revealed that the doublet of tau 64 and Thus, hyperphosphorylation of different tau isoforms (with69 is first detected in the subcortical regions where NFT or without exon 10) may lead to similar electrophoreticare found, neocortical areas being affected later [402]. profiles. These data confirm the observation that both sizeThese results are in good agreement with previous neuro- and phosphorylation of tau isoforms are responsible for thepathological results that show a cortical involvement observed differences in tau electrophoretic mobility.[179,200]. It is interesting to note that the presence of NFTin cortical areas is always correlated to dementia. We had 4.3. Frontotemporal dementiathe opportunity to analyze materials obtained from a non-demented very young (33-year-old) PSP patient. In this 4.3.1. Pick’s diseasecase, abnormally phosphorylated tau proteins were found Pick’s disease is a rare form of neurodegenerativein both basal ganglia and thalamus, whereas they were disorder characterized by a distinct progressive dementingabsent in all of the other areas studied including amygdala, process. Early in the clinical course, patients show signs ofhippocampus, and Brodmann’s areas 4, 9, 11, 17, 18, 20 frontal disinhibition including mood disturbances and


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 neuriticdegeneration in PSP and CBD, as well as NFT (arrow) and some swollen neurons. A comparable severity of pathologic alterations is observed in theprefrontal 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 motorcortex 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 Pickbodies (G). Pick bodies are preferentially distributed in layers II and V–VI of the frontopolar neocortex, where they coexist with immunolabeled swollencells (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).


progressive language impoverishment leading to mutism cial cortical layers of the frontal and temporal cortex [49].[78]. Neuropathologically, Pick’s disease is characterized However, while Pick’s disease is easy to diagnose neuro-by prominent frontotemporal lobar atrophy, gliosis, severe pathologically, using the characteristic Pick bodies im-neuronal loss, ballooned neurons and the presence of munostained with antibodies against phosphorylated tauneuronal inclusions called Pick bodies in both cortical and proteins such as AD2 [59,89,196], FLD has no specificsubcortical structures [47,386]. Pick bodies are labeled by neuropathological hallmarks although a classification inanti-PHF-tau antibodies, with a higher density in the subgroups has been proposed [131]. To date, no tauhippocampus than in the neocortex [59,89,196] (Fig. 8G pathology has been described by common biochemical orand I). In the hippocampus, Pick bodies are numerous in immunohistochemical methods.the granule cells of the dentate gyrus (Fig. 8G), in the CA1field, the subiculum and the entorhinal cortex, whereas in 4.4. Genetic disorders with tau pathologythe neocortex, they are mainly found in layers II and VI ofthe anterior segment of temporal and frontal lobes (Fig. 8H

4.4.1. Familial frontotemporal dementia andand I). Some NFT may be also found in the hippocampus

chromosome 17-linked pathologiesand are usually considered as part of aging.

The biochemical analysis using a quantitative Western4.4.1.1. Introduction. Historically, frontotemporal demen-blot approach with phosphorylation-dependent anti-tautia (FTD) were often classified as a form of Pick’s disease,antibodies has revealed that in all studied cases of Pick’seven when Pick cells or Pick bodies were not found [78].disease, a major 55 and 64 kDa tau doublet is observed inHowever, this denomination may involve different sub-the isocortex, in the limbic areas and in subcortical nucleigroups of pathologies (see above), and the Lund and[59,89] (Fig. 6). In addition, a very faint band is observedManchester groups published in 1994 a consensus onat 69 kDa. In the neocortex, all Brodmann areas of theClinical and Neuropathological Criteria for Frontotemporalprefrontal and temporal cortices are affected. The parietalDementia [49]. This publication clarified the position ofcortex is sometimes involved while the occipital cortex isPick’s disease within FTD, and several of the reportedspared. In subcortical structures, the doublet of pathologi-cases of familial Pick’s disease were probably cases ofcal tau is found in the striatum, substantia nigra, locusfamilial FTD. Indeed it is difficult to ascertain familiescoeruleus, and brainstem. The 55 and 64 kDa doublet iswhich have the classic pathological features of Pick’scharacteristic of Pick’s disease because it is different fromdisease from the literature [48], because they often havethe tau triplet of AD or the doublet tau55, 64 in CBD andunusual clinical features.PSP [59,272] (Fig. 6). Moreover, pathological tau proteins

