Chapter 4 Tau Protein and the Dementias

Chapter 4 Tau Protein and the Dementias

THE DEMENTIAS 2 4 Tau Protein and the Dementias MICHEL GOEDERT • MARIA GRAZIA SPILLANTINI Tau Isoforms in Human Brain and Their Interactions with M...

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THE DEMENTIAS 2

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Tau Protein and the Dementias MICHEL GOEDERT • MARIA GRAZIA SPILLANTINI

Tau Isoforms in Human Brain and Their Interactions with Microtubules

Neuropathology of FTDP-17

Phosphorylation of Tau

Relevance of Tau Mutations for the Sporadic Tauopathies

Tau Filaments as Nerve Cell Amyloid

Pathogenesis of FTDP-17

Animal Models of the Tauopathies

Mutations in Tau Outlook Functional Effects of Tau Mutations

Over the past 20 years, a basic understanding of the most common dementias has emerged from the coming together of two independent lines of research. First, the molecular study of the neuropathologic lesions that define these diseases led to the identification of their major components. Second, the study of rare, inherited forms of disease resulted in the discovery of gene defects that cause inherited variants of the different diseases. In most cases, the defective genes were found to encode the major components of the neuropathologic lesions or factors that increase their expression. It follows that a toxic property of the proteins that make up the filamentous lesions underlies the inherited forms of these diseases. A corollary insight is that a similar toxic property may also cause the much more common sporadic forms of disease. Three proteins—β-amyloid, tau, and α-synuclein— account for the abnormal protein deposits in more than 90% of dementias.1,2 Alzheimer’s disease (AD) is the most common dementia. Neuropathologically, it is defined by the presence of abundant extracellular neuritic plaques made largely of β-amyloid and intraneuronal neurofibrillary lesions composed of the microtubule-associated protein tau.1 Similar tau deposits, in the absence of extracellular deposits, are also the defining characteristics of a number of other neurodegenerative diseases, which include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD), and argyrophilic grain disease (AGD).3,4 Following the discovery in the 1980s that the paired helical filament (PHF) of AD, the major component of the neurofibrillary pathology, is made of

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tau protein,5–9 the relevance of tau for the neurodegenerative process was hotly debated and questioned repeatedly. The remaining doubts were laid to rest in 1998, when mutations in the tau gene were found to cause the inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).10–12 The study of FTDP-17 has established that primary lesions in tau can lead to neurodegeneration and dementia, with the formation of tau filaments being the likely gain of toxic function. It follows that dysfunction of tau is most probably also of central importance for the pathogenesis of sporadic diseases with a filamentous tau pathology. This is strongly supported by the extensive evidence implicating the tau gene as a susceptibility locus for PSP and CBD.3,4,13

Tau Isoforms in Human Brain and Their Interactions with Microtubules Tau is a natively unfolded microtubule binding protein that is believed to be important for the assembly and stabilization of microtubules.14,15 In nerve cells, it is normally found in axons, but in tau diseases it is redistributed to the cell body and dendrites. In normal adult human brain, there are six isoforms of tau, produced from a single gene by alternative mRNA splicing6,16–18 (Fig. 4-1). They differ from one another by the presence or absence of a 29- or 58-amino acid insert in the amino-terminal half of the protein and by the inclusion, or not, of a 31 amino acid

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Figure 4-1 Schematic diagram of the human tau gene and the six tau isoforms (352 to 441 amino acids) that are generated in brain through alternative mRNA splicing. The human tau gene consists of 16 exons (E) and extends over approximately 140 kb. E0, which forms part of the promoter, and E14 are non-coding (in white). Alternative splicing of E2 (in red), E3 (in green) and E10 (in yellow) gives rise to the six tau isoforms. The constitutively spliced exons (E1, E4, E5, E7, E9, E11, E12, E13) are indicated in blue. E6 and E8 (in violet) are not transcribed in human brain. E4a (in orange) is only expressed in the peripheral nervous system, where its presence gives rise to the tau isoform known as “big tau.” Black bars indicate the microtubule-binding repeats, with three isoforms having three repeats each and three isoforms having four repeats each. Exons and introns are not drawn to scale.

