Virginia M-Y Lee,1 Michel Goedert,2 and John Q Trojanowski

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April 7, 2001 15:58 Annual Reviews AR121-37

Annu. Rev. Neurosci. 2001. 24:1121–159Copyright c© 2001 by Annual Reviews. All rights reserved

NEURODEGENERATIVE TAUOPATHIES

Virginia M-Y Lee,1 Michel Goedert,2

and John Q Trojanowski11Center for Neurodegenerative Disease Research, Department of Pathology andLaboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia,Pennsylvania 19104; e-mail: [email protected],[email protected] Research Council, Laboratory of Molecular Biology, Hills Road, Cambridge,CB2 2QH, United Kingdom; e-mail: [email protected]

Key Words Alzheimer’s disease, frontotemporal dementia, mutation,neurodegenerative disease, filamentous deposits, pathology, tau protein

■ Abstract The defining neuropathological characteristics of Alzheimer’s diseaseare abundant filamentous tau lesions and deposits of fibrillar amyloidβ peptides.Prominent filamentous tau inclusions and brain degeneration in the absence ofβ-amyloid deposits are also hallmarks of neurodegenerative tauopathies exemplified bysporadic corticobasal degeneration, progressive supranuclear palsy, and Pick’s dis-ease, as well as by hereditary frontotemporal dementia and parkinsonism linked tochromosome 17 (FTDP-17). Because multipletau gene mutations are pathogenicfor FTDP-17 and tau polymorphisms appear to be genetic risk factors for sporadicprogressive supranuclear palsy and corticobasal degeneration, tau abnormalities arelinked directly to the etiology and pathogenesis of neurodegenerative disease. Indeed,emerging data support the hypothesis that differenttaugene mutations are pathogenicbecause they impair tau functions, promote tau fibrillization, or perturbtaugene splic-ing, thereby leading to formation of biochemically and structurally distinct aggre-gates of tau. Nonetheless, different members of the same kindred often exhibit diverseFTDP-17 syndromes, which suggests that additional genetic or epigenetic factors influ-ence the phenotypic manifestations of neurodegenerative tauopathies. Although theseand other hypothetical mechanisms of neurodegenerative tauopathies remain to betested and validated, transgenic models are increasingly available for this purpose,and they will accelerate discovery of more effective therapies for neurodegenerativetauopathies and related disorders, including Alzheimer’s disease.

INTRODUCTION

The study of sporadic and familial neurodegenerative diseases over the past decadehas led to the realization that many of these disorders are characterized by distincthallmark brain lesions that have in common the formation of filamentous de-posits of abnormal brain proteins. Thus, a group of heterogeneous dementias and

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1122 LEE ¥ GOEDERT ¥ TROJANOWSKI

movement disorders that are characterized neuropathologically by prominent intra-cellular accumulations of abnormal filaments formed by the microtubule-associatedprotein tau appears to share common mechanisms of disease. They are collectivelyknown as neurodegenerative tauopathies (Table 1). Despite their diverse pheno-typic manifestations, brain dysfunction and degeneration in tauopathies is linkedto the progressive accumulation of filamentous tau inclusions, and this, togetherwith the absence of other disease-specific neuropathological abnormalities, pro-vided circumstantial evidence implicating abnormal tau in disease onset and/orprogression. However, this view remained unproven and highly controversial un-til 1998, when multipletau gene mutations were discovered in frontotemporaldementia and parkinsonism linked to chromosome 17 (FTDP-17), thereby pro-viding unequivocal evidence that tau abnormalities alone are sufficient to causeneurodegenerative disease (Foster et al 1997, Hutton et al 1998, Poorkaj et al1998, Spillantini et al 1998c). This seminal finding opened up new avenues for

TABLE 1 Diseases with tau-based neurofibrillary pathology

Alzheimer’s disease

Amyotrophic lateral sclerosis/parkinsonism–dementia complexa

Argyrophilic grain dementiaa

Corticobasal degenerationa

Creutzfeldt-Jakob disease

Dementia pugilisticaa

Diffuse neurofibrillary tangles with calcificationa

Down’s syndrome

Frontotemporal dementia with parkinsonism linked to chromosome 17a

Gerstmann-Str¨aussler-Scheinker disease

Hallervorden-Spatz disease

Myotonic dystrophy

Niemann-Pick disease, type C

Non-Guamanian motor neuron disease with neurofibrillary tangles

Pick’s diseasea

Postencephalitic parkinsonism

Prion protein cerebral amyloid angiopathy

Progressive subcortical gliosisa

Progressive supranuclear palsya

Subacute sclerosing panencephalitis

Tangle only dementiaa

aDiseases in which tau-positive neurofibrillary pathology are the most predominant neu-ropathologic feature.

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NEW INSIGHTS INTO TAUOPATHIES 1123

investigating the role of tau abnormalities in mechanisms of brain dysfunction anddegeneration.

This review is designed to integrate and interpret the remarkable recent advancesthat have led to new insights into the mechanistic role that tau abnormalities playin neurodegenerative disease. It begins with a brief summary of our current under-standing of the humantau gene and the functions of the six alternatively splicedtau isoforms that are expressed in the normal adult human brain. What is knownabout the role of tau abnormalities in Alzheimer’s disease (AD) is considered next,and this is followed by an overview of several prototypical, as well as some novelsporadic, tauopathies. This information provides the context and perspective inwhich to present an update on the increasing number of pathogenictau gene mu-tations, as well as a summary of the neuropathological and biochemical profiles ofthe tau pathologies in FTDP-17. Finally, the review concludes with an update ofthe current status of efforts to develop transgenic (TG) and other animal modelsof human neurodegenerative tauopathies.

STRUCTURE, FUNCTION, AND MOLECULARGENETICS OF TAU

Tau proteins are lowMr microtubule-associated proteins that are abundant in thecentral nervous system (CNS), where they are expressed predominantly in axons.They are also expressed in axons of peripheral nervous system neurons but arebarely detectable in CNS astrocytes and oligodendrocytes (Cleveland et al 1977b,Binder et al 1985, Shin et al 1991, Couchie et al 1992, LoPresti et al 1995). Humantau proteins are encoded by a single gene consisting of 16 exons on chromosome17q21, and the CNS isoforms are generated by alternative mRNA splicing of 11 ofthese exons (Neve et al 1986, Goedert et al 1988, Andreadis et al 1992) (Figure 1).In adult human brain, alternative splicing of exons (E)2, E3, and E10 generatessix tau isoforms ranging from 352 to 441 amino acids in length (Figure 1), whichdiffer by the presence of either three (3R-tau) or four (4R-tau) carboxy-terminaltandem repeat sequences of 31 or 32 amino acids each that are encoded by E9,E10, E11, and E12 (Goedert et al 1989a,b; Andreadis et al 1992). Additionally,the triplets of 3R-tau and 4R-tau isoforms differ as a result of alternative splicingof E2 and E3 to generate tau isoforms without (0N) or with either 29 (1N) or 58(2N) amino acid inserts of unknown functions (Goedert et al 1989b). In adulthuman brain, the ratio of 3R-tau to 4R-tau isoforms is∼1, but the 1N, 0N, and2N tau isoforms comprise about 54%, 37%, and 9%, respectively, of total tau(Goedert & Jakes 1990, Hong et al 1998). In addition, the alternative splicing oftau is developmentally regulated such that only the shortest tau isoform (3R/0N) isexpressed in fetal brain, whereas all six isoforms appear in the postnatal period ofthe human brain (Goedert et al 1989a). In the peripheral nervous system, inclusionof E4a in the amino-terminal half results in the expression of higherMr proteinstermed big tau (Georgieff et al 1991, Couchie et al 1992, Goedert et al 1992c).

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Figure 1 Schematic representation of the human tau gene and the six central nervous system(CNS) tau isoforms generated by alternative mRNA splicing. The human tau gene contains 16exons, including exon (E)0, which is part of the promoter. Alternative splicing of E2, E3, and E10(gray boxes) produces the six tau isoforms. E6 and E8 (stippled boxes) are not transcribed in thehuman CNS. E4a (striped box), which is also not transcribed in the human CNS, is expressed inthe peripheral nervous system, leading to the larger tau isoforms, termed big tau (see text). Theblack bars depict the 18–amino acid microtubule binding repeats and are designated R1 to R4.The relative sizes of the exons and introns are not drawn to scale.

Since its discovery>25 years ago, a number of well-defined functions of tauprotein have been discovered and extensively characterized (for review, see Bu´eeet al 2000). Most notably, tau binds to and stabilizes microtubules (MTs), in ad-dition to promoting MT polymerization (Weingarten et al 1975, Cleveland et al1977b). The MT binding domains of tau are localized to the carboxy-terminal halfof the molecule within the four MT binding motifs. These motifs are composed ofhighly conserved 18–amino acid long binding elements separated by flexible, butless conserved, interrepeat sequences that are 13–14 amino acids long (Himmleret al 1989, Lee et al 1989, Butner & Kirschner 1991). The binding of tau to MTsis a complex process mediated in part by a flexible array of weak MT binding sitesthat are distributed throughout the MT binding domain delineated by these repeatsand their interrepeat sequences (Lee et al 1989, Butner & Kirschner 1991). In ad-dition, sequences flanking the repeats contribute to microtubule binding (Gustkeet al 1994). 4R-tau isoforms are more efficient at promoting MT assembly andhave a greater MT binding affinity than do 3R-tau isoforms (Goedert & Jakes1990, Butner & Kirschner 1991). It is interesting to note that the interrepeat se-quence between the first and second MT binding repeats has more than twicethe binding affinity of any individual MT binding repeat (Goode & Feinstein1994). This region is unique to 4R-tau and is believed to be responsible for thehigher MT binding affinity of 4R-tau isoforms compared with 3R-tau isoforms(Goedert & Jakes 1990). Notably, because other microtubule-associated proteins

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probably perform similar functions, it is possible they can compensate for a defi-ciency or loss of tau, which may account for the report that tau knockout mice didnot have any overt phenotype (Harada et al 1994). However, a more recent studyhas reported some subtle behavioral impairments in older knockout mice (Ikegamiet al 2000).

TAU PHOSPHORYLATION AND REGULATIONOF TAU FUNCTIONS

There are 79 potential serine (Ser) and threonine (Thr) phosphate acceptor residuesin the longest tau isoform, and phosphorylation at∼30 of these sites has beenreported in normal tau proteins (reviewed in Billingsley & Kincaid 1997, Bu´eeet al 2000). Tau phosphorylation is developmentally regulated such that fetal tau ismore highly phosphorylated in embryonic compared with adult CNS (Kanemaruet al 1992, Bramblett et al 1993, Goedert et al 1993, Watanabe et al 1993), andthe degree of phosphorylation of all six tau isoforms decreases with age, probablybecause of the activation of phosphatases (Mawal-Dewan et al 1994). The tauphosphorylation sites are clustered in regions flanking the MT binding repeats,and it is well established that increasing tau phosphorylation negatively regulatesMT binding (Drechsel et al 1992, Bramblett et al 1993, Yoshida & Ihara 1993,Biernat et al 1993). The importance of individual sites in tau in regulating MTbinding has been debated for some time. For example, phosphorylation of Ser262,which lies within the first MT binding domain, is thought to play a dominant rolein reducing the binding of tau to MTs (Biernat et al 1993). A similar role may beconsidered for phosphorylation of Ser396, which is located adjacent to the carboxy-terminal end of the fourth MT binding domain (Bramblett et al 1993), but otherdata argue that phosphorylation of neither of these sites is sufficient to eliminatethe binding of tau to MTs (Seubert et al 1995). It is interesting that both sites arephosphorylated in fetal tau and that they are hyperphosphorylated in all six tauisoforms that form abnormal paired helical filaments (PHFs) in the neurofibrillarytangles (NFTs) of the AD brain (Seubert et al 1995). The regulation of the bindingof tau to MTs may be also be regulated by sites outside the MT binding repeats.For example, although the evidence is fragmentary, it has been suggested that aheptapeptide sequence (224KKVAVVR 230) located within a proline-rich domain,amino-terminal to the MT binding domains, promotes MT binding in combinationwith the repeat regions (Goode et al 1997). Thus, it is likely that phosphorylation atmultiple sites, especially those flanking the MT binding repeats, but also additionalintra- and intermolecular interactions, regulate the MT binding function of tau.Only little is known about the regulation of tau phosphorylation. One study hasreported increased phosphorylation of tau at Ser202/Thr205 in mice that lackReelin or both the very-low-density lipoprotein receptor and the apolipoproteinE receptor 2 (Hiesberger et al 1999). It suggests that tyrosine phsophorylationof the disabled-1 adaptor protein may play a role in regulating the level of tau

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phosphorylation. It remains to be seen whether this finding can be extended toadditional phosphorylation sites in tau and to mice mutant for other componentsof this developmental pathway.

For the reasons discussed above, considerable research has focused on theprotein kinases and protein phosphatases that regulate tau phosphorylation, and alarge number of Ser/Thr protein kinases have been implicated or have been sug-gested as playing a role in regulating tau functions in vivo (reviewed in Billingsley& Kincaid 1997, Buee et al 2000, Hong et al 2000). These kinases include mito-gen-activated protein kinase (Drewes et al 1992, Drechsel et al 1992, Goedertet al 1992a), glycogen synthase kinase 3β (GSK-3β) (Hanger et al 1992,Mandelkow et al 1992), cyclin-dependent kinase 2 (cdk2) (Baumann et al 1993),cdk5 (Baumann et al 1993, Kobayashi et al 1993), cAMP-dependent protein ki-nase (Litersky & Johnson 1992), Ca2+/calmodulin-dependent protein kinase II(Baudier & Cole 1987), and MT-affinity regulating kinase (Drewes et al 1997).In addition, several members of the family of stress-activated protein kinases alsophosphorylate tau at multiple sites (Goedert et al 1997; Reynolds et al 1997a,b).Nonetheless, it is important to emphasize that many of these studies provide onlyin vitro evidence to implicate specific kinases and that it remains unclear what rolethey play in the in vivo phosphorylation of tau.

Recent data have implicated two protein kinases, GSK-3β and cdk5, in the invivo regulation of tau phosphorylation. GSK-3β is a Ser/Thr kinase that is abundantin brain and associates with MTs (Mandelkow et al 1992, Ishiguro et al 1994, Singhet al 1995, Takahashi et al 1995, Cohen 1999). Cotransfection of nonneuronalcells with human tau and GSK-3β induces hyperphosphorylation of tau associatedwith a loss of MT binding (Lovestone et al 1996). In cultured neuronal cells,GSK-3β-mediated phosphorylation of tau is inhibited by insulin and IGF-1 via aphosphatidylinositol 3-kinase and protein kinase B–dependent signaling pathway(Hong & Lee 1997). In addition, direct inhibition of GSK-3β by lithium salts orATP competitive inhibitors reduces tau phosphorylation and affects MT stability(Hong et al 1997, Munoz-Montano et al 1997, Lovestone et al 1999, Takahashiet al 1999, Leost et al 2000). Cdk5 is a Ser/Thr protein kinase highly enriched inneurons that colocalizes to the cytoskeleton and contributes to the phosphorylationof tau (Baumann et al 1993, Kobayashi et al 1993, Lew & Wang 1994). It isactivated by interaction with regulatory subunits, the best characterized of whichis p35 (Ishiguro et al 1994, Lew et al 1994, Tsai et al 1994). Recently, Sobue et al(2000) demonstrated that cdk5 complexes with tau in a manner that depends onthe phosphorylation of tau, and that tau anchors cdk5 to MTs. Moreover, cdk5-mediated tau phosphorylation stimulates further phosphorylation of tau by GSK-3β (Yamaguchi et al 1996, Sengupta et al 1997). However, further work is neededto determine the relative contributions of individual kinases to tau phosphorylationin vivo.

Because protein phosphatases are required for counterbalancing the effects oftau protein kinases, they have also been an intense focus of research. A numberof studies have implicated several phosphatases in regulating tau phosphorylation,including PP1, PP2A, PP2B, and PP2C (reviewed in Billingsley & Kincaid 1997,

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Buee et al 2000). They all dephosphorylate tau in vitro with overlapping speci-ficities; however, their role in vivo is unclear. Both PP2A and PP2B are present inhuman brain tissue, and they dephosphorylate tau in a site-specific manner. Bothenzymes dephosphorylate Ser396 (Matsuo et al 1994), whereas PP2A also dephos-phorylates tau at multiple additional sites (Goedert et al 1992a, Drewes et al 1993,Billingsley & Kincaid 1997). Of the phosphatase activity in rat brain, PP2A is themajor activity toward tau phosphorylated by a number of protein kinases (Goedertet al 1992a, 1995a). PP1 and PP2A bind to tau, and this interaction is believedto mediate an association with MTs (Sontag et al 1995, Liao et al 1998). PP2Ahas also been demonstrated to bind directly to MTs, an interaction that regulatesits activity in vitro (Sontag et al 1999). Lastly, inhibition of PP1 and PP2A byokadaic acid in cultured human NT2N neurons results in increased tau phospho-rylation, accompanied by decreased tau binding to MTs, selective destruction ofstable MTs, and rapid degeneration of axons (Merrick et al 1997). As with thekinases implicated in the phosphorylation of tau, further studies are necessary todefine the specific role of individual phosphatases in the in vivo regulation of thephosphorylation state of tau.

AD NEUROFIBRILLARY PATHOLOGY IS MADE OFABNORMALLY PHOSPHORYLATED TAU

Filamentous neuronal or neuronal and glial tau inclusions associated with the de-generation of affected brain regions are the defining neuropathological features oftauopathies. In AD, NFTs and neuropil thread pathology are found in conjunctionwith the deposition ofβ-amyloid (Aβ) fibrils in the extracellular space. By lightmicroscopy, the neurofibrillary lesions of AD are stained with anti-tau antibod-ies (Brion et al 1985, Grundke-Iqbal et al 1986). Ultrastructurally, the dominantcomponents of neurofibrillary lesions in AD are paired helical filaments (PHFs)and straight filaments (Kidd 1963). PHFs are composed of two strands of filamenttwisted around one another with a periodicity of 80 nm and a width varying from8 to 20 nm (Crowther & Wischik 1985) whereas straight filaments lack this helicalperiodicity (Crowther 1991). Both PHFs and straight filaments are composed pre-dominantly of abnormally hyperphosphorylated tau proteins (Goedert et al 1988,Kondo et al 1988, Kosik et al 1988, Wischik et al 1988, Lee et al 1991). Analysisof PHFs purified from AD brains by sodium dodecyl sulphate–polyacrylamidegel electrophoresis has revealed three major bands of approximately 68, 64, and60 kDa, as well as a minor band of approximately 72 kDa (Greenberg & Davies1990, Lee et al 1991) (Figure 2). Upon dephosphorylation, six bands are resolvedthat correspond to the six isoforms of tau found in adult human brain (Lee et al1991, Greenberg et al 1992, Goedert et al 1992b). The relative proportions ofthe tau isoforms observed in AD PHFs are similar to those that are character-istic of the six soluble tau isoforms observed in normal adult human brain (seeTrojanowski & Lee 1994, Morishima-Kawashima et al 1995, Goedert et al 1995b,Hong et al 1998). Although many phosphorylation sites identified in PHFtau

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Figure 2 Schematic representation of Western blot banding patterns of insoluble and solu-ble tau from different tauopathies. The cartoon depicts the typical banding pattern of nonde-phosphorylated and dephosphorylated insoluble (filamentous) tau (top panels) as well as sol-uble tau (bottom panels) from brains of patients with the diseases indicated following resolu-tion by sodium dodecyl sulphate–polyacrylamide gel electrophoresis and immunoblotting withphosphorylation-independent anti-tau antibodies. Nondephosphorylated insoluble tau from thebrain of patients with Alzheimer’s disease (AD) and some frontotemporal dementia and parkin-sonism linked to chromosome 17 (FTDP-17), mutations that do not affect splicing (V337M andR406W), runs as three major bands of 68, 64, and 60 kDa and as a minor, variable band of 72kDa. When dephosphorylated, it resolves into six bands that correspond to soluble tau. In corti-cobasal degeneration (CBD) and progressive supranuclear palsy (PSP), as well as FTDP-17 withthe P301L mutation, the two prominent 68- and 64-kDa insoluble tau bands are detected (the72-kDa minor band is variably detected) and align with four tandem repeat sequences (4R-tau)following dephosphorylation. The soluble fraction shows all six isoforms, indicating that there isselective aggregation of 4R-tau. In contrast, in FTDP-17 mutations that affect mRNA splicing,there is expression of predominantly soluble 4R-tau throughout the entire brain. Only 4R-tau isdeposited in a filamentous form. In Pick’s disease (PiD) and some FTDP-17 mutations (K257T,G389R) that do not affect splicing, the lower two 64- and 60-kDa insoluble tau bands predomi-nate. Following dephosphorylation, a predominance of 3R-tau is observed. All six tau isoformsare expressed in the soluble fraction in PiD. Major tau proteins are depicted by solid bars and thethickness of the bars correlates with the relative abundance of the specific tau isoform. A dashedbar is used to depict the minor, and more variable, 72- and 68-kDa tau isoforms.

have also been found to be phosphorylated to some extent in tau proteins isolatedfrom biopsies of normal human brain (Matsuo et al 1994), it is clear that PHFtauis hyperphosphorylated and abnormally phosphorylated (Morishima-Kawashimaet al 1995, Hasegawa et al 1996, Hoffmann et al 1997, Zheng-Fischhofer et al1998).

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Numerous protein kinases and protein phosphatases have been implicated inthe dysregulation of tau phosphorylation in the AD brain (for detailed reviews, seeBillingsley & Kincaid 1997, Buee et al 2000, Hong et al 2000). A recent study hassuggested that cdk5 may play a specific role in this process (Patrick et al 1999).It showed that p25, a truncated form of p35, accumulates in neurons in the brainsof AD patients. The calcium-dependent cysteine protease calpain is believed togenerate p25 from p35 (Kusakawa et al 2000, Lee et al 2000, Nath et al 2000).The accumulation of p25 correlated with increased cdk5 kinase activity and thebinding of p25 to cdk5 constitutively activated cdk5. Finally, the expression of thecdk5/p25 complex in various cell lines increased tau phosphorylation and disruptedthe cytoskeletal network. Thus, it is possible that the cdk5/p25 complex may playa mechanistic role in the conversion of normal tau into PHFtau in AD; however, itwill be important to confirm and extend these results in additional in vitro and invivo studies.

The mechanisms underlying PHF formation in neurons are still unclear, but itis possible that hyperphosphorylation disengages tau from MTs, thereby increas-ing the pool of unbound tau. Unbound tau may be more resistant to degradationand more prone to aggregate than MT-bound tau. This suggests that an increasedability of pathological tau to intereact with MTs may be beneficial. The organicosmolytes trimethylamine N-oxide and betaine have been shown to increasetau-promoted assembly of MTs (Tseng & Graves 1998). These compounds werealso shown to restore the ability of tau phosphorylated by cAMP-dependent proteinkinase or GSK-3β to promote MT assembly (Tseng et al 1999). Tau is a highlyflexible, extended molecule with little secondary structure (Schweers et al 1994,Goedert et al 1999a, Barghorn et al 2000). By circular dichroism spectroscopy,it appears as a random coil (Cleveland et al 1977a), even when carryingFTDP-17 mutations (Goedert et al 1999a, Barghorn et al 2000) or in the pres-ence of trimethylamine N-oxide (Tseng & Graves 1998). Binding of tau to MTsgenerates some ordered structures, indicating that MTs can induce conformationalchanges in tau (Woody et al 1983). Trimethylamine N-oxide and betaine probablyinduce a tubulin and/or tau conformational change that favors assembly.

Along related lines, Lu et al (1999) demonstrated that the prolyl isomerase Pin1binds to a single phosphothreonine residue (Thr231) in tau and that this restoredthe ability of tau phosphorylated by cdc2 kinase to intereact with MTs. Pin1 wasreported to copurify with PHFs, resulting in a depletion of soluble Pin1 in ADbrain. Because depletion of Pin1 is believed to induce mitotic arrest and apoptoticcell death, its sequestration in NFTs could contribute to neurodegeneration.

SYNTHETIC TAU FILAMENTS

Hyperphosphorylation is believed to be an early event in the pathway that leadsfrom soluble to insoluble and filamentous tau protein (Braak et al 1994). However,it is unclear whether it is sufficient for assembly into filaments. Currently, thereis no experimental evidence that links hyperphosphorylation of tau to filament

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assembly. The availability of large quantities of recombinant human tau isoformsand the ease with which tau fragments can be expressed has facilitated studiesaimed at producing synthetic tau filaments. Early experiments had shown thatPHF-like filaments can be assembled in vitro from bacterially expressed, non-phosphorylated 3R fragments of tau (Crowther et al 1992, Wille et al 1992). Theformation of these filaments lent strong support to the view that the repeat regionof tau is the only component necessary for the morphological appearance of thePHF. However, these studies failed to provide any insight into filament formationin vivo because the tau filaments were obtained only with truncated tau under non-physiological conditions. This contrasts with PHFs from AD brain, which consistof full-length tau protein (Goedert et al 1992b).

More recently, experiments using sulphated glycosaminoglycans (GAGs) tostimulate phosphorylation of tau by a number of protein kinases have led to the ob-servation that sulphated GAGs induce the assembly of full-length tau into filaments(Goedert et al 1996, Perez et al 1996). Assembly of individual 3R-tau isoformsgave filaments with a typical paired-helical-like morphology, when incubated withheparin or heparan sulphate, whereas assembly of individual 4R-tau isoform gavefilaments with a straight appearance. By immunoelectron microscopy, the paired-helical-like filaments were decorated by antibodies directed against the aminoand carboxy termini of tau, but not by an antibody against the MT-binding region(Goedert et al 1996). A short amino acid sequence (VQIVYK) in the third MT-binding repeat of tau has recently been shown to be essential for heparin-inducedfilament assembly (von Bergen et al 2000).

Assembly of tau into filaments in the presence of sulphated GAGs occurs aftera lag period and is heavily concentration dependent, consistent with a nucleation-dependent process (Goedert et al 1996, Perez et al 1996, Arrasate et al 1997,Hasegawa et al 1997, Friedhoff et al 1998). Phosphorylation of tau at Ser/Thr-Pro sites does not significantly influence heparin-induced assembly (Goedert et al1996). However, it has been reported that phosphorylation at other sites, such asSer214 and Ser262, is strongly inhibitory toward assembly (Schneider et al 1999).Subsequent to this work, RNA (Kampers et al 1996, Hasegawa et al 1997) andarachidonic acid (Wilson & Binder 1997) were also shown to induce the bulkassembly of full-length recombinant tau into filaments. This work has providedrobust methods for the assembly of full-length tau into filaments. Pathologicalcolocalization of sulphated GAGs (Snow et al 1990, Goedert et al 1996, Verbeeket al 1999) and RNA (Ginsberg et al 1998) with hyperphosphorylated tau proteinsuggests that these findings may also be relevant for the assembly of tau in AD.

SPORADIC TAUOPATHIES

The amyloid cascade hypothesis for the pathogenesis of AD proposes that thedeposition and fibrillization of Aβ peptides to form extracellular senile plaques isthe central event that causes formation of NFTs and neuronal loss (Hardy & Allsop

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1991). Compelling evidence in support of a causative pathologic role of tau pro-tein in neurodegeneration is provided by recent studies of tauopathies other thanAD, which share an abundant filamentous tau pathology and brain degeneration inthe absence of extracellular amyloid deposits (Table 1). Progressive supranuclearpalsy (PSP), corticobasal degeneration (CBD), and Pick’s disease (PiD) are threesuch disorders. A recent consensus conference has classified them as disordersbelonging to a group of diseases known as frontotemporal dementia (FTD) (Pick’sConference 2001). Clinically, PSP is characterized by supranuclear gaze palsy aswell as by prominent postural instability (Steele et al 1964). Neuropathologically,PSP is characterized by atrophy of the basal ganglia, subthalamus, and brainstem,with corresponding neuronal loss and gliosis. Within these brain regions, there isa high density of fibrillary tau pathology, including neuropil threads, and NFTs thatare typically round or globose (Pollock et al 1986, Hauw et al 1994, Litvan et al1996). Glial fibrillary tangles in both astrocytes (tufted astrocytes) and oligoden-drocytes (coiled bodies) are also often present (Hauw et al 1990, Yamada et al 1992,Komori 1999). In contrast to AD, ultrastructural analysis of these neurofibrillarylesions has revealed 15- to 18-nm straight filaments, and filaments with a longperiodicity have also been observed (Tellez-Nagel & Wisniewski 1973, Roy et al1974).

The filamentous tau pathology of PSP correlates with the biochemical identifi-cation of insoluble, hyperphosphorylated tau in affected brain regions. However,in contrast to the three major bands identified in AD, only the two highMr bands(68 and 64 kDa) are present (the minor 72-kDa band is variably detected) (Flamentet al 1991, Vermersch et al 1994) (Figure 2). These bands are made of hyperphos-phorylated tau isoforms with four MT repeats (Spillantini et al 1997, Sergeant et al1999). They exhibit the same profile of phosphorylation-dependent tau epitopesas those detected in PHFtau from AD brains (Schmidt et al 1996). Furthermore,in PSP, the relative abundance of tau mRNA containing E10 has been reported tobe increased in the brainstem but not in the cortex, which is consistent with thedistribution of the neurofibrillary pathology (Chambers et al 1999).

Polymorphisms in thetau gene may contribute to the risk of developing PSPbecause a polymorphic dinucleotide repeat in the intron between E9 and E10 of thetaugene has been linked to PSP (Conrad et al 1997). Subjects with the homozygoustau allele A0, characterized by 11 TG repeats, were found to be overrepresented inPSP patients (95.5%) compared with controls (57.4%) and AD (49.7%) patients.Subsequent studies have confirmed this correlation in the Caucasian (but not Asian)population (Bennett et al 1998, Higgins et al 1998, Hoenicka et al 1999, Morriset al 1999a). Moreover, two extendedtau gene haplotypes consisting of eightcommon single-nucleotide polymorphisms in addition to the dinucleotide repeatpolymorphism have been described (Baker et al 1999). The haplotypes are incomplete linkage dysequilibrium and span the entire humantau gene. The morecommon haplotype, H1, is significantly overrepresented in Caucasians with PSP.In addition, two missense mutations in E4a are associated with the H1 haplotypeand have been linked to PSP, and a 238-bp deletion in the intron flanking E10 of

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the tau gene is inherited as part of the less-common H2 extended haplotype andthus shows a negative assciation with PSP (Higgins et al 1998, Baker et al 1999,Bonifati et al 1999, Ezquerra et al 1999). The relationships of the H1 haplotypeand the A0 allele to the pathogenesis of PSP are unknown, but it is possible thatthe 238-bp deletion flanking E10 in the H1 haplotype might affect E10 splicing,thereby increasing the relative proportion of 4R-tau.

CBD is an adult-onset progressive neurodegenerative disorder involving thecerebral cortex, deep cerebellar nuclei, and substantia nigra, in association withprominent neuronal achromasia (Rebeiz et al 1967, 1968). Neuropathological ex-amination shows depigmentation of the substantia nigra, as well as an asymmetricfrontoparietal atrophy that is often most severe in the pre- and postcentral regions.In affected regions, there is neuronal loss with spongiosis, gliosis, and prominentglial and neuronal intracytoplasmic filamentous tau pathology (Iwatsubo et al 1994,Mori et al 1994). The glial tau pathology in CBD consists of characteristic astro-cytic plaques (Feany & Dickson 1995), as well as numerous tau-immunoreactiveinclusions in the white matter in both astrocytes and oligodendrocytes (coiled bod-ies) (Komori et al 1998, Komori 1999). A striking feature of CBD is the extensiveaccumulation of tau-immunoreactive neuropil threads throughout gray and whitematter (Feany & Dickson 1995, Feany et al 1996). The tau filaments in CBDinclude both PHF-like filaments and straight tubules (Ksiezak-Reding et al 1994,Komori 1999).

The biochemical profile of insoluble tau in CBD is similar to that of PSP inthat it consists of two major bands of 64 and 68 kDa and a variable, minor bandof 72 kDa (Ksiezak-Reding et al 1994, Bu´ee-Scherrer et al 1996) (Figure 2).However, the isoforms present in the tau pathology of CBD may differ from thosefound in PSP. Antibodies specific for the insert encoded by E3 did not detect thefibrillary tau pathology in CBD either biochemically or immunohistochemically instudies from one group (Ksiezak-Reding et al 1994, Feany et al 1995). However,another report failed to confirm this finding (Sergeant et al 1999). The latter studydemonstrated that the fibrillary inclusions in CBD are composed predominantlyof 4R-tau isoforms that also contain the inserts encoded by E2 and to E3. Anothersimilarity between PSP and CBD was recently described by Di Maria et al (2000),who showed that CBD is associated with the A0 allele of thetau gene, as well asthe H1 haplotype. Thus, the current biochemical and genetic data strongly suggestthat there is a substantial overlap between PSP and CBD. This is also apparentwith respect to the clinical (Hauw et al 1994) and pathological (Feany et al 1996)features. Rather than representing two separate and distinct disorders, PSP andCBD may be different phenotypic manifestations of the same underlying diseaseprocess.

PiD, a variant of FTD, is defined neuropathologically by the presence of tau-immunoreactive Pick bodies (Constantinidis et al 1974, Pollock et al 1986, Feanyet al 1996, Pick’s Conference 2001). Neuropathologically, it is characterizedby a frontotemporal lobar and limbic atrophy associated with marked neuronalloss, spongiosis, and gliosis, with ballooned neurons and Pick bodies (Lund &

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Manchester Groups 1994, Dickson 1998). Pick bodies are detected by antibodiesto hyperphosphorylated tau and are most numerous in layers II and VI of the neo-cortex and in the dentate granule neurons of the hippocampus (Iwatsubo et al 1994,Probst et al 1996). Ultrastructurally, Pick bodies are composed of a mixture ofwide, straight filaments and wide, long-period twisted filaments (Munoz-Garcia &Ludwin 1984, Murayama et al 1990, Dickson 1998).

Western blot analyses have revealed that the insoluble tau in PiD is distinctfrom that in AD, CBD, and PSP in that it comprises two major bands of 60 and 64kDa and a variable, minor band of 68 kDa (Bu´ee-Scherrer et al 1996, Delacourteet al 1996, Lieberman et al 1998) (Figure 2). Because the two major PiD taubands appear to lack the MT binding repeat encoded by E10, they are believedto be composed exclusively of 3R-tau (Sergeant et al 1997, Mailliot et al 1998).Ser262 has been shown not to be phosphorylated, in contrast to AD, CBD, or PSP(Probst et al 1996, Delacourte et al 1998). However, a separate study has detecteda signal in Pick bodies and PiD tau using an antibody specific for phosphorylatedSer262 (Lieberman et al 1998). This may reflect heterogeneity of phosphorylationat Ser262 in PiD.

In contrast to PiD, the majority of patients with FTD show frontotemporal neu-ron loss, gliosis, and microvacuolar (spongiform) change but no disease-specificdiagnostic lesions. This neuropathological entity is referred to by several names,including frontotemporal lobar degeneration (FTLD) and dementia lacking dis-tinctive histology (DLDH), but there is no agreement on the most appropriatenomenclature for this form of FTD (Mann 1998). However, this may changesoon because one study has defined this neuropathology more precisely usingquantitative morphometric methods (Arnold et al 2000). Moreover, recent evi-dence suggests that FTLD (DLDH) may be a novel tauopathy that is caused bya selective reduction or complete loss of all six brain tau isoforms in affectedand unaffected brain regions (Zhukareva et al 2001). The explanation for this isenigmatic because there was no concomitant loss of tau mRNA compared withcontrol and AD brains. Although the majority of FTD patients with FTLD (DLDH)neuropathology showed a dramatic loss of tau protein in brain regions with andwithout neuronal degeneration, others showed less-substantial but still statisticallysignificant reductions in brain tau levels. Although the pathogenic mechanism un-derlying this marked reduction in all six brain tau proteins in FTLD (DLDH) is notknown, the consequence of this loss may be similar to the losses of tau functionresulting from some of thetaugene mutations in FTDP-17.