In 1994, Wilhelmsen and colleagues have described anin Pick’s disease can not be detected by the monoclonalautosomal dominantly-inherited disease related to familialantibody 12E8 raised against the phosphorylated residueFTD, characterized by adult-onset behavioral disturbances,Ser262 [325]. This result indicates that this site is notfrontal lobe dementia, parkinsonism and amyotrophyphosphorylated in tau proteins aggregated in Pick bodies.[412]. They demonstrated a genetic linkage between thisFinally, the characteristic electrophoretic pattern ofpathology, denominated disinhibition–dementia–parkin-pathological tau in Pick’s disease is well correlated withsonism–amyotrophy complex (DDPAC), and chromosomethe presence of Pick bodies [89].17q21-22 [269,412]. Since then, several families sharingPick bodies are commonly encountered in granulestrong clinical and pathological features and for whichneurons of the dentate gyrus of the hippocampus [89,196],there is a linkage with chromosome 17q22-22 have beenand these neuronal cells do not contain tau isoforms withdescribed [29,182,295,411]. They have been included in aexon 10 [145]. As expected, Pick bodies and the taugroup of pathologies referred to as frontotemporal de-doublet tau 55 and 64 are not labeled with immunologicalmentia with parkinsonism linked to chromosome 17probes directed against the sequence encoded by exon 10(FTDP-17) [121].[354]. Thus, particular sets of tau isoforms that aggregate

in subpopulations of neurons may lead to a specificelectrophoretic tau profile [90,272]. 4.4.1.2. FTDP-17. Although a clinical heterogeneity

could be described between and within the families with4.3.2. Non-Alzheimer non-Pick frontal lobe degeneration FTDP-17, usual symptoms include behavioral changes,

Frontal lobe degeneration (FLD) is a common neuro- loss of frontal executive functions, language deficit andlogical disorder that leads to dementia [163]. The first hyperorality. Parkinsonism and amyotrophy are describedsymptoms appear in the presenium and the onset is usually in some families, but are not consistent features. Neuro-slow and insidious. The clinical characteristics are quite pathologically, brains of FTD patients exhibit an atrophysimilar to that of Pick’s disease, with disturbances of of frontal and temporal lobes, a severe neuronal cell loss, abehavior and speech. A ‘frontal’ distribution of mor- grey and white matter gliosis, and a superficial laminarphologic changes is defined, since neuronal cell loss, spongiosis. One of the main important characteristic is thespongiosis and gliosis are mainly described in the superfi- filamentous pathology affecting the neuronal cells, or the


both neuronal and glial cells in some cases. The absence of intronic mutations in the splicing region following exon 10amyloid aggregates is usually established [121,371]. at position 13 [373], 113 [210], 114 [210] and 116

FTDP-17 has been related to mutations on the tau gene [143] have been reported. A fifth intronic mutation with a[210,322,372,373]. Tau mutations always segregate with likely pathogenic effect was recently described at positionthe pathology and are not found in the control subjects, 133 [336] (Table 1).suggesting their pathogenic role. To date, 17 mutations Depending on their functional effects, mutations on tauhave been described in the tau gene among the different proteins may be divided into two groups: the mutationsfamilies with cases diagnosed as FTDP-17 (Table 1). Ten affecting the alternative splicing of exon 10, and leading tomissense mutations in coding regions K257T [319], I260V changes in the proportion of 4R- and 3R-tau isoforms, and(M. Hutton, personal communication), G272V [210,372], the mutations modifying tau interactions with microtu-N279K [73,82,92], P301L [105,182,210,371], P301S [60], bules. The first group includes intronic mutations (13,S305N [178,214], V337M [177,322], G389R [296,319], 113, 114, 116) and some missense mutations. IntronicR406W [210,328], one silent mutation L284L [82], one mutations disturb a stem loop structure in the 59 splice sitesingle amino acid deletion (DK280) [82,336], and four of exon 10 that stabilizes this region of the pre-mRNA

Table 1aTau gene mutations and FTDP-17

Tau gene Location Effects Tau Filamentous References

Mutation Pathology inclusionstau mRNAs tau proteins

K257T missense Exon 9 ND ND Pick doublet? Pick bodies [319]

R1 Spillantini (pers. comm)

I260V

G272V missense 6 mRNAs mutated Reduced binding AD triplet PHF1SF [210,372]

to microtubules Neurons only

N279K missense Exon 10 Create an exon Increased PSP doublet Twisted ribbon [73,82,92]

R1–R2 IR splicing enhancer 4R-tau isoforms filaments

⇒Increased E101mRNAs Neurons and glia

DK280 deletion ⇒No E101mRNAs Increased 3R-tau ND ND [82,336]

(mechanism unknown) 1 reduced binding

to microtubules

L284L silent Destroy an exon splicing Increased PSP doublet Ultrastructure: ND [92]

silencing element 4R-tau isoforms Neurons and glia

⇒Increased E101 mRNAs

P301L missense Exon 10 E101 mRNAs mutated Reduced binding PSP doublet Twisted ribbon [105,182,210,371]

P301S R2 to microtubules minor 72–74kDa filaments [60]

variant Neurons and glia

S305N missense Exon 10 Create an exon Increased PSP Doublet SF [178,214,247]

R2–R3 IR splicing enhancer 4R-tau isoforms? Neurons and glia

⇒Increased E101mRNAs

13 intronic Intron 10 Disturbance of Increased PSP doublet Twisted ribbon filaments [373]

113 stem loop structure 4R-tau isoforms minor 72–74kDa filaments [143,159,210]

114 ⇒Increased E101mRNAs variant Neurons and glia

116

133 Inhibition of splicing? ND ND ND [336]

V337M missense Exon 12 6 mRNAs mutated Reduced binding PHF1SF [322]

R3–R4 IR to microtubules AD triplet Neurons only

G389R missense Exon 13 ND Pick doublet? Pick bodies-like [296,319]

R406W Reduced binding AD triplet PHF1SF [210,328]

to microtubules Neurons only

a 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.


[159,210,373,397] (Fig. 9). Sequence analysis of this 69 kDa (Fig. 6) [82,208,328]. Finally, the twisted ribbonsplicing region in different animals indicates that the lack filaments described in neurons and glial cells are aof the stem loop structure is associated with an increase in common neuropathological feature in all of the neurode-tau mRNAs containing exon 10 [159]. Indeed, without this generative disorders belonging to this first group.stem loop, access of U1snRNP to this site may be The second group of tau mutations found in FTDP-17facilitated, increasing the formation of exon 101 tau includes several missense mutations. The effects of muta-mRNAs and thus the 4R-tau isoform [82,159,397] (Fig. 6). tions G272V, P301L, P301S, V337M and R406W in an inInterestingly, in these families, abnormally phosphorylated vitro system of microtubule assembly were reported by4R-tau isoforms aggregate into filaments and display a tau Goedert and colleagues. These authors showed that mu-electrophoretic profile similar to the major tau doublet at tated tau isoforms bind microtubules to a lesser extent than64 and 69 kDa found in PSP and CBD wild type isoforms. They suggest that the mutated isoforms[59,118,244,372,373]. Some missense mutations (N279K may induce microtubule disassembly [137,177]. These dataand S305N) also modify the splicing of exon 10 [82,123]. are now confirmed by a number of studies [82,208]. WhenFor instance, the change in nucleotide for N279K and missense mutations are located in tau regions common toS305N mutations also creates an exon-splicing enhancer all isoforms, outside exon 10 (V272G, V337M, R406W),sequence [82]. The silent mutation L284L increases the the six tau isoforms do not bind properly to microtubules.formation of tau mRNAs containing exon 10, presumably These proteins aggregate into PHF and straight filamentsby destroying an exon splicing silencing element [82]. similar to those described in AD, and are present inFamilies with one of these three missense mutations neuronal cells. Their biochemical characterization shows adisplay the same electrophoretic tau pattern than those tau electrophoretic profile similar to the AD tau-triplethaving intronic mutations, namely a tau doublet at 64 and (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 repeatdomain R2 (N279K, L284L, S305N) (slashed frame), or in intron 10 (E1013,113, 114, 116) (dotted line) affect the alternative splicing of exon 10. Theymodify 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 ofthe 4R-tau /3R-tau proportion. Mutations located in tau region common to all six isoforms, outside exon 10 (V272G, V337M, G389R, R406W), affect thebinding 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 themicrotubules. Mutations located in exons are indicated as peptidic sequence (framed part) and intronic mutations are indicated as nucleotidic sequence(dotted part).


mutations are located in exon 10 (P301L, P301S), 4R-tau probably important in the pathogenesis of PSP, it remainsisoforms are affected, do not bind to microtubules, and to be determined whether it represents a primary eventaggregate into twisted ribbon filaments. This type of leading to the development of PSP. It should be noted thatfilamentous inclusions is described in both neurons and this polymorphism was also recently described in otherglial cells. The biochemical characterization shows a tau pathologies including CBD and Parkinson’s diseaseelectrophoretic profile similar to the major tau doublet [95,312].encountered in PSP and CBD (tau64 and 69; Fig. 6).

The DK280 mutation is particular, since it modifies the4.4.3. Myotonic dystrophy

ratio 4R-tau /3R-tau and could also affect the interactionMyotonic dystrophy is an autosomal dominant and

between tau and microtubules. This mutation may decreaseslowly progressive multisystemic disorder characterized

the formation of tau mRNAs containing exon 10 and thus,principally by myotonia, muscular atrophy, cataract and

enhancing the formation of 3R-tau isoforms. Moreover,endocrine dysfunction [173]. Affected individuals present

this deletion mutation is also responsible for a considerablywith a highly variable phenotype, ranging from an asymp-

reduced ability of tau to promote microtubule assembly,tomatic condition to a severe congenital form. Impairment

and is stronger than the effect of the P301L mutation. Noof intellectual and cognitive function in myotonic

data are currently available on the biochemistry of taudystrophy has been reported [221]. The molecular basis of

aggregates in this family [82,336].the defect is an unstable CTG trinucleotide repeat in the 39

Mutations of the tau gene and their involvement inuntranslated region of a gene encoding a putative Ser /Thr

FTDP-17 emphasize the fact that abnormal tau proteinsprotein kinase (myotonic dystrophy protein kinase)

may play a central role in the etiopathogenesis of neurode-(DMPK) located on chromosome 19 [63]. Expanded repeat

generative disorders, without any implication of theshows particular effect on DMPK transcripts. In fact, these

amyloid cascade. The functional effects of the mutationsDMPK transcripts are retained within the nucleus and are

suggest that a reduced ability of tau to interact withabsent from the cytoplasm [83,168].

microtubules may be upstream of hyperphosphorylationTypically, neuropathological observations in myotonic

and aggregation. These mutations may also lead to andystrophy show reduced brain weight and minor abnor-

increase in free cytoplasmic tau (especially 4R-tau iso-malities in gyral architecture. Microscopically, a disor-

forms), and therefore facilitating their aggregation intodered cortical cellular arrangement is described with

filaments [422]. In this respect, it is interesting to note thatneurons present in subcortical white matter, and in-

overexpression of tau was reported to block dynein-me-tracytoplasmic inclusion bodies in cortical and subcortical

diated axonal transport [108].structures [305]. The presence of abnormally frequent NFThas also been reported in the temporal lobe, especially in

4.4.2. PSP polymorphismthe parahippocampal gyrus from patients with myotonic

Although most cases of PSP are usually considered to bedystrophy [233]. By immunoblotting, PHF-tau are also

sporadic, De Yebenes and colleagues reported a familydetected in the hippocampus, the entorhinal cortex and in

with autosomal dominant PSP, and mentioned six othermost of the temporal areas. The amounts of pathological

families previously described [84]. Nevertheless, the typi-tau proteins are higher in the most severely affected

cal missense or 59 splice site mutations described in exonmyotonic dystrophy cases but always lower than in AD

10 of the tau gene in FTDP-17 cases were not found inbrain. Their profile differs from the characteristic triplet of

PSP cases [183,210]. However, Conrad and colleaguesAD, with no or low amounts of the tau69 variant but high

identified a polymorphic dinucleotide repeat sequence inamounts of the tau55 variant [403]. Interestingly, this

the intron 9 of the tau gene, in a Caucasian population withpathology emphasizes the possible link between the ge-

PSP [77]. These authors described a significant over-netic dysfunction of the Ser /Thr protein kinase and the

representation of the A0 allele, characterized by thepresence of pathological tau proteins. These observations

presence of 11 TG repeat, and of the homozygous geno-demonstrate that changes in kinase expression can induce a

type A0/A0 in the PSP cohort (95.5%), compared tocascade of pathological events, including the formation of

normal controls (57.4%) or patients with AD (49.7%).NFT in specific brain areas [403].