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repeat, encoded by exon 10 of Tau, in the carboxy-terminal half of the protein. The exclusion of exon 10 leads to the production of three isoforms, each containing three repeats, and its inclusion leads to a further three isoforms, each containing four repeats. The repeats constitute the microtubule-binding region of tau protein.19,20 In normal adult human cerebral cortex, there are similar levels of three-repeat and four-repeat isoforms.21 In developing human brain, only the shortest tau isoform (three repeats and no amino-terminal inserts) is expressed. The tau molecule can be subdivided into an amino-terminal domain that projects from the microtubule surface and a carboxy-terminal microtubule-binding domain.22 High-resolution nuclear magnetic resonance (NMR) spectroscopy was used to identify residual structure in a fragment of tau with three microtubule-binding repeats.23 Three regions exhibited a preference for helical conformation, suggesting that these regions may adopt a helical structure when bound to microtubules. Structural work has also begun to shed light in a more direct manner on the way that tau and microtubules interact. Microtubules were assembled with tubulin and tau in the absence of paclitaxel (Taxol) and in the presence of the natural osmolyte trimethylamine N-oxide (TMAO).24 One of the repeats in tau had been labeled with nanogold and was localized by three-dimensional analysis of electron micrographs. The tau repeats were found to bind to the inner surface of the microtubule, in a region that overlapped with the paclitaxel (Taxol)-binding site on β-tubulin. Paclitaxel (Taxol) binds to a site in β-tubulin, where α-tubulin has a conserved loop of eight amino acids (TVVPGGDL). Interestingly, part of the tau repeat motif (THVPGGN) resembles this sequence. Because tubulin cannot have evolved to bind paclitaxel (Taxol), these findings may answer the question of what natural substrate binds in this pocket of β-tubulin. In this model, part of the proline-rich region of tau must provide the link between the amino-terminal projection domain on the outside of the microtubule and the repeat motifs on the inside surface. It could thread through one of the holes between protofilaments. Another model has been derived from experiments in which gold-labeled tau was bound to preassembled, paclitaxel (Taxol)-stabilized microtubules.25 Tau was found to bind only to the outer surface of the microtubule, where it localized along the outer ridges of the protofilaments.

Phosphorylation of Tau In normal brain, tau is phosphorylated at a number of sites3 and phosphorylation negatively regulates its ability to interact with microtubules.26–28 Many of the phosphorylated sites are serine/threonine-prolines, 17 of which are present in the longest human brain tau isoform. Most of these sites flank the microtubule-binding repeats. Proline-directed protein kinases, such as mitogen-activated protein (MAP) kinase,29–31 glycogen synthase kinase-3 (GSK3),32,33 cyclin-dependent kinase-5 (CDK5),34,35 and stress-activated protein (SAP) kinases36 phosphorylate these sites in vitro. Moreover, lithium chloride treatment has been shown to reduce the level of tau phosphorylation,37,38 suggesting that GSK3 is a physiologic tau kinase. In addition, other sites in tau are phosphorylated in vitro by cyclic AMP-dependent protein kinase (PKA),39,40 protein kinase B (PKB),41 calcium/calmodulin-dependent protein kinase II (CamKII),42,43 and microtubule-affinity-regulating kinase (MARK).44

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Some of these sites are located within the repeat region. Protein phosphatase 2A (PP2A) is the major phosphatase activity in brain toward tau phosphorylated by proline-directed and other kinases.31,45 Phosphorylation is developmentally regulated, such that, in fetal brain, tau is more strongly phosphorylated than in adult brain.46,47 An increase in tau phosphorylation reminiscent of that present during development was found in the brain of the hibernating ground squirrel.48 In adult mouse brain, hyperphosphorylation of tau was observed following starvation and cold-water stress.49,50 Inhibition of PP2A activity rather than activation of protein kinases appears to be responsible for this hyperphosphorylation of tau, which can be triggered by hypothermia.51 In human diseases with filamentous deposits, tau protein is hyperphosphorylated.3,52 This is an early event that appears to precede filament assembly. For sites that are also phosphorylated in tau from normal brain, a higher proportion of tau molecules is phosphorylated in filamentous tau. In addition, filamentous tau is phosphorylated at more serine and threonine residues than tau from normal adult brain. In particular, phosphorylation of S214 and S422 was found to be specific for abnormal tau.53,54 The mechanisms underlying filament formation in neurons are still unclear, but it is possible that hyperphosphorylation disengages tau from microtubules, thereby increasing the pool of unbound tau, which may be more resistant to degradation and more prone to aggregation than microtubule-bound tau. It suggests that an increased ability of pathologic tau to interact with microtubules may be beneficial. This could in principle be achieved by protein kinase inhibitors and/or activation of PP2A. Organic osmolytes, such as betaine and TMAO, have been shown to restore the ability of phosphorylated tau to interact with microtubules,55 probably through a conformational change in tubulin and/or tau. Similarly, the prolyl isomerase Pin1, which binds to phosphothreonines 212 and 231 in tau, has been reported to restore the ability of phosphorylated tau to interact with microtubules and to facilitate its dephosphorylation by PP2A.56–58

Tau Filaments as Nerve Cell Amyloid In human diseases with tau pathology, the normally soluble tau protein is present in an abnormal hyperphosphorylated, filamentous form. In AD, tau filaments consist primarily of PHFs, with straight filaments (SFs) being a minority species.59 Electron micrographs of negatively stained isolated filaments show images in which the width of the filament varies between about 8 and 20 nm, with a spacing between crossovers of about 80 nm.60 Although the filament morphologies and their tau isoform composition vary between diseases, it is the repeat region that forms the core of the filament, with the amino- and carboxy-terminal regions forming a fuzzy coat around the filament.7 During the course of the disease, the fuzzy coat is often proteolyzed, such that filaments comprise only the repeat region of tau.61 However, it is the full-length protein that assembles into filaments in the first place.62 Incubation of bacterially expressed human tau with sulfated glycosaminoglycans leads to bulk assembly of full-length tau into filaments.63,64 By immunoelectron microscopy, these filaments can be decorated by antibodies directed against the

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N- and C-terminal regions of tau, but not by an antibody against the microtubulebinding repeat region, exactly like the tau filaments from AD. The assembly is a nucleation-dependent process and a short amino acid sequence (VQIVYK) in the third microtubule-binding repeat was found to be essential for heparin-induced filament assembly.65 By NMR spectroscopy on three tau repeats, this region showed a marked preference for extended or β-strand-like conformation.23 A separate NMR study on four tau repeats detected additional β-strand–like conformation in repeats 2 and 4.66 In addition to sulfated GAGs, RNA and arachidonic acid have also been shown to induce the bulk assembly of full-length tau into filaments.67–69 This work has provided robust methods for assembling full-length tau into filaments. It has also made it possible to obtain structural information and to identify compounds that inhibit tau filament formation. Filaments assembled from either three- or four-repeat tau showed cross-β structure by selected area diffraction, x-ray diffraction from macroscopic fibers, and Fourier transform infrared spectroscopy.70 This work was extended to PHFs and SFs extracted from diseased human brain. There had been controversy in the literature with regard to the internal molecular fine structure of these filaments. The difficulty had been to prepare from human brain pure preparations of filaments for analysis. This problem was circumvented by using selected area diffraction from small groups of filaments of defined morphology. Using this approach, PHFs and SFs had a clear cross-β structure, which is the defining feature of amyloid fibers.70 They share this structure with the extracellular deposits present in systemic and organ-specific amyloid diseases. It is therefore appropriate to consider the tauopathies a form of brain amyloidosis. Small molecule inhibitors of arachidonic acid- and heparin-induced filament formation of full-length tau have been identified.71–73 Prominent among these are a number of phenothiazines, polyphenols, and porphyrins, which inhibit tau filament formation with IC50 values in the low micromolar range and are believed to stabilize soluble oligomeric tau species. The continued identification of inhibitory compounds may pave the way for the development of mechanism-based therapies for the tauopathies.

Mutations in Tau Frontotemporal dementias occur as familial forms and, more commonly, as sporadic diseases. They are characterized by a remarkably circumscribed atrophy of the frontal and temporal lobes of the cerebral cortex, often with additional, subcortical changes. In 1994, an autosomal-dominantly inherited form of frontotemporal dementia with parkinsonism was linked to chromosome 17q21.2.74 Subsequently, other forms of frontotemporal dementia were found to be linked to this region, resulting in the denomination FTDP-17 for this class of disease. All cases of FTDP-17 have so far shown a filamentous pathology made of hyperphosphorylated tau protein (Fig. 4-2). In June 1998, the first mutations in Tau in FTDP-17 were reported.10–12 At the time of writing, 37 different mutations have been described in more than 100 families with FTDP-17 (Fig. 4-3). Known mutations are missense, deletion, or silent mutations in the coding region or intronic mutations located close to the splice-donor site of the intron following the alternatively spliced exon 10.

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Figure 4-2 Pathologies of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), as revealed by immunohistochemistry for hyperphosphorylated tau protein and the presence of tau filaments. A, The P301L mutation in exon 10 gives rise to a neuronal and glial tau pathology. Filaments consist of narrow twisted ribbons (left) as the majority species and ropelike filaments (right) as the minority species. B, Mutations in the intron following exon 10 give rise to a neuronal and glial tau pathology. Filaments consist of wide twisted ribbons. C, The V337M mutation in exon 12 gives rise to a neuronal tau pathology. Filaments consist of paired helical filaments (left) and straight filaments (right) like the tau filaments of Alzheimer’s disease. D, The G389R mutation in exon 13 gives rise to a neuronal tau pathology. Filaments consist of straight filaments (left) as the majority species and twisted filaments (right) as the minority species. The tau pathology resembles that of Pick’s disease.

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Figure 4-3 Mutations in the tau gene in FTDP-17. A, Schematic diagram of the six tau isoforms (352 to 441 amino acids) that are expressed in adult human brain, with mutations in the coding region indicated using the numbering of the 441 amino acid isoform. Twenty-five missense mutations, two deletion mutations, and three silent mutations are shown. B, Stem-loop structure in the pre-mRNA at the boundary between exon 10 and the intron following exon 10. Nine mutations are shown, two of which (S305N and S305S) are located in exon 10. Exon sequences are boxed and shown in capital, with intron sequences being shown in lowercase letters.

Functional Effects of Tau Mutations Tau mutations fall into two largely nonoverlapping categories—those that influence the alternative splicing of tau pre-mRNA and those whose primary effect is at the protein level. Several mutations in exon 10 of Tau, such as ΔK280, ΔN296, and N296H, have effects at both RNA and protein levels.75–78 In accordance with their location in the microtubule-binding region of tau, most missense mutations reduce the ability of tau to interact with microtubules, as reflected by a reduction in the ability of mutant tau to promote microtubule assembly.79,80 Mutations S305N and Q336R are exceptions because they slightly increase the ability of tau to promote microtubule assembly,81,82 in addition to having additional effects that may be pathogenic. A reduction in microtubule function is observed when mutant tau is expressed in a number of cell types.83–86 Expression of tau with a variety of mutations caused varying degrees of reduced

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microtubule binding and stability, as well as disorganized microtubule morphology. A number of mutations in Tau may cause FTDP-17, at least in part, by promoting the aggregation of tau protein.82,87–92 Several studies have demonstrated that some of these mutations, including R5L, K257T, I260V, G272V, ΔK280, P301L, P301S, G335V, Q336R, V337M, and R406W, promote heparin- or arachidonic acidinduced filament formation of tau in vitro relative to wild-type tau. This effect is particularly marked for mutations P301L and P301S. Furthermore, the assembly of mutant tau into filaments following conditional expression in neuroglioma cells has been reported.93 Additional mechanisms may play a role in the case of some coding region mutations. For instance, protein phosphatase 2A is known to be the major tau phosphatase in brain and to bind to the tandem repeats in tau. Accordingly, several mutant tau proteins have shown reduced binding to protein phosphatase 2A.94 Intronic mutations and most coding region mutations in exon 10 (N279K, L284L, ΔN296, N296N, N296H, G303V, S305N, and S305S) increase the splicing of exon 10, thus changing the ratio of three- and four-repeat isoforms, resulting in the overproduction of four-repeat tau.11,12,75,77,78,81,95–99 Mutation ΔK280 in exon 10 and the +19 intronic mutation are apparent exceptions because they reduced the splicing of exon 10 in transfection experiments.75,100 However, it remains to be seen whether these mutations lead to an overproduction of three-repeat tau in human brain. Approximately half of the known Tau mutations have their primary effect at the RNA level. Thus, to a significant degree, FTDP-17 is a disease of the alternative mRNA splicing of exon 10 of the tau gene. It follows that a correct ratio of three-repeat to four-repeat tau isoforms is essential for preventing neurodegeneration and dementia in mid-life. This is all the more surprising because tau isoform ratios in adult brain are not conserved between species.21,101,102 Thus, in rodents, only four repeat isoforms are expressed, whereas in chicken brain tau isoforms with three, four, and five repeats are present. The regulation of the alternative splicing of exon 10 has been extensively studied. Multiple cis-acting exon splicing enhancers (ESEs) and exon splicing silencers (ESSs) are known to regulate use of the weak 3′ and 5′ splice sites.75,103–107 These elements are located in exon 10 itself and in the intron following exon 10. Exon 10 sequences include three non-redundant ESEs located in the first half of the exon, which are separated by a central ESS from additional ESE sequences at the 3′ end. Sequences located at the end of exon 10 and at the beginning of the intron following exon 10 inhibit the splicing of exon 10, probably because of the presence of a stem-loop structure that limits access of the splicing machinery to the 5′-splice site.11,12 The determination of the three-dimensional structure of a 25-nucleotide-long RNA from the exon 10-5′-intron junction has shown that this sequence forms a stable, folded stem-loop structure.108,109 The stem consists of a single G-C base pair that is separated from a double helix of six base pairs by an unpaired adenine. As is often the case with single nucleotide purine bulges, the unpaired adenine at position –2 does not extrude into solution but intercalates into the double helix. The apical loop consists of six nucleotides that adopt multiple conformations in rapid exchange. Downstream of this intron splicing silencer (ISS), an intron splicing modulator has been described.107 It mitigates exon 10 expression by the ISS.

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Pathogenic mutations in the tau gene may alter exon 10 splicing by affecting several of the regulatory elements described earlier. Thus, the intronic mutations (+3, +11, +12, +13, +14, and +16) destabilize the inhibitory stem-loop structure. The S305N mutation and the +3 intronic mutation may also enhance exon 10 splicing by increasing the strength of the 5′-splice site through improved binding of U1snRNA. However, the finding that the S305S mutation, which causes reduced binding of U1snRNA, leads to a predominance of four-repeat tau110 argues against this as the primary effect of the mutations. The N279K mutation may improve the function of the first ESE, thus enhancing exon 10 splicing. Mutation L284L, which enhances exon 10 splicing, may do so by disrupting a potential ESS or by lengthening the first ESE. The effects of the three mutations at codon 296 (ΔN296, N296N, and N296H) are probably through disruption of the ESS. The high fidelity of splice-site selection results from the cooperative binding of trans-acting factors to cis-acting sequences.111 Heterogenous nuclear ribonucleoproteins (hnRNPs) and serine-arginine rich (SR) proteins are involved in splicesite selection. The SR domain-containing proteins Tra2β, SF2/ASF, and SRp30c have been found to interact with the first ESE in the 5′ end of exon 10 and to function as activators of the alternative splicing of exon 10.112,113 In transfection experiments, several other SR proteins, such as SRp20, have been shown to promote the exclusion of exon 10.105,114 Moreover, phosphorylation of SR proteins by CDC2-like kinases has also been found to result in the skipping of exon 10.115

Neuropathology of FTDP-17 To a significant degree, the morphologies of tau filaments and their isoform compositions are determined by whether Tau mutations affect mRNA splicing of exon 10 or whether they are missense mutations located inside or outside exon 10 (Fig. 4-2).116,117 The latter give rise to a number of different pathologies. Mutations in Tau that result in increased splicing of exon 10 lead to the formation of wide twisted ribbon-like filaments that consist only of four-repeat tau isoforms.118 Where examined, the tau pathology was widespread and present in both nerve cells and glial cells. This has been shown for the intronic mutations97,98,116–119 and for mutations N279K, L284L, S305N, S305S, ΔN296, N296N, and N296H in exon 10.75,95,110,120–124 Mutation P301L in exon 10, which does not affect alternative mRNA splicing, leads to the formation of narrow twisted ribbons that contain four-repeat tau isoforms.80,125,126 Biochemical studies have demonstrated that filaments extracted from the brains of patients with the P301L mutation contain predominantly mutant tau.127 Tau pathology is widespread and present in both nerve cells and glial cells.125,126 Compared with mutations that affect the splicing of exon 10, the glial component is less pronounced. Most coding region mutations located outside exon 10 lead to a neuronal tau pathology, without a significant glial component. However, tau deposits in both nerve cells and glial cells have been described for mutations R5H and R5L in exon 1, I260V and L266V in exon 9, and L315R and K317M in exon 11.92,128–132 Two mutations, V337M in exon 12 and R406W in exon 13, lead to the formation of

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PHFs that contain all six tau isoforms, like the tau filaments in AD.133,134 Using an antibody specific for tau protein with the R406W mutation, both wild-type and mutant proteins were detected in the abnormal filaments.135 Mutations K257T, L266V, G272V, S305N, L315R, S320F, Q336R, E342V, K369I, and G389R can lead to a tau pathology similar or identical to that of PiD.82,125,130,131,136–142 These findings indicate that, depending on the positions of Tau mutations in exons 9-13 and the nature of these mutations, a filamentous tau pathology ensues, which resembles that of either PSP, CBD, AD, or PiD.

Pathogenesis of FTDP-17 The pathway leading from a mutation in Tau to neurodegeneration is unknown. The likely primary effect of most missense mutations is a change in conformation that results in a reduced ability of tau to interact with microtubules.79,80 It can be overcome by natural osmolytes, such as TMAO, probably through the promotion of tubulin-induced folding of tau.143 The primary effect of these mutations may be equivalent to a partial loss of function, with resultant microtubule destabilization and deleterious effects on cellular processes, such as rapid axonal transport. However, in the case of mutations whose primary effect is at the RNA level, this appears unlikely. The net effect of these mutations is a simple overproduction of tau isoforms with four repeats, which are known to interact more strongly with microtubules than isoforms with three repeats.21 It is therefore possible that in cases of FTDP-17 with intronic mutations and those coding region mutations whose primary effect is at the RNA level, microtubules are more stable than in brain from control individuals. Moreover, some mutations, such as P301L and P301S in exon 10, will only affect 20% to 25% of tau molecules, with 75% to 80% of tau being wild-type, arguing against a simple loss of function of tau as a decisive mechanism. Mice without tau protein are largely normal and exhibit no signs of neurodegeneration.144 A correct ratio of wild-type three-repeat to four-repeat tau may be essential for the normal function of tau in human brain. However, the fact that the tau isoform composition is not conserved among humans, rodents, and chickens argues against this possibility.21,101,102 An alternative hypothesis is that a partial loss of function of tau is necessary for setting in motion the “gain of toxic function” mechanism that will lead to neurodegeneration. This hypothesis requires that an overproduction of tau isoforms with four repeats results in an excess of tau over available binding sites on microtubules, resulting in the cytoplasmic accumulation of unbound four-repeat tau. It would probably necessitate the existence of different binding sites on microtubules for three-repeat and four-repeat tau. Validation of this hypothesis will require structural information at the atomic level. From the previous discussion, a reduced ability of tau to interact with microtubules emerges as the most likely primary effect of the FTDP-17 mutations. It will lead to the accumulation of tau in the cytoplasm of brain cells and result in its hyperphosphorylation. Over time, hyperphosphorylated tau protein will assemble into abnormal filaments. It is at present unknown whether the filaments themselves cause nerve cell loss or whether nonassembled, conformationally altered tau is toxic.

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Relevance of Tau Mutations for the Sporadic Tauopathies The study of FTDP-17 has established that dysfunction of tau protein can cause neurodegeneration and dementia. It follows that tau dysfunction is most probably also of central importance for the pathogenesis of sporadic diseases with a filamentous tau pathology, such as AD, PSP, CBD, AGD, and PiD. This is further underlined by the fact that the aforementioned diseases are partially or completely phenocopied by cases of FTDP-17.3,4 Ten missense mutations in Tau (K257T, L266V, G272V, S305N, L315R, S320F, Q336R, E342V, K369I, and G389R) have been shown to give rise to a clinical and neuropathologic phenotype reminiscent of PiD.82,125,130,131,136–142 The finding that overproduction of four-repeat tau causes disease and leads to the assembly of tau with four repeats in nerve cells and glial cells may shed light on the pathogenesis of PSP, CBD, and AGD. Neuropathologically, all three diseases are characterized by a neuronal and glial pathology, with the filaments comprising predominantly fourrepeat tau.121,145–148 PSP and CBD can be phenocopied by some Tau mutations. Thus, individuals with mutations R5L, N279K, ΔN296, G303V, S305S, and the +16 intronic mutation have presented with a clinical picture similar to PSP,99,110,129,149–151 whereas some individuals with mutations N296N, P301S, and K317M suffered from a disease resembling CBD.96,132,152,153 Intronic mutation +14 and missense mutation K317M can give rise to cases of FTDP-17 with motor neuron disease, extending the phenotypic spectrum even further.132,154 An association between PSP and a dinucleotide repeat polymorphism in the intron between exons 9 and 10 of Tau was described in 1997.155 Subsequently, a similar genetic association was found for CBD.156 The alleles at this locus carry 11 to 15 repeats. The A0 allele, with 11 repeats, is present in more than 90% of patients with PSP and in about 70% of controls. Following from this work, two common Tau haplotypes, named H1 (allele frequency of 80%) and H2 (allele frequency of 20%) were identified in populations of European descent, with haplotype H1 being a risk factor for PSP and CBD.157,158 Both alleles differ in nucleotide sequence and intron size but are identical at the amino acid level. A recent study has shown that a genomic inversion polymorphism underlies the H1 and H2 haplotypes, explaining the extended linkage disequilibrium in this region and the suppressed H1/H2 recombination.159 It extends over a 900-kb region that encompasses the tau gene along with several other genes. H1 shows considerable diversity and has a normal pattern of linkage disequilibrium, except with H2, whereas H2 appears to be an unrecombining haplotype. Several subhaplotypes of H1 have been identified, and one of these (H1B, also known as H1c) has been linked to PSP and CBD.160,161 One study has also reported an association between this subhaplotype and sporadic, late-onset AD.162 The H1B risk has been localized to a 22 kb regulatory region in the large intron preceding coding exon 1 of Tau and could be explained by a single nucleotide polymorphism creating a binding site for transcription factor CP2 (erythrocyte factor related to Drosophila Elf1 [LBP-1c; LSF]).162 In addition, several groups have described a significant association between the H1 haplotype and idiopathic Parkinson’s disease, a disease without significant tau pathology.163–166 The functional consequences resulting from the presence of the H1 or H2 haplotype are incompletely understood. It has been reported that H1 is more effective

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than H2 at driving expression of a reporter gene in transfected cells, suggesting that expression of tau from the H1 haplotype may be higher than from the H2 haplotype.167 Furthermore, the H2 haplotype has also been found to be associated with an earlier age of onset in sporadic cases of frontotemporal dementia lacking tau pathology.168 The intron between exons 9 and 10 of Tau also contains the putative intronless gene Saitohin, which encodes a predicted protein of 128 amino acids that is poorly conserved.169,170 It remains to be seen whether saitohin exists as a bona fide protein and, if so, what its physiologic function may be.

Animal Models of the Tauopathies The identification of mutations in Tau in FTDP-17 is rapidly leading to the production of transgenic mouse lines that reproduce the essential molecular and cellular features of the human tauopathies (Figs. 4-4 and 4-5). They represent a marked improvement over earlier lines that expressed wild-type human tau in nerve cells and showed signs of axonopathy and amyotrophy but failed to develop abundant tau filaments and nerve cell death.171–173 Mouse lines expressing human tau with mutations P301L, G272V, V337M, R406W, P301S, and the triple mutation G272V, P301L, and V337M in nerve cells or glial cells have been published.174–185 Abundant tau filaments in nerve cells were found in lines expressing four-repeat P301L or R406W human tau under the control of the murine prion protein promoter and four-repeat P301S human tau under the control of the murine Thy1 promoter. Filamentous tau protein was hyperphosphorylated in a similar way to the human diseases, and hyperphosphorylation at most sites appeared to precede the assembly of tau into filaments. Moreover, an increase in the phosphorylation of soluble tau resulted in increased filament formation, suggesting that phosphorylation can drive filament assembly.186 In lines transgenic for P301L and P301S tau, nonapoptotic nerve cell loss and a pronounced inflammatory reaction were detected in the spinal cord.179,187,188 The mice suffered from a severe paraparesis and showed signs of neurogenic muscle atrophy. In a mouse line expressing P301L tau in oligodendrocytes, coexpression of mutant human α-synuclein resulted in the appearance of thioflavin S-positive staining that was not observed in the single transgenic lines.189 Moreover, in vitro experiments showed that α-synuclein can induce the formation of tau filaments, giving a possible explanation for the co-occurrence of tau and α-synuclein in some neurodegenerative diseases. In mouse lines expressing P301L tau in nerve cells, coexpression of mutant human amyloid precursor protein (APP) or the intracerebral injection of β-amyloid fibrils resulted in an increase in the number of tanglebearing cells.190,191 In a mouse line triple transgenic for mutant APP, presenilin-1 and P301L tau, the intracerebral injection of anti-Aβ antibodies or of a γ-secretase inhibitor resulted in the disappearance of somatodendritic staining in younger, but not in older, animals.192 It thus appears that extracellular β-amyloid deposits can exacerbate the intraneuronal pathology caused by the expression of mutant human tau protein. However, one must bear in mind that these experiments are artificial, in that mutant APP and mutant tau have not been encountered together in human disease. So far, β-amyloid deposition has not been found to induce the formation of filamentous tau deposits in transgenic mice.

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Figure 4-4 Tau protein immunoreactivity in brain and spinal cord from mice transgenic for mutant (P301S) human tau protein. A and B, Cerebral cortex. C, Amygdala. D, Dentate nucleus of the cerebellum. E and F, Brainstem. G and H, Spinal cord. Scale bars: A–C, E, F, 40 μm (in A); D, H, 60 μm (in D); G, 250 μm.

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A

B

C

D

E

F

Figure 4-5 Tau filaments in brain and spinal cord from mice transgenic for mutant (P301S) human tau protein. A and B, Cerebral cortex. C and D, Brainstem. E and F, Spinal cord. B, D, F, Higher magnification of parts of the cytoplasmic regions from (A, C, E). The electron micrographs in (C, D) show immunogold labeling of filaments using a phosphorylation-dependent anti-tau antibody. Scale bars: C, 1.5 μm; A, E, 5.5 μm (in E); B, D, F, 300 nm (in F).

Filamentous tau deposits made of wild-type human tau were observed in a mouse line expressing all six human brain tau isoforms in the absence of endogenous mouse tau.193 The observed imbalance between levels of three- and fourrepeat isoforms may have caused tau pathology in this line, where nerve cells with

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and without tau inclusions were reported to die. A closer correspondence was observed between cell death and an abnormal re-expression of cell cycle markers, suggesting a possible cause and effect relationship.194 However, this contrasts with a line transgenic for P301S tau, where cell cycle markers were not reexpressed.195 Endogenous mouse tau has been reported to assemble into filaments in a neurodegenerative condition caused by inactivation of the gene encoding prolyl isomerase Pin1.196 Models of tauopathy have also been developed by expressing mutant human tau in rat basal forebrain and substantia nigra using viral vector constructs.197,198 Filamentous tau deposits formed over a period of several months when human P301L tau was expressed. In the nigrostriatal system, this caused a significant loss of dopaminergic nerve cells, a reduction in striatal dopamine content, and amphetamine-stimulated rotational behavior consistent with a specific lesion effect. Taken together, these experimental models of human tauopathy reaffirm the notion derived from studies of human diseases that a pathologic pathway leading from soluble, monomeric, to insoluble, filamentous tau causes neurodegeneration. What is unclear, however, is the precise molecular nature of the offending tau species. Assembly of tau into filaments is a complex process that is likely to involve a number of poorly defined intermediates of varying solubility and, perhaps, toxicity. An apparent dissociation between inclusion formation and neurodegeneration was reported in a model based on the inducible expression of human P301L tau to high levels.199 Mouse models of the human tauopathies differ from invertebrate models, in that overexpression of wild-type and mutant human tau in Caenorhabditis elegans and Drosophila melanogaster results in extensive phosphorylation and nerve cell degeneration, in the apparent absence of filament formation.200–205 Phosphorylation of tau was more extensive in the fly than in the worm. In Drosophila, phosphorylation of S262 and S356 in the microtubule-binding repeat region of tau by PAR-1 kinase, the fly homologue of MARK, appeared to be necessary for the subsequent phosphorylation at other sites, suggesting the existence of a hierarchical and temporally ordered phosphorylation process.204 However, in a separate study,203 PAR-1 kinase was found to act as a suppressor of tau toxicity. Other protein kinases, including GSK3, CDK5, and SAP kinases, increased tau phosphorylation and toxicity. As expected, increased PP2A activity was accompanied by reduced tau phosphorylation and toxicity.201,203 In contrast to what has been described in FTDP-17,206 tau-induced neurodegeneration involved programmed cell death.201 All in all, it thus appears that conformationally altered, hyperphosphorylated, nonfilamentous human tau protein is neurotoxic in invertebrates. The future will tell whether this is also true in mice and men.

Outlook It is now well established that a pathway leading from soluble to insoluble, filamentous tau protein is central to the neurodegenerative process in the human tauopathies. The availability of animal models that exhibit the essential molecular and cellular features of the human diseases has opened the way to a detailed understanding of the neurodegenerative process and the identification of genetic

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