FAMILIAL TAUOPATHIES—FTDP-17 SYNDROMES

The group of syndromes known as FTDP-17 consists of autosomal-dominantlyinherited neurodegenerative diseases with diverse, but overlapping, clinical andneuropathological features (Foster et al 1997). Neuropathologically, they all showthe presence of an abundant filamentous tau pathology in nerve cells, and for some

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in glial cells (reviewed in Spillantini et al 1998a, Crowther & Goedert 2000, Honget al 2000). The first such disorder was linked to chromosome 17 in 1994, whenWilhelmsen et al (1994) described a familial disease they called “disinhibition-dementia-parkinsonism-amyotrophy complex” and demonstrated genetic linkageof this disease to chromosome 17q21-22. Subsequently, a number of related neu-rodegenerative disorders were linked to the same region on chromosome 17 (Wijkeret al 1996, Bird et al 1997, Foster et al 1997, Heutink et al 1997, Murrell et al1997, Lendon et al 1998). Clinically, they are characterized primarily by FTD andparkinsonism (Foster et al 1997), but the different FTDP-17 syndromes appear toreflect the burden of tau pathology and degeneration in brain regions known tosubserve specific cognitive, executive, or motor functions. Despite this pheno-typic heterogeneity, the neuropathology of FTDP-17 is characterized by markedneuronal loss in affected brain regions, with extensive neuronal or neuronal andglial fibrillary pathology composed of hyperphosphorylated tau protein, but with-out evidence of Aβ deposits or other disease-specific brain lesions in the majorityof the cases (Murrell et al 1999, Lippa et al 2000, Rizzini et al 2000, Spillantiniet al 2000).

Because thetau gene had been localized to chromosome 17q21-22, it wasan obvious candidate for the disease locus. In 1998, several groups identifiedpathogenic mutations in thetau gene that segregated with FTDP-17 (Clark et al1998, Dumanchin et al 1998, Hutton et al 1998, Poorkaj et al 1998, Spillantiniet al 1998c). To date,>20 distinct pathogenic mutations in thetau gene havebeen identified in a large number of families with FTDP-17 (Table 2, Figure 3).Eleven missense mutations in coding regions of thetau gene are known, includ-ing mutations in E9 [K257T (Pickering-Brown et al 2000, Rizzini et al 2000),I260V (M Hutton, personal communication), and G272V (Hutton et al 1998)],E10 [N279K (Clark et al 1998, Delisle et al 1999, Yasuda et al 1999, Arima et al2000), P301L (Clark et al 1998, Dumanchin et al 1998, Hutton et al 1998, Birdet al 1999, Houlden et al 1999, Mirra et al 1999, Kodama et al 2000), P301S(Bugiani et al 1999, Sperfeld et al 1999), and S305N (Iijima et al 1999)], in E12[V337M (Poorkaj et al 1998) and E342V (Lippa et al 2000)], and in E13 [G389R(Murrell et al 1999, Pickering-Brown et al 2000)] and R406W (Hutton et al 1998,Van Swieten et al 1999)]. Three silent mutations in E10 [L284L (D’Souza et al1999), N296N (Spillantini et al 2000), and S305S (Stanford et al 2000)] as wellas a deletion mutation [1K280 (Rizzu et al 1999)] have also been identified. Inaddition, five substitutions in six different positions of the intron following E10have been identified at positions+3 (Spillantini et al 1998c, Tolnay et al 2000),+12 (Yasuda et al 2000),+13 (Hutton et al 1998),+14 (Clark et al 1998, Huttonet al 1998), and+16 (Hutton et al 1998, Hulette et al 1999, Goedert et al 1999b,Morris et al 1999b). Besides mutations in the intron following E10, additionalpathogenic mutations may be present in other introns of thetau gene. Thus, amutation in the intron following E9 has been described in a patient with familialFTD (Rizzu et al 1999). It disrupts one of the several (A/T)GGG repeats that mayplay a role in the regulation of the alternative splicing of E10.

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TABLE 2 Tau mutations identified in FTDP-17a

Mutation Location E10 Splicing MT Assembly Phenotype Reference

K257T E9, R1 No change Reduced PiD-like Pickering-Brown et al(2000), Rizzini et al(2000)

1260V E9, R1 ND ND NA M Hutton, personalcommunication

G272V E9, R1 No change Reduced FTDP-17 Hutton et al (1998)

N279K E10, IR1-2 Increased No effect PSP-like Clark et al (1998)

1280K E10, IR1-2 Decreased Reduced FTDP-17 Rizzu et al (1999)

L284L E10, IR1-2 Increased No effect AD-like D’Souza et al (1999)

N296N E10, R2 Increased No effect CBD-like Spillantini et al (2000)

P301L E10, R2 No change Reduced FTDP-17, Hutton et al (1998)CBD-like,PSP-like

P301S E10, R2 No change Reduced FTDP-17, Bugiani et al (1999),CBD-like Sperfeld et al (1999)

S305N E10, IR2-3 Increased No effect CBD-like D’Souza et al (1999),Hasegawa et al (1999),Iijima et al (1999)

S305S E10, IR2-3 Increased No effect PSP-like Stanford et al (2000)

E10+3 I10 Increased No effect FTDP-17 Spillantini et al (1998c)

E10+12 I10 Increased No effect FTDP-17 Yasuda et al (2000)

E10+13 I10 Increased No effect NA Hutton et al (1998)

E10+14 I10 Increased No effect FTDP-17, Hutton et al (1998)PSP-like

E10+16 I10 Increased No effect FTDP-17, Hutton et al (1998)PSP-likeCBD-like

E9+33 I9 ND ND NA Rizzu et al (1999)

V337M E12, IR3-4 No change Reduced FTDP-17 Poorkaj et al (1998)

E342V E12, IR3-4 ND ND FTDP-17 Lippa et al (2000)

G389R E13 No change Reduced PiD-like Murrell et al (1999)

R406W E13 No change Reduced PSP-like Hutton et al (1998)

aFTDP-17, frontotemporal demential and parkinsonism linked to chromosome 17; E, exon; I, intron; R, microtubule (MT)binding repeat; IR, interrepeat regions; ND, not determined; NA, not available; PiD, Pick’s disease; PSP, progressive supranu-clear palsy; AD, Alzheimer’s disease; CBD, corticobasal degeneration; increased, enhanced E10 utilization; decreased,reduced E10 utilization.

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Figure 3 Schematic representation of mutations in the tau gene identified in frontotemporaldementia and parkinsonism linked to chromosome 17. The longest human brain tau isoform isshown with known coding region mutations indicated above. The gray boxes near the aminoterminus represent the alternatively spliced inserts encoded by exons (E)2 and E3, whereas theblack boxes represent each of the four microtubule (MT) binding repeats (not drawn to scale).The second MT binding repeat is encoded by E10. Part of the mRNA sequence encoding E10 andthe intron following E10 is shown. Mutations in E10 and the downstream intron are indicated.Intronic nucleotides that are part of intron 10 are shown in lower case.

Data emerging from several laboratories continue to add increasing supportin favor of the hypothesis that FTDP-17 mutations lead to tau dysfunction anddisease by one or more of three distinct mechanisms. Intronic and some exonicmutations affect the alternative splicing of E10 and consequently alter the relativeproportion of 4R-tau and 3R-tau. The other exonic mutations impair the abilityof tau to bind MTs and to promote MT assembly. Some of these mutations alsopromote the assembly of tau into filaments. Moreover, additional mechanismsmay play a role in the case of some coding region mutations (Yen et al 1999,Goedert et al 2000). The intronic mutations clustered around the 5′ splice site ofE10, as well as several mutations within E10 (N279K, L284L, N296N, S305N,and S305S), increase the ratio of 4R-tau to 3R-tau by altering the splicing of E10(Hong et al 1998; Hutton et al 1998; Spillantini et al 1998c; D’Souza et al 1999;Delisle et al 1999; Grover et al 1999; Hasegawa et al 1999; Varani et al 1999;Yasuda et al 1999, 2000; Spillantini et al 2000; Stanford et al 2000). As a result ofthese mutations, there is a relative increase in E10-containing tau mRNAs, and thisprobably reflects increased utilization of the E10 5′ splice site, as demonstrated inexon trapping experiments. Biochemical analysis of insoluble tau extracted fromautopsied FTDP-17 brain tissue of patients with these mutations reveals exclusively4R-tau isoforms (Spillantini et al 1997, 1998c; Clark et al 1998; Hong et al 1998;Reed et al 1998; Hulette et al 1999; Goedert et al 1999b; Yasuda et al 2000).Furthermore, 4R-tau protein levels are increased in both affected and unaffectedregions of FTDP-17 brains (Hong et al 1998, Spillantini et al 1998c, Goedert et al1999b, Yasuda et al 2000).

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The regulation of splicing of E10 in thetaugene appears to be complex and mayinvolve multiplecis-acting regulatory elements that either enhance or inhibit theutilization of the E10 5′ splice site, many of which are affected by the mutationsidentified in thetau gene (D’Souza et al 1999, Grover et al 1999, D’Souza &Schellenberg 2000, Gao et al 2000, Jiang et al 2000). Splicing regulatory elementswithin E10 appear to include an exon-splicing enhancer (ESE) and an exon splicingsilencer (ESS) (D’Souza et al 1999, D’Souza & Schellenberg 2000, Gao et al 2000).The ESE consists of three domains, a potential SC35 binding element, a purine-richsequence, and an AC-rich sequence (D’Souza & Schellenberg 2000). Immediatelydownstream of the ESE within E10 is a purine-rich ESS. The flanking exons of thetaugene also appear to affect E10 splicing (Gao et al 2000). For example, it appearsthat E9 and E11 exert opposite effects, i.e. E9 may promote E10 splicing, whereasE11 may suppress it. Lastly, intronic sequences immediately downstream of E10inhibit its splicing (D’Souza et al 1999, Grover et al 1999, D’Souza & Schellenberg2000, Gao et al 2000, Jiang et al 2000). This inhibition may be secondary to theformation of a stem-loop structure that sequesters the E10 5′ splice site fromthe splicing machinery, including the U1- and U6-snRNPs (Grover et al 1999;Varani et al 1999, 2000; Jiang et al 2000) (Figure 3). The determination of thethree-dimensional structure of a 25-nucleotide-long RNA from the E10 5′-intronjunction by nuclear magnetic resonance spectroscopy has shown that this sequenceforms a stable, folded stem-loop structure (Varani et al 1999, 2000). The stemconsists of a single G-C base pair that is separated from a double helix of 6 bp byan unpaired adenine (Figure 3). As is often the case with single-nucleotide purinebulges, the unpaired adenine at position−2 does not extrude into solution butintercalates into the double helix. The apical loop consists of six nucleotides thatadopt multiple conformation in rapid exchange. Known intronic mutations andthe mutations in codon 305 are located in the upper part of the stem and reducethe thermodynamic stability of the stem loop (Varani et al 1999, 2000; Yasudaet al 2000). Moreover, the relative proportions of 3R-tau and 4R-tau isoformsfrom nonhuman species correlate with the predicted stability of this stem-loopstructure (Grover et al 1999). However, another study has concluded that this ESSmay function as a linear sequence that is independent of a stem-loop structure(D’Souza & Schellenberg 2000).

Pathogenic FTDP-17 mutations in thetau gene may alter E10 splicing by af-fecting several of the regulatory elements described above. Thus, the intronicmutations, as well as the exonic mutations at codon 305 (S305N and S305S),may destabilize the inhibitory stem-loop structure (Grover et al 1999, Varani et al1999) (Figure 3). The S305N mutation and the+3 intronic mutation may alsoenhance E10 splicing by increasing the strength of the 5′ splice site (Spillantiniet al 1998c, Iijima et al 1999). However, the finding that the S305S mutation thatweakens the E10 5′ splice site also leads to a predominance of 4R-tau argues againstthis effect of these mutations (Stanford et al 2000). The N279K mutation mayimprove the function of the ESE by lengthening the purine-rich sequence withinthis regulatory element (TAAGAA to GAAGAA), thus enhancing E10 splicing

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(D’Souza & Schellenberg 2000). Moreover, the thymidine nucleotide present inthe wild-type (WT) sequence may function as an inhibitor of splicing (Tanaka et al1994). The observation that the1K280 mutation, which deletes the three adjacentpurine residues (AAG), abolishes E10 splicing supports this hypothesis (D’Souzaet al 1999). The silent L284L mutation that enhances E10 splicing may do soby disrupting a potential ESS (UUAG to UCAG) (Si et al 1998, D’Souza et al1999). However, because mutation of this consensus sequence does not increaseE10 splicing (D’Souza & Schellenberg 2000), a second possibility is that the mu-tation lengthens the AC-rich element within the ESE. Thus, the L284L mutationmay affect either an enhancing or an inhibiting regulatory splicing element. Theeffect of the N296N mutation on splicing of E10 is probably due to disruption ofan ESS (D’Souza & Schellenberg 2000, Spillantini et al 2000).

The mechanisms by which these changes in the ratio of 3R-tau to 4R-tau (3R/4R-tau) lead to neuronal and glial dysfunction and cell death remain unclear. 4R-tauand 3R-tau may bind to distinct sites on MTs (Goode & Feinstein 1994, Goodeet al 1997), and it is possible that a specific ratio of tau isoforms is necessary fornormal MT function. Thus, the altered ratio of 3R/4R-tau may directly affect MTfunction. In addition, overproduction of 4R-tau may lead to an excess of free tauin the cytoplasm, leading to its hyperphosphorylation and assembly into filaments.

In contrast to the FTDP-17 mutations discussed above, other mutations alter theability of tau to interact with MTs. Specifically, mutations K257T, G272V,1K280,P301L, P301S, V337M, G389R, and R406W reduce the binding of tau to MTsand decrease its ability to promote MT assembly in in vitro assays (Hasegawaet al 1998, Hong et al 1998, Bugiani et al 1999, D’Souza et al 1999, Murrellet al 1999, Rizzu et al 1999, Barghorn et al 2000, Pickering-Brown et al 2000,Rizzini et al 2000). These effects are not observed with the tau missense muta-tions that affect E10 splicing (Hong et al 1998, D’Souza et al 1999, Hasegawa et al1999). Similar effects on MT function are observed when tau is expressed in avariety of cell lines, including SHSY5Y neuroblastoma cells (Dayanandan et al1999), Chinese hamster ovary (CHO) cells (Dayanandan et al 1999, Matsumuraet al 1999, Vogelsberg-Ragaglia et al 2000), monkey kidney (COS) cells (Arawakaet al 1999, Sahara et al 2000), and Sf9 insect cells (Frappier et al 1999). Expressionof a variety of tau missense mutations including G272V,1280K, P301L, V337M,and R406W in these cells caused varying degrees of reduced MT binding, disorga-nized MT morphology, and defects in MT assembly and MT instability. However,in two studies, many mutations had only a modest or no effect on MT bindingand/or function, both in in vitro assays and in transfected cell lines (DeTure et al2000, Sahara et al 2000). The discrepancies between these and other studies aremost likely due to the differences in the levels of expression, the methods used forthe quantification of tau levels, and the binding of tau to MTs. Nevertheless, evenif these missense mutations cause only a modest reduction in MT binding affinity,this could have large cumulative effects on affected neurons over the human lifespan. Furthermore, increased cytosolic concentrations of unbound mutant tau pro-teins may facilitate aggregation of these abnormal proteins, with or without theirWT counterparts, into filamentous inclusions.

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A subset of missensetau gene mutations may cause FTDP-17, at least in part,by promoting tau aggregation. Several studies have demonstrated that some ofthese mutations, including K257T, G272V,1280K, P301L, P301S, V337M, andR406W, promote heparin- or arachidonic acid–induced tau filament formation invitro relative to WT tau (Arrasate et al 1999, Nacharaju et al 1999, Goedert et al1999a, Barghorn et al 2000, Gamblin et al 2000, Rizzini et al 2000). Furthermore,aggregation of mutant tau proteins in intact cells also has been demonstrated.Thus, CHO cells expressing tau with the1K280 mutation, but not other mutations(V337M, P301L, and R406W), formed insoluble amorphous and fibrillar tau ag-gregates (Vogelsberg-Ragaglia et al 2000). In addition, expression of the1K280,and R406W mutants in CHO and other cells led to reduced levels of tau phospho-rylation relative to other mutant constructs and WT tau (Dayanandan et al 1999,Matsumura et al 1999, Perez et al 2000, Sahara et al 2000, Vogelsberg-Ragagliaet al 2000).

All known mutations in thetau gene lead to the formation of filaments madeof hyperphosphorylated tau protein (Crowther & Goedert 2000). However, thefibrillary lesions observed with mutations in E10 or the intron following E10 arebiochemically and ultrastructurally distinct from the lesions caused by mutationsthat are located outside E10. Coding region mutations located outside E10 affect allsix isoforms of tau. Thus, as one might predict, tau fibrillary lesions are composedof all six tau isoforms (Hong et al 1998, Murrell et al 1999, Van Swieten et al1999) (Figure 2). For some mutations (V337M and R406W), the morphologiesand biochemical characteristics of tau filaments are indistinguishable from thoseof AD (Spillantini et al 1996, Hong et al 1998, Van Swieten et al 1999). Othercoding region mutations located outside E10 (K252T, G272V, E342V, and G389R)give rise to a tau pathology that closely resembles that of PiD (Spillantini et al1998b, Murrell et al 1999, Lippa et al 2000, Rizzini et al 2000). In contrast,mutations located within E10 itself or the intron following E10 lead to aggregationof predominantly 4R-tau (Clark et al 1998; Hong et al 1998; Hutton et al 1998;Reed et al 1998; Spillantini et al 1998b,c; Hulette et al 1999; Mirra et al 1999;Nasreddine et al 1999; Goedert et al 1999b; Yasuda et al 2000). Ultrastructurally,these lesions are composed of twisted ribbons that are similar to the filamentsobserved in 4R-tau disorders, particularly CBD (Reed et al 1998, Spillantini et al1998b, Bird et al 1999, Bugiani et al 1999, Delisle et al 1999, Hulette et al 1999,Iijima et al 1999, Mirra et al 1999, Goedert et al 1999b, Yasuda et al 2000).

Finally, a family with a syndrome known as hereditary dysphasic disinhibitiondementia 2 (HDDD2), which appears similar to some of the syndromes seen inFTDP-17 kindreds, has been reported to show linkage to 17q21-22 with a lod(logarithm of odds) score of 3.68; however, notau gene mutation or any othergenetic abnormality has been identified in this family (Lendon et al 1998). It issurprising, however, that recent studies of three brains from affected members ofthe HDDD2 kindred revealed that HDDD2 shares significant neuropathologicaland biochemical abnormalities with sporadic FTD patients classified as FTLD(DLDH) (Lendon et al 1998, Zhukareva et al 2001). As discussed above regardingFTLD (DLDH), the loss of tau proteins in several of the HDDD2 brains, together

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with the preservation of tau mRNA, suggests that the abundance of tau protein maybe controlled posttranscriptionally, either at the level of tau mRNA translation orthrough mechanisms that regulate mRNA stability. Thus, the HDDD2 kindredappears to be the familial counterpart of sporadic FTLD (DLDH), both of whichmay define a novel and distinct tauopathy caused by a reduction of brain tau.

Although the biochemical and structural characteristics of the tau aggregatesin FTDP-17 appear to be predictable, based on our understanding of the func-tions of tau protein and tau gene splicing, the basis for the clinical phenotypesand topographical distributions of pathology is more enigmatic. For example, itis not clear why the clinical and neuropathologic phenotype of individuals withFTDP-17 mutations ranges from FTD (including subtypes thereof, such as PiD,CBD, and PSP) to multisystem neurodegeneration. However, sometaugene mu-tations cause a similar phenotype in different families or in different members ofthe same family. For instance, the N279K mutation typically causes a phenotypereminiscent of PSP with superimposed dementia (Reed et al 1998, Delisle et al1999, Yasuda et al 1999). In contrast, there are several clinical and pathologicdescriptions of families with the P301L mutation that demonstrate a highly vari-able phenotype ranging from PSP to CBD to PiD (Spillantini et al 1998b, Birdet al 1999, Mirra et al 1999, Nasreddine et al 1999). Even more perplexing is thereport of two brothers from one P301L family (Bird et al 1999), with frontal lobedegeneration in one individual and PSP-like pathology in the other. Similarly, ina family with the P301S mutation, one individual presented with FTD whereashis son presented clinically with CBD (Bugiani et al 1999). Although only a fewreports of this kind have been published, they suggest that there is extensive over-lap between the various tau-related disorders and that the clinical and pathologicdistinctions between them may be due to other genetic and/or epigenetic factorsthat modify the effects of the primary mutation. Currently, the specific geneticand/or environmental modifiers that might determine the phenotype of a specificindividual remain unknown, but these are fields of active investigation, and thegeneration of animal models of tau-mediated neurodegeneration may facilitatethis research (Figure 4).

EXPERIMENTAL ANIMAL MODELS OF TAUOPATHIES

Experimental and TG animal models of tauopathies will serve as informative sys-tems for elucidating the role of abnormalities in tau in the onset and progression ofa variety of neurodegenerative disorders. In addition, they may be useful modelsfor the development and testing of novel therapies. Early efforts to produce an-imal models with tau pathology were largely based on the hypothesis that thedevelopment of extracellular Aβ pathology in TG mice would induce intraneu-ronal tau pathology. However, although various TG mouse lines accumulate Aβ

plaques, none has developed AD-like tau pathology (Games et al 1995, Hsiao et al1996, Sturchler-Pierrat et al 1997). More recently, several animal models of taupathology were produced by overexpressing human tau proteins (Table 3).

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Figure 4 Model of disease pathways in tauopathies. Mutations and/or polymorphisms in the taugene in conjunction with environmental and additional genetic factors initiate pathogenic processesthat cause regional and cell type–specific tau pathology and neurodegeneration, thus leading tospecific clinicopathologic phenotypes. PiD, Pick’s disease; CBD, corticobasal degeneration; PSP,progressive supranuclear palsy; FTDP-17, frontotemporal dementia and parkinsonism linked tochromosome 17.

Initial reports described TG mouse lines expressing 4R2N or 3R0N human tauutilizing cDNA constructs with either the Thy1 or the 3-hydroxy-3-methylglutarylcoenzyme A reductase promoters (G¨otz et al 1995, Brion et al 1999). Both linesdeveloped somatodendritic expression of tau, suggestive of “pretangle” pathology,but no filamentous tau inclusions were observed and the animals were phenotyp-ically normal. The lack of filament formation may have been due to the rela-tively modest expression levels of human tau, and this notion is supported by the

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finding that massive overexpression of 4R/2N human tau in lamprey reticulospinalneurons led to the formation of PHF-like tau inclusions with degeneration of asubset of these neurons (Hall et al 1997, 2000). Subsequently, a series of papershas described lines of TG mice expressing high levels of 3R/0N or 4R/2N humantau utilizing cDNA constructs with either the Thy1 or the prion protein promoter(Ishihara et al 1999, Spittaels et al 1999, Duff et al 2000, Probst et al 2000).These mice developed numerous abnormal tau-immunoreactive nerve cell bodiesand dendrites and large numbers of pathologically enlarged axons containing tau-immunoreactive spheroids. These changes were most prominent in spinal cord butwere also seen in brain. They were accompanied by histological and behavioralsigns of amytrophy. Mice doubly transgenic for 4R2N tau and GSK-3β showedincreased levels of tau phosphorylation and a marked reduction in the number ofspheroids and associated histological and behavioral changes at 3–4 months of age(Spittaels et al 2000). In this system, therefore, hyperphosphorylation of tau corre-lates inversely with pathology. Although the tau pathology most closely resemblesthat observed in the amyotrophic lateral sclerosis/parkinsonism–dementia complex(Matsumoto et al 1990), it differs in several respects from that found in humandiseases. Thus, besides tau, the spheroids in these TG mice also contain neurofil-ament proteins and tubulin. They are not detected by Congo red and Thioflavin Sand do not bind Gallyas silver. However, a recent report has shown that as thesetau TG mice aged to over 18 months, modest numbers of filamentous tau tangleswith similar properties to those found in AD could be detected in hippocampusand entorhinal cortex (Ishihara et al 2001). Moreover, like NFTs in AD, the tautangles in these aged mice were ubiquitinated, did not contain neurofilaments ortubulin, and were detected by Congo red, Thioflavin S, and Gallyas silver stainingmethods. It is interesting that mice transgenic for the entire humantau gene ex-pressed all six tau isoforms but failed to develop significant pathology (Duff et al2000).

The discovery of mutations in the tau gene in FTDP-17 is leading to the pro-duction of TG mouse lines expressing mutant human tau in neurons and glial cells.Lewis et al (2000) developed several lines expressing modest levels of 4R/0N tauwith and without the P301L mutation. In contrast to mice expressing WT tau, miceexpressing tau with the P301L mutation exhibited an age- and gene dose-dependentaccumulation of tau tangles in both brain and spinal cord, with associated nerve cellloss and reactive gliosis. Similar results have been reported by G¨otz et al (2001)in TG lines expressing 4R2N tau with the P301L mutation. The tau tangles foundin these mice appeared to comprise only the mutant human tau, which suggeststhat the P301L mutation probably causes neurodegeneration by promoting the ag-gregation of the mutant tau. This is supported by recent biochemical studies usingantibodies specific for P301L tau that demonstrated recovery of mutant but notWT tau from the insoluble fraction isolated from brain tissue of individuals withthe P301Ltaugene mutation (Rizzu et al 2000).

Other approaches to the development of tau pathology in TG mice have madeuse of molecules known to interact with tau. For example, TG mice overexpressing

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human p25, an activator of cdk5, develop disturbances in cytoskeletal architectureand behavioral alterations (Ahlijanian et al 2000). However, there was no biochem-ical evidence of an accumulation of insoluble, hyperphosphorylated tau in thesemice. TG mice expressing apolipoprotein E4, an allelic risk factor for sporadicAD (Corder et al 1993), showed an age-dependent increase in tau phosphorylationthat correlated with the level of apolipoprotein E4 expression (Tesseur et al 2000).Although these mice showed somatodendritic expression of phosphorylated tau,there was no evidence of fibrillary pathology. Finally, TG mice expressing antibod-ies to nerve growth factor inside nerve cells developed a prominent age-dependentneurodegenerative pathology, including neuronal loss and hyperphosphorylated,insoluble tau in cortex and hippocampus (Capsoni et al 2000). However, as forthe apolipoprotein E4 TG mice described above, no evidence of fibrillary taupathology was presented. In summary, although several TG mouse models showfeatures of various tau-related disorders, they still fall short of demonstrating theentire constellation of the most characteristic features of human tauopathies.

CONCLUSION

The accumulation of filamentous tau inclusions is a common feature of a wide vari-ety of neurodegenerative disorders, many of which are distinguished by the distincttopographic and cell type–specific distributions of inclusions. The biochemicaland ultrastructural characteristics of thetau abnormalities, which are frequentlyrelated to the inclusion or exclusion of E10, also reveal a significant phenotypicoverlap. The discovery of multiple mutations in thetau gene that lead to the ab-normal aggregation of tau and cause FTDP-17 demonstrates that tau dysfunctionis sufficient to produce neurodegenerative disease. The mutations lead to specificcellular alterations, including altered expression, function, and biochemistry of tauprotein. The finding that specific polymorphisms and mutations lead to diversephenotypes raises the possibility that the clinical and pathological expression ofthese disorders may be influenced by other genetic and epigenetic factors.

All these disorders have as a common theme accumulation of hyperphosphory-lated tau protein in a filamentous form, which almost certainly perturbs the functionof MTs and interferes with axonal transport. It remains to be established whethera protein kinase/phosphatase imbalance is an early mechanistic step leading to thegeneration of filamentous tau in some tauopathies. Genetic and/or environmentalfactors could initiate a cascade of events that leads to the abnormal phosphorylationof tau through incompletely defined pathways (Figure 4). It also remains to beseen whether the mere presence of tau filaments inside brain cells is sufficient tocause them to die. Similarly, the precise mechanisms by which tau protein assem-bles into filaments in human brain remain to be discovered. Further investigationinto the mechanisms of tau dysfunction, as well as the identification of potentialdisease-modifying factors, will provide additional insight into novel strategies fordisease treatment and prevention. The development of additional animal models

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of tauopathies that more closely recapitulate human diseases will facilitate thisundertaking.

The aggregation of tau in AD and various tauopathies is but one example of ab-normal protein-protein interactions that result in the intracellular accumulation offilamentous proteins. Abnormal protein aggregation is observed in a large numberof neurodegenerative disorders (Prusiner 1998, Goedert et al 1998, Trojanowskiet al 1998). Thus, besides tau pathology, AD is characterized by the extracellularaccumulation of Aβ fibrils in the form of amyloid plaques; Lewy body disorderscontain intracytoplasmic filamentous aggregates ofα-synuclein; trinucleotide re-peat disorders have intranuclear inclusions composed of fibrous polyglutamines;and spongiform encephalopathies demonstrate aggregates of proteinase-resistantprion protein. Aggregation of proteins in the brain is a common theme in a diversegroup of disorders, and insight into the pathogenesis of any one of these disordersmay have implications for our understanding of the mechanisms that underlie allthese diseases.

ACKNOWLEDGMENTS

VM-YL is the John H Ware third Chair of Alzheimer’s disease research at theUniversity of Pennsylvania. Work done in our laboratories is supported by grantsfrom the National Institute of Aging of the National Institutes of Health, the DanaFoundation, the US Alzheimer’s Association, the UK Medical Research Council,and the UK Alzheimer’s Research Trust. We thank Drs. MS Forman and V vanDeerlin for their input.

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Annual Review of Neuroscience Volume 24, 2001

CONTENTSPDZ DOMAINS AND THE ORGANIZATION OF SUPRAMOLECULAR COMPLEXES, Morgan Sheng, Carlo Sala 1

THE ROLE AND REGULATION OF ADENOSINE IN THE CENTRAL NERVOUS SYSTEM, Thomas V. Dunwiddie, Susan A. Masino

31

LOCALIZATION AND GLOBALIZATION IN CONSCIOUS VISION, S. Zeki 57

GLIAL CONTROL OF NEURONAL DEVELOPMENT, Greg Lemke 87TOUCH AND GO: Decision-Making Mechanisms in Somatosensation, Ranulfo Romo, Emilio Salinas 107

SYNAPTIC MODIFICATION BY CORRELATED ACTIVITY: Hebb''s Postulate Revisited, Guo-qiang Bi, Mu-ming Poo 139

AN INTEGRATIVE THEORY OF PREFRONTAL CORTEX FUNCTION, Earl K. Miller, Jonathan D. Cohen 167

THE PHYSIOLOGY OF STEREOPSIS, B. G. Cumming, G. C. DeAngelis 203

PARANEOPLASTIC NEUROLOGIC DISEASE ANTIGENS: RNA-Binding Proteins and Signaling Proteins in Neuronal Degeneration, Kiran Musunuru, Robert B. Darnell

239

ODOR ENCODING AS AN ACTIVE, DYNAMICAL PROCESS: Experiments, Computation, and Theory, Gilles Laurent, Mark Stopfer, Rainer W Friedrich, Misha I Rabinovich, Alexander Volkovskii, Henry DI Abarbanel

263

PROTEIN SYNTHESIS AT SYNAPTIC SITES ON DENDRITES, Oswald Steward, Erin M. Schuman 299

SIGNALING AND TRANSCRIPTIONAL MECHANISMS IN PITUITARY DEVELOPMENT, Jeremy S. Dasen, Michael G. Rosenfeld

327

NEUROPEPTIDES AND THE INTEGRATION OF MOTOR RESPONSES TO DEHYDRATION , Alan G. Watts 357

THE DEVELOPMENTAL BIOLOGY OF BRAIN TUMORS, Robert Wechsler-Reya, Matthew P. Scott 385

TO EAT OR TO SLEEP? OREXIN IN THE REGULATION OF FEEDING AND WAKEFULNESS, Jon T. Willie, Richard M. Chemelli, Christopher M. Sinton, Masashi Yanagisawa

429

SPATIAL PROCESSING IN THE BRAIN: The Activity of Hippocampal Place Cells, Phillip J. Best, Aaron M. White, Ali Minai 459

THE VANILLOID RECEPTOR: A Molecular Gateway to the Pain Pathway, Michael J Caterina, David Julius 487

PRION DISEASES OF HUMANS AND ANIMALS: Their Causes and Molecular Basis, John Collinge 519

VIKTOR HAMBURGER AND RITA LEVI-MONTALCINI: The Path to the Discovery of Nerve Growth Factor, W. Maxwell Cowan 551

EARLY DAYS OF THE NERVE GROWTH FACTOR PROTEINS, Eric M. Shooter 601

SEQUENTIAL ORGANIZATION OF MULTIPLE MOVEMENTS: Involvement of Cortical Motor Areas, Jun Tanji 631

INFLUENCE OF DENDRITIC CONDUCTANCES ON THE INPUT-OUTPUT PROPERTIES OF NEURONS, Alex Reyes 653

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NEUROTROPHINS: Roles in Neuronal Development and Function, Eric J Huang, Louis F Reichardt 677

CONTRIBUTIONS OF THE MEDULLARY RAPHE AND VENTROMEDIAL RETICULAR REGION TO PAIN MODULATION AND OTHER HOMEOSTATIC FUNCTIONS, Peggy Mason

737

ACTIVATION, DEACTIVATION, AND ADAPTATION IN VERTEBRATE PHOTORECEPTOR CELLS, Marie E Burns, Denis A Baylor 779ACTIVITY-DEPENDENT SPINAL CORD PLASTICITY IN HEALTH AND DISEASE, Jonathan R Wolpaw, Ann M Tennissen 807QUANTITATIVE GENETICS AND MOUSE BEHAVIOR, Jeanne M Wehner, Richard A Radcliffe, Barbara J Bowers 845

EARLY ANTERIOR/POSTERIOR PATTERNING OF THE MIDBRAIN AND CEREBELLUM, Aimin Liu, Alexandra L Joyner 869

NEUROBIOLOGY OF PAVLOVIAN FEAR CONDITIONING, Stephen Maren 897

{{alpha}}-LATROTOXIN AND ITS RECEPTORS: Neurexins and CIRL/Latrophilins, Thomas C Südhof 933IMAGING AND CODING IN THE OLFACTORY SYSTEM, John S Kauer, Joel White 963

THE ROLE OF THE CEREBELLUM IN VOLUNTARY EYE MOVEMENTS, Farrel R Robinson, Albert F Fuchs 981

ROLE OF THE REELIN SIGNALING PATHWAY IN CENTRAL NERVOUS SYSTEM DEVELOPMENT, Dennis S Rice, Tom Curran 1005

HUMAN BRAIN MALFORMATIONS AND THEIR LESSONS FOR NEURONAL MIGRATION, M Elizabeth Ross, Christopher A Walsh 1041

MORPHOLOGICAL CHANGES IN DENDRITIC SPINES ASSOCIATED WITH LONG-TERM SYNAPTIC PLASTICITY, Rafael Yuste, Tobias Bonhoeffer

1071

STOPPING TIME: The Genetics of Fly and Mouse Circadian Clocks, Ravi Allada, Patrick Emery, Joseph S. Takahashi, Michael Rosbash

1091

NEURODEGENERATIVE TAUOPATHIES, Virginia M-Y Lee, Michel Goedert, John Q Trojanowski 1121

MATERNAL CARE, GENE EXPRESSION, AND THE TRANSMISSION OF INDIVIDUAL DIFFERENCES IN STRESS REACTIVITY ACROSS GENERATIONS, Michael J Meaney

1161

NATURAL IMAGE STATISTICS AND NEURAL REPRESENTATION, Eero P Simoncelli, Bruno A Olshausen 1193

Nerve Growth Factor Signaling, Neuroprotection, and Neural Repair, Michael V Sofroniew, Charles L Howe, William C Mobley 1217

FLIES, GENES, AND LEARNING, Scott Waddell, William G Quinn 1283

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Virginia M-Y Lee,1 Michel Goedert,2 and John Q Trojanowski

Documents

Transcript of Virginia M-Y Lee,1 Michel Goedert,2 and John Q Trojanowski