Recently, these data were confirmed by several studies andextended to a haplotype, including numerous singlenucleotide polymorphisms spread out along the entire tau 4.4.4. Prion disorders with NFT

¨gene and one intronic 238bp deletion Gerstmann–Straussler–Scheinker disease (GSS) is an[17,22,33,109,183,184,291,304]. The deletion of 218 bp autosomal dominant neurodegenerative disorder with awas described in the intron flanking exon 10, but its wide spectrum of clinical presentations including ataxia,significance remains unclear [17]. It could influenced the spastic paraparesis, extrapyramidal signs, and dementiaexon 10 splicing and, thus, the proportion of tau-4R [128]. Neuropathologically, prion plaques are observed inisoform. Finally, even though these recent data indicate many brain areas, associated with a severe neuronal lossthat the dinucleotide polymorphism in the tau gene is and spongiosis. Exceptionally, NFT with tau proteins


similar to PHF-tau of AD have also been described in GSS childhood, adolescence or, occasionally, in adulthood.[129,130]. Common neurological manifestations are clumsiness, atax-

One patient from a large French GSS family with the ia, supranuclear gaze paresis, seizures and psychomotormutation (A117V) in codon 117 of the prion gene de- retardation [394]. Neuropathologically, brains from NPCveloped NFT, especially around prion plaques, while other patients show neuronal distension in cortex and swollenmembers of this family did not. The tau profile from the axons in brainstem. In NPC cases with a chronic progres-patient with GSS and NFT displayed some common sive course, NFT with PHF are present in many parts offeatures with AD, but also many differences. The three the brain, including hippocampus, neocortex and severalPHF-tau components (tau55, 64, 69) were present in subcortical structures [267]. PHF-tau in tangle-rich NPCextremely low levels, as well as their catabolic products. brains are indistinguishable from PHF-tau in AD brainsMost of the tau were highly aggregated and immuno- [16]. Recent data suggest that this cholesterol storage maydetected as ‘smears’ intensely stained from the top to the be related to genetic defects in intracellular LDL-derivedbottom of the Western blot. The tau profile of the other cholesterol trafficking linked to a gene referred to as NPC1members of the GSS family, whose brain did not contain located on chromosome18 [67,266].NFT, is normal. The reason why some patients with GSSdevelop NFT remains unknown [390].

5. Tau proteins as peripheral markers4.4.5. Down syndrome

Due to the trisomy of chromosome 21, Down syndrome Aggregated tau proteins are the major constituent of(DS) patients have numerous somatic dysfunctions that NFT, and their biochemical or immunohistochemical de-occur during development. In particular, a deficit of growth tection in the central nervous system of AD patients isand maturation of the brain is consistently described, and well-correlated with the severity of dementia. Therefore,the patients develop a variable degree of cognitive impair- their presence has been investigated in peripheral tissuesment, usually leading to dementia after 50 years of age and biological fluids, in the hope to define an ideal marker[195]. Neuropathologically, a severe neuronal loss is of AD that could be used as a diagnostic tool.described in the hippocampal formation and neocortex as Recently, a consensus report on the molecular andwell as in subcortical structures. The formation of NFT and biochemical markers of AD has defined the criteria of suchamyloid deposits occurs prior to neuronal loss. A high a test, emphasizing that the proposed marker should have adensity of diffuse amyloid deposits is observed after 15 sensitivity of at least 80% for detecting AD and ayears, followed by the massive deposition of senile plaques specificity of at least 80% for discriminating other de-in the next decade of life. Neurofibrillary degeneration mentias, and should be reliable, non-invasive, simple towith tau accumulation appears later [197,275]. The hip- use and inexpensive [1]. Moreover, these biomarkerspocampal formation, including the entorhinal cortex, con- should be able to diagnose the disease at an early asympto-tains the highest number of NFTs, with layer II of matic stage, thus increasing the efficiency of a hypotheticalentorhinal cortex involved in all the DS cases older than preventive treatment.35, followed by the subiculum and CA1–CA3 sectors incases older than 45, and the perirhinal cortex in the oldest 5.1. Olfactory systemcases [195] (Fig. 10D and F). The laminar distribution ofNFTs and SPs is similar to that in AD [197]. Using an In 1989, Talamo and colleagues reported that neurons inimmunoblot approach, it has been demonstrated that DS the human olfactory epithelium taken at autopsy maybrain extracts contain significant amount of insoluble tau. express AD-type epitopes, such as phosphorylated neuro-This insolubility is correlated to an abnormal phosphoryla- filaments or tau proteins [383]. Other reports also indicatedtion, as demonstrated by the detection of the typical AD a pathology of olfactory mucosa or olfactory cortex in ADtriplet of pathological tau proteins in the isocortex of DS patients [318]. In fact, tau antibodies revealed dystrophicolder than 35 years [117,169] (Fig. 6), indicating that neurites and NFT in autopsic or biopsic samples frombiochemical dysfunctions linked to tau pathology during olfactory epithelium of AD patientsDS are very similar to those found in AD. [241,254,331,382,416]. However, it has been shown that

the detection of pathological tau proteins may be related to4.4.6. Niemann–Pick Type C disease aging of the olfactory system [416], or may appear

Niemann–Pick Type C disease (NPC) is a cholesterol predominantly in the latest stages of AD [192]. Thus, thestorage disease with defects of the intracellular trafficking usefulness of a biopsy sample from the olfactory epi-of exogenous cholesterol derived from low density lipopro- thelium as an early and specific diagnostic tool is illusory.teins. NPC includes juvenile dystonic lipidosis, ophthal-moplegic lipidosis, neurovisceral storage disease with 5.2. Cerebrospinal fluidvertical supranuclear ophthalmolegia, and juvenileNiemann–Pick disease. The onset may be in infancy, early The presence of tau proteins in the cerebrospinal fluid


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 andhigh 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 theinferior temporal cortex (E, F). Note the presence of NFT (arrowhead), neuritic plaques (arrow) and considerable neuritic changes (small arrows) in theDown 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 (onF)5400 mm (A, B, D, E) and 100 mm (C, F).

have been reported by numerous studies. Most of these use remain unclear. Tau antigens could derive from PHF, aa sandwich ELISA method, that allows the quantitation of specific lesion, or could be released following neuronaltotal tau proteins (PHF-tau and normal tau) [395]. A cell death, an aspecific feature of neurological disorders.significant increase in tau concentration has been shown in Concerning the biochemical characterization of the CSF-CSF of AD patients and the sensitivity of this test depends tau proteins, Johnson and colleagues have shown thaton the control population used, ranging to 50–60% to tau-immunoreactive materials in CSF are mostly made of85–100% [9,11,12,30,31,122,193,220,224,246,287,292,29- dephosphorylated and truncated N-terminal tau fragments4,334]. A high variability of the CSF-tau level exists [228].among the different studies with concentration ranging Overall, an increase in tau proteins concentration in CSFfrom 40 to 820 pg/ml in AD cases, and from 27 to 380 has been described in AD, but several issues remainpg/ml in control cases (for review, see Ref. [9]). Spe- unclear. Extensive and accurate analysis of CSF could becificity of the assay seems to be low when studied helpful to define tau proteins species present in physiologi-populations include AD patients and patients with other cal conditions, or released during the progression of aneurodegenerative disorders exhibiting some similar clini- given neurodegenerative disease. Thus, determining thecal features like vascular dementia [9,31,361] or FTD isoform content of tau should add specificity to the[153]. biological test, because many neurodegenerative disorders

The origin and the nature of intrathecal tau proteins can be distinguished by their set of tau isoforms that


accumulate in neurons (see Section 4). Finally, recent Likewise, a specific electrophoretic profile of tau proteinsstudies suggest that a combined assessment of the two could discriminate among these disorders, even though anbasic components of AD lesions, Ab1-42 which is sig- important overlap has been described for some of them.nificantly decreased and tau proteins significantly in- These different biochemical signatures may be related tocreased, improves the specificity and sensitivity of the the expression of different tau isoforms, according to thebiological test [7,8,209,230]. 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

6. Animal models a subtype of neurons. For instance, only isoforms withoutexon 10 aggregate in granule cells of the dentate gyrus that

The development of experimental animal models that exhibit Pick bodies in Pick’s disease. These data suggestreproduce the features of neurodegenerative diseases is that different tau isoforms (with or without exon 10) areuseful in order to elucidate their pathogenic mechanisms, expressed in subsets of neurons that exhibit differentialand to investigate potential therapeutic interventions. In the vulnerability, in addition to possibly variable sets offield of the tauopathies, several models of transgenic mice enzymes (e.g. kinases, phosphatases). Notwithstanding theexpressing either the longest tau isoform (4R-tau) or the regional or laminar distribution or the electrophoreticshortest one (3R-tau) have been recently described pattern of tau proteins, their aggregation is always corre-

¨[46,150,218,376]. Previous data reported by Gotz and lated to dementia when association neocortical areas arecolleagues indicated that in transgenic mice expressing the involved. The recent discovery of mutations on the taulongest human brain tau isoform under the control of the gene, resulting in an abnormal aggregation of tau isoformshuman Thy-1 promoter, transgenic human tau proteins are into filamentous inclusions in FTDP-17, demonstrates thatpresent in nerve cell bodies, axons and dendrites. These abnormal tau metabolism is sufficient to induce nerve cellproteins are phosphorylated at sites that are hyperphos- degeneration. Finally, an aberrant cell trafficking of tauphorylated in AD PHF, and their somatodendritic pattern is proteins can be considered, since in neurodegenerativehomogeneous or granular, but not fibrillar as described in disorders, hyperphosphorylated tau proteins accumulate inAD neurofibrillary lesions [150]. Likewise, Spitteals and somatodendritic compartments, instead of being locatedcolleagues have described a similar transgenic model and predominantly in axons. Since tau trafficking is phos-reported that the induced intraneuronal excess of tau phorylation-dependent, an abnormal phosphorylation of tauproteins caused an axonopathy, which is related to the proteins may lead to aberrant cell trafficking and taulevel of expression of the transgene. A two- to three-fold aggregation.increase in tau protein in the brain and spinal cord of Altogether, these data indicate that numerous mecha-homozygous transgenic mice resulted in somatodendritic nisms including cell vulnerability, regulation of manyredistribution, which is presumably a pretangle stage, and enzymes, tau mutations or aberrant cell trafficking couldconformational alterations of the transgenic proteins [376]. interact to disturb tau metabolism, and result in theFurthermore, transgenic mice expressing the shortest disorganization of the cytoskeleton commonly observed inhuman tau isoform have been extensively described in two all of these neurodegenerative illnesses. But the key eventrecent studies [46,218]. Results indicate that the transgenic is always the disorganization of the cytoskeleton leading totau expressed in these mice accumulate in the somatoden- nerve cell degeneration.dritic compartment, but are also detected in many axons. Asubstantial fraction of these proteins are insoluble, and theamount of these proteins progressively accumulates withage and disease progression, as in AD and other Acknowledgementstauopathies. Thus, transgenic mice models of tauopathiesexhibit similarities with the pathological mechanisms We thank Drs C. Bouras, J.P. David, M.B. Delisle, A.

ínvolved in AD, especially in regard to the aberrant Destee, C. DiMenza, D. Gauvreau, P. Giannakopoulos, V.intracellular targeting of tau proteins. Nevertheless, and Haroutunian, D. Leys, F. Pasquier, D.P. Perl, H. Petit, Y.like most of the animal models, they do not fully reproduce Robitaille, M.M. Ruchoux, and P. Vermersch for providingall of the features leading to the onset of tauopathies. human materials as well as clinical and neuropathological

evaluation of the cases, Dr J.H. Morrison for his constantsupport and interest, and C. Brown, G.I. Lin, B. Wicinski,

7. Concluding remarks W.G.M. Janssen and A.P. Leonard for expert technicalassistance. This work was supported by the Institut de la

´ Ággregation of tau proteins in filamentous inclusions is Sante et de la Recherche Medicale, the Centre National deá common feature of numerous neurodegenerative dis- la Recherche Scientifique, Aventis, Conseil Regional Nord

ôrders. The laminar and regional distribution of NFT or Pas-de-Calais (Pole Neurosciences), NIH Grantsother inclusions are different among dementing conditions. AG02219, AG05138 and AG14382, and the Brookdale


Shin, P.G. Pentchev, E.D. Carstea, J.Q. Trojanowski, Paired helicalFoundation. T.B. is the recipient of a fellowship from thefilament tau (PHF-tau) in Niemann–Pick type C disease is similar toPhilippe Foundation.PHF-tau in Alzheimer’s disease, Acta Neuropathol. 90 (1995) 547–551.

[17] M. Baker, I. Litvan, H. Houlden, J. Adamson, D. Dickson, J.Perez-Tur, J. Hardy, T. Lynch, E. Bigio, M. Hutton, Association of

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