Transgenic Models of Tauopathies and Synucleinopathies

John Q. Trojanowski and Virginia M.-Y. Lee

The Center for Neurodegenerative Disease Research, Divisionof Anatomic Pathology, Department of Pathology andLaboratory Medicine, The University of Pennsylvania Schoolof Medicine, Philadelphia, PA

Rapidly emerging concepts about the pathobiolo-gy and defining phenotypes of two major classes ofneurodegenerative disease known as tauopathiesand synucleinopathies are bringing these diseasesinto shaper focus. Significantly, recent research hassubstantially advanced understanding of these neu-rodegenerative disorders thereby providing freshopportunities for the development of transgenic (TG)mouse models. Since the availability of such animalmodels will accelerate efforts to discover moreeffective therapies, we review the current status ofefforts to generate informative TG mouse models fortauopathies and synucleinopathies and other neu-rodegenerative disorders characterized by promi-nent filamentous brain lesions.

IntroductionFilamentous brain lesions are hallmarks of many

diverse neurodegenerative diseases (see Table 1), mostof which are poorly understood and nearly all of whichlack effective therapies (for recent reviews, see ref. 7, 8,12, 15, 17). For example, filamentous tau lesions arecharacteristic of a group of common as well as rare neu-rodegenerative disorders referred to as tauopathies (seeTable 2), while filamentous �-synuclein lesions are sig-nature brain lesions of another group of diverse and vari-ably frequent neurodegenerative diseases known assynucleinopathies (see Table 3). Indeed, increasing evi-

dence suggests that filamentous aggregates resultingfrom abnormal protein-protein interactions play a mech-anistic role in the dysfunction and death of neuronsand/or glia in many neurodegenerative diseases(reviewed in 7, 8, 12, 15, 17). Despite the fact that dif-ferent proteins form the abnormal filaments in diverseneurodegenerative diseases, it is plausible that similarpathologic mechanisms may cause filament formation.Notably, most of the protein subunits of these abnormalfilaments are soluble polypeptides that do not self-assemble into polymeric fibrils in the normal humanbrain. Further, lesions specific to each of these disordersmay share similar toxic properties that compromise thefunction or viability of affected brain cells. Thus,insights into any one of the diseases listed in Tables 1-3could provide insights into one or more of the other dis-orders as well.

The elucidation of these and other hypotheticalmechanisms leading to the neurodegenerative diseaseswill require animal models that recapitulate key pheno-typic aspects of these disorders. Recent dramaticadvances in understanding tauopathies and synucle-inopathies are the focus of the reports in this sympo-sium. Significantly, many of the more recent advancesprovide new opportunities for the development of trans-genic (TG) mouse models of these diseases (7, 8, 12, 15,17). The availability of animal models would substan-tially accelerate efforts to discover more effective thera-pies for tauopathies and synucleinopathies. Therefore,we review the current status of TG mouse models ofthese diseases and highlight some of the more promisingpossibilities for the generation of informative animalmodels for tau and synuclein neurodegenerative brainpathologies in the near future.

FTDP-17 as a prototype for the tauopathiesFilamentous tau inclusions, in addition to extensive

neuron loss and gliosis, are hallmark neuropathologiclesions of neurodegenerative tauopathies including AD,Down’s syndrome (DS), several variants of prion dis-

Brain Pathology 9: 733-739(1999)

SYMPOSIUM: Tau and Synuclein in Neuropathology

Transgenic Models of Tauopathies andSynucleinopathies

Corresponding author:Dr. J.Q. Trojanowski or Dr. V.M.-Y. Lee, Center forNeurodegenerative Disease Research, Department ofPathology and Laboratory Medicine, University ofPennsylvania, School of Medicine, HUP-Maloney Bldg., 3rdFloor, 3600 Spruce Street, Philadelphia, PA 19104-4283; Tel.:215-662-6399 or 6427; Fax: 215-349-5909; E-mail address: [email protected], [email protected]

eases, progressive supranuclear palsy (PSP), amy-otrophic lateral sclerosis/parkinsonism-dementia com-plex of Guam (ALS/PDC), Pick’s disease (PiD), corti-cobasal degeneration (CBD), sporadic frontotemporaldementias (FTDs), hereditary frontotemporal dementiawith Parkinsonism linked to chromosome 17 (FTDP-17)syndromes. (Table 2) Although the tau pathologies inthe brains of patients with AD, DS and several othertauopathies coexist with additional diagnostic brainlesions (e.g., abundant deposits of A� in AD and DS),the brains of patients with a number of neurodegenera-tive tauopathies are characterized almost exclusively byprominent tau inclusions. Examples of the latter arePiD, CBD, PSP, ALS/PDC and FTDP-17 (8, 12, 17).Given the location of the tau gene near the linkage site,tau had been speculated for some time to be a candidategene for FTDP-17; however, there had been little or noevidence to substantiate this hypothesis until Poorkajand coworkers reported the first pathogenic tau genemutation (22). This was followed shortly thereafter byother publications (3, 5, 14, 24) leading to the identifi-cation of more than 10 different pathogenic tau genemutations in more than 20 kindreds. Moreover, reportsof new tau mutations and the identification of newFTDP-17 kindreds continue to appear, and it is highlylikely that additional tau mutations will be discovered asincreasing research attention is focused on hereditaryFTDP-17 (12, 17). Although FTDP-17 is a geneticallydetermined counterpart of seemingly sporadic FTDs, itmust be acknowledged that the role of genetics in thisgroup of FTDs remains largely unexplored. Not all ofthese disorders are linked to chromosome 17 and not allthose linked to chromosome 17 have been shown tohave tau mutations. This notwithstanding, the remark-able discovery of pathogenic tau mutations providesunequivocal support for the hypothesis that defects inthe tau gene alone are sufficient to cause a neurodegen-erative disease.

734 J. Q. Trojanowski and V. M-Y. Lee: Transgenic Models of Tauopathies and Synucleinopathies

Disease Lesion/components Location

Alzheimer’s disease (AD) SPs/A� Extracellular

NFTs/PHFtau Intracytoplasmic

Tauopathies NFTs/AD-like PHFtau Intracytoplasmic

Parkinson’s disease LBs/�-synuclein Intracytoplasmic

Dementia with LBs LBs/�-synuclein Intracytoplasmic

LB variant of AD SPs/A� Extracellular

NFTs/PHFtau Intracytoplasmic

LBs/�-synuclein Intracytoplasmic

Multiple system atrophy GCIs/�-synuclein Intracytoplasmic

Prion diseases Amyloid plaques/Prions Extracellular

Amyotrophic lateral sclerosis Spheroids/NF subunits Intracytoplasmic

SOD1

Tri-nucleotide repeat Inclusions/Expanded Intranuclear and

diseases polyglutamine tracts dendritic

Neuronal intranuclear Inclusions/Expanded Intranuclear

inclusion disease polyglutamine tracts

Table 1. Sporadic and hereditary neurodegenerative diseasescharacterized by prominent filamentous brain lesions. See textfor abbreviations.

Neurodegenerative Diseases with Filamentous Tau Lesions

Sporadic/Familial Alzheimer’s disease

Amyotrophic lateral sclerosis/parkinsonism-dementia complex

Argyrophilic grain dementia

Corticobasal degeneration

Dementia pugilistica

Diffuse neurofibrillary tangles with calcification

Down syndrome

Frontotemporal dementia with Parkinsonism linked to chromosome 17

Gerstmann-Straussler-Scheinker disease

Hallervorden-Spatz disease

Inclusion body myositis

Jakob-Creutzfeldt disease

Multiple system atrophy

Niemann-Pick disease type C

Pick’s disease

Prion protein cerebral amyloid angiopathy

Progressive supranuclear palsy

Subacute sclerosing panencephalitis

Tangle-predominant Alzheimer’s disease

Table 2. Sporadic and hereditary neurodegenerative diseasescharacterized by filamentous tau lesions.

Neurodegenerative Diseases with Filamentous Synuclein Lesions

Sporadic/familial Parkinson’s disease

Sporadic/Familial Alzheimer’s disease

Dementia with Lewy bodies

Multiple system atrophy

Down syndrome

Hallervorden-Spatz disease

Prion diseases

Table 3. Sporadic and hereditary neurodegenerative diseasescharacterized by filamentous synuclein lesions.

The discovery of tau gene mutations in FTDP-17 kin-dreds represents important and unique new opportuni-ties for research into the pathogenic mechanisms ofFTDP-17 and related tauopathies. These discoveriesalso will enable rapid development of animal models ofthese disorders since FTDP-17 syndromes are autoso-mal dominantly inherited disorders with diverse clinicalfeatures that are characterized by abundant insolubleintracellular filamentous tau inclusions (12, 17). Tauinclusions are abundant not only in neurons, but also inastrocytes and oligodendrocytes in the brains of affectedmembers of some of the FTDP-17 pedigrees (12, 17).Additionally, clinical and pathological features ofFTDP-17 syndromes overlap with those seen in severalother tauopathies including PSP, CBD, PiD and AD.This may be explained in part by studies that appear tolink different intronic and exonic mutations in the taugene to specific losses of normal tau function or to toxicgains of function. For example, depending upon thetopography of a given mutation in the tau gene, a muta-tion may alter the splicing of tau mRNAs and the finelyregulated expression of each of the 6 tau isoforms in theadult human brain; impair the ability of tau to bind toand promote the assembly of microtubules (MTs); orreduce the solubility of tau isoforms and augment theirfibrillogenesis (3, 4, 10, 12-14, 17, 24, 27).

Insights into how these tau gene mutations causebrain degeneration benefited from extensive prior under-standing of the normal biology of tau proteins that hadaccumulated as a result of decades of basic research onMTs and MT associated proteins. The role of alterantivesplicing and phosphorylation in the generation of vari-ous tau isoforms is reviewed by Buée and Delacourte inthis symposium. In brief, 6 tau isoforms (i.e. the 3R0N,3R1N, 3R2N, 4R0N, 4R1N and 4R2N tau isoforms; seealso below) are generated by alternative mRNA splicingof 11 exons in the tau gene. Alternative splicing of E10gives rise to tau isoforms with 3 or 4 MT binding repeats(i.e. 3R and 4R). Further, demonstration that the ratio of3R tau to 4R tau isoforms in the normal adult humanbrain is ~1 suggests that the alternative splicing of thetau gene is tightly regulated (13).

Intronic and exonic tau gene mutations that affectE10 splicing as well as exonic mutations leading to mis-sense substitutions at or near the MT binding repeatsthat impair tau functions (including the ability of tau tobind to and promote MT assembly) have been identifiedin families with FTDP-17 (3,4,10,12-14,17,27). Further,these and other studies indicate that multiple mecha-nisms are operative in regulating E10 splicing. IncreasedE10 splicing augments expression of 4R tau proteins in

the brains of FTDP-17 patients. In addition to E10 splicemutations, several tau missense mutations located in ornear MT-binding repeats appear to cause FTDP-17 byaltering the biochemical properties of tau as well as thefunctional interactions of tau with MTs. Thus, emergingdata suggest the hypothesis that the topography of eachtau gene mutation (i.e. FTDP-17 tau genotype) is criti-cal to disease pathogenesis and predictive of a specifictau dysfunction (3, 4, 8, 10, 12-14, 17, 24, 27).

The discovery of E10 splice mutations in a subset ofFTDP-17 kindreds has provided important clues fordeveloping a better understanding of seemingly sporadictauopathies including PiD, CBD and PSP. Thus, theselective aggregation of insoluble 3R tau or 4R tau iso-forms as cytoplasmic inclusions in familial and sporadicneurodegenerative disorders suggests that the de-regula-tion of E10 splicing may be a fundamental pathogenicmechanism in the tauopathies. Since it is plausible thatdifferent forms of familial and sporadic tauopathies canbe caused by perturbing any of the multiple and com-plex mechanisms that regulate the stability, splicing andfunctions of the tau gene and the proteins it encodes,further analyses of tau gene regulation and tau proteinexpression will undoubtedly lead to new approaches tounderstanding the pathogenesis of tauopathies.

Although the notion that tau might play a fundamen-tal role in the onset and progression of neurodegenera-tive diseases has been regarded with skepticism sincethe discovery of familial AD (FAD) mutations, the dis-covery of pathogenic tau mutations directly demon-strates that tau abnormalities can cause neurodegenera-tion in the absence of A� deposits. For example, it ispossible that some of the missense FTDP-17 tau genemutations might cause disease by impairing the abilityof tau to bind MTs which could destabilize MTs, disruptaxonal transport, lead to dying back of axons and thedeath of neurons. Alternatively, the formation of intra-cytoplasmic filamentous tau inclusions could represent again of toxic function leading to the death of affectedcells, and these inclusions could be due to alterations inratio of 4R tau to 3R tau isoforms that are the conse-quence of other FTDP-17 mutations in tau introns.Indeed, although the formation of tau pathologies maybe downstream consequences of FAD mutations, thedevelopment of these pathologies could be an essentialand necessary mechanistic step for the degeneration ofneurons in FAD. Accordingly, tau dysfunction and fila-mentous tau aggregates must be considered plausibletargets for the development of novel and more effectivedrugs for the treatment not only of FTDP-17, but alsofor the treatment of AD. Moreover, such therapies also

735J. Q. Trojanowski and V. M-Y. Lee: Transgenic Models of Tauopathies and Synucleinopathies

may be relevant to the treatment of other tauopathiessince tau pathologies might initiate neurodegenerativedisease or represent a final common pathway in therelentlessly progressive brain degeneration associatedwith many of these brain disorders (12,17). For thesereasons, TG mouse models of FTDP-17 tauopathies alsomay serve as informative models for research into therole tau pathologies play in the onset and progression ofAD and related tauopathies.

Tau transgenic miceAlthough TG mouse lines over expressing 3R0N or

4R2N or human tau using cDNAs driven by 3-hydroxy-3-methylglutaryl coenzyme A reductase and Thy-1 pro-moters, respectively, resulted in “pre-tangle” tau pathol-ogy, but no filamentous tau inclusions (2, 9), it must beemphasized that efforts to produce animal models of taupathologies have been very limited (8, 12, 17). In con-trast, many years of intense, but failed, efforts to gener-ate TG mice with A� deposits by investigators in a largenumber of laboratories preceded the eventual achieve-ment of a TG mouse model of AD amyloidosis (6).Thus, intense empirical efforts to develop TG mousemodels of tau pathologies are needed and justifiablenow, and these efforts should be greatly facilitated bythe discovery of the FTDP-17 tau gene mutations. Itmay be necessary to express transgene-derived tau pro-teins at higher levels than those achieved in the previouslines of tau TG mice to induce filamentous tau inclu-sions.

Notably, intraneuronal injections in the lamprey oftau cDNA containing plasmids followed by the massiveover expression of 4R2N human tau has been shown tolead to the formation of inclusions formed by aggregat-ed tau fibrils that appeared similar to paired helical fila-ments (PHFs) in AD NFTs. This was associated with thedegeneration of some affected neurons in the lampreycentral nervous system (11). Encouraged by theseresults, and the formation of “pre-tangle” tau pathologyin the TG mice described earlier (2, 9), we recently pro-duced TG mouse lines that express 5-10 fold higher lev-els of wild type human 3R0N tau than endogenousmouse tau. These mice developed filamentous intraneu-ronal inclusions composed of tau and neurofilaments(NFs), but the fibrils in these inclusions exhibited theultrastructural features of straight filaments rather thanPHFs characteristic of AD NFTs (unpublished observa-tions). With advancing age, these TG mice acquired aphenotype that was more similar to some variants ofFTDP-17, PSP and ALS/PDC rather than to AD.Although some NF proteins do occur in variable num-

bers of NFTs, NF proteins appear to accumulate aftertau during the formation of NFTs (23). Accordingly, itwill be important and informative to cross these tau TGmice with NF knockout mice to attempt to develop fila-mentous tau tangles without NFs.

In future models it may prove useful to utilize con-structs with tau gene mutations, including those muta-tions that are considered to act by either a loss of taufunction or a toxic gain of function, to generate tau TGmice. In addition to neuron specific promoters, it alsowill be critical to generate TG mice using glial specificpromoters to drive transgene protein expression. Thereason for this is that tangles occur in glia in manytauopathies (12, 17), and the development of TG mousemodels that acquire glial tau pathology will enableinvestigation of disease mechanisms that lead to the dys-function of affected glial cells. Finally, minigenes thatenable overexpression of all 6 human tau isoforms withand without intronic or exonic FTDP-17 tau gene muta-tions using mouse tau gene knock-out animals may leadto more authentic TG mouse models of tauopathies.Crossing these TG mice with TG mouse models of ADamyloidosis may result in model systems that moreaccurately recapitulate the tangle and plaque pathologyof AD. Thus, using model systems like those discussedhere, it should be possible to make rapid progress in elu-cidating how and why glial and neuronal tau pathologieslead to the onset and progression of diverse sporadic andhereditary tauopathies in the very near future.

SynucleinopathiesA few years after a peptide derived from �-synuclein

(i.e. “NAC” or the non-amyloid component of amyloid)initially implicated this synaptic protein in AD (7, 15),the A53T and A30P �-synuclein gene mutations werediscovered in rare familial PD kindreds (16, 21). Thiswas rapidly followed by reports showing that �-synu-clein is a major component of Lewy bodies (LBs) andLewy neurites in sporadic Parkinson’s disease (PD),dementia with LBs and the LB variant of AD.Antibodies to �-synuclein were shown to detect moreLewy neurites and LBs than previous antibodies. Bothnormal and mutant �-synuclein were demonstrated toassemble into filaments like those seen in LBs (1, 7, 15,25). Thus, these discoveries have re-focused attention onthe increasingly compelling hypothesis that LBs andLewy neurites play a mechanistic role in the degenera-tion of affected neurons in Lewy body disease (7,15).Moreover, mutations in the presenilin and A� precursorprotein genes have been linked to accumulations ofmany �-synuclein positive LBs in >60% of FAD brains,


and in >50% of DS brains with AD pathology. Morerecently, �-synuclein has been shown to form filamen-tous glial cell inclusions (GCIs) in oligodendroglia ofmultiple system atrophy (MSA) (7, 15). In addition, it iswell known that AD and PD occur in the same patientmore frequently than expected, and although the mech-anisms that account for this have not been clarified (20),it is plausible that �-synuclein plays a role in thesemechanisms. Taken together, there now is compellingsupport for the hypothesis that filamentous �-synucleininclusions play a mechanistic role in the pathogenesis ofneurodegenerative disorders (7, 15).

Further support for this hypothesis comes from stud-ies showing that TG mice that develop LB-like NFinclusions show evidence that the viability of affectedneurons is compromised with advancing age, and theyare more vulnerable to degenerate following traumaticbrain injury (19, 26). Moreover, LBs and dystrophicLewy neurites could be deleterious even to those neu-rons that harbor these lesions and survive for a period oftime. If �-synuclein lesions disrupt transport oforganelles and proteins in perikarya and processes ofaffected neurons, this may be followed by a “dyingback” of processes and disconnection of neuronal cir-cuits.

Synuclein transgenic miceAlthough no full-length reports have been published

describing failed or successful efforts to produce TGmouse models of synucleinopathies by over expressingnormal or mutant human �-synuclein, it is likely thatsuch reports will appear soon. Indeed, at least one �-synuclein TG mouse line has been generated, and it wasreported to develop perikaryal �-synuclein aggregates,but it remains unclear if these aggregates are associatedwith neuronal dysfunction or degeneration (18). Effortsto generate �-synuclein TG mice with a neurodegenera-tive phenotype will face a number of hurdles. For exam-ple, it will be necessary to design TG mice that take intoaccount the fact that the normal mouse a-synuclein pro-tein harbors the A53T substitution as well as the fact thatthere are a number of other synucleins (e.g., �-synucle-in, �-synuclein, synoretin) that are products of distinct-ly different genes, but also are expressed in the brain (7,15). Thus, it may be necessary to generate TG mousemodels of synucleinopathies using a strategy involving�-synuclein, �-synuclein, �-synuclein and synoretinknockout mice (like the NF knockout mice describedabove for tauopathy TG mouse models) so that normaland mutant human �-synuclein can be overexpressed inTG mice without the potential confounds of endoge-

nously expressed mouse synucleins. Moreover, crossesof such mice with other TG mouse models of AD amy-loidosis and tauopathies offer the prospect of developinganimal models of LB variant of AD and forms of FADand DS with associated LB pathology. While this mayappear to be a daunting task, the aggregation of brainproteins is emerging as a common mechanistic theme inseveral sporadic and hereditary neurodegenerative dis-eases and the remarkable advances in understanding thepathobiology of PD and related synucleinopathies willstimulate intense efforts to develop TG mouse models ofthese and related disorders in the near future.

SummaryCurrent understanding of the mechanisms that con-

vert normal soluble tau and �-synuclein into insolublefilamentous aggregates characteristic of tauopathies andsynucleinopathies, respectively, is still very fragmen-tary, and advances is this area of research have beenimpeded by the lack of animal and cell culture models.Although PHF-like tau filaments as well as LB-like andGCI-like �-synuclein filaments can be produced in a testtube, the conditions required are highly artificial, and invitro paradigms have limited utility as models of in vivomechanisms of neurodegeneration. Thus, it is essentialto develop TG mouse models of these filamentouslesions, despite the fact that previously published effortsto produce TG models of tauopathies did not result inTG mice that acquired filamentous tau lesions (2, 8, 9).However, the injection of constructs into lamprey neu-rons to overexpress tau did result in somatodendritic tauexpression, PHF-like filament formation as well as evi-dence of nerve cell degeneration in this simple verte-brate (11). Thus, these studies taken together with ourown unpublished data on tau TG mice provide proof ofthe concept that, when sufficiently overexpressed inneurons, tau can be induced to form filaments that resultin neuron degeneration. Moreover, the recent identifica-tion of tau gene mutations in FTDP-17 syndromes, andadvances in understanding the pathobiology of othertauopathies as well as the role of �-synuclein in PD andrelated synucleinopathies open up fresh opportunities todevelop TG mouse models of these neurodegenerativediseases in the near future. Significantly, while these TGmouse models will be critical for studies to addressimportant questions about mechanisms of disease intauopathies and synucleinopathies, they also may helpclarify mechanisms of brain degeneration in a largergroup of other neurodegenerative diseases characterizedby filamentous brain pathologies. Finally and mostimportantly, these models also can be exploited for test-


ing potentially effective therapeutic agents targeted atmechanisms of brain degeneration in tauopathies, synu-cleinopathies and other neurodegenerative disorders.

AcknowledgementsThe authors thank members of their laboratory and

their collaborators within and outside the University ofPennsylvania for their important contributions to thestudies reviewed here. The families of the many patientsstudied by our group over the past decade have made itpossible to pursue many of the research advances dis-cussed here. The studies summarized here from our lab-oratory were supported by grants from the NationalInstitute on Aging of the National Institutes of Health,the Dana Foundation and the Alzheimer’s Association.

References

1. Baba M, Nakajo S, Tu P-H, Tomita T, Nakaya K, Lee VM-Y, Trojanowski JQ, Iwatsubo T (1998) Aggregation of �-synuclein in Lewy bodies of sporadic Parkinson’s diseaseand dementia with Lewy bodies. Am J Pathol 152: 879-884

2. Brion J-P, Tremp G, Octave J-N (1999) Transgenic expres-sion of the shortest human tau affects its compartmental-ization and its phosphorylation as in the pre-tangle stageof Alzheimer’s disease. Am J Pathol 154: 255-270

3. Clark LN, Poorkaj P, Wszolek Z, Geschwind DH,Nasreddine ZS, Miller B, Li D, Payami H, Awert F,Markopoulou K, Andreadis A, D’Souza I, Lee VM-Y, ReedL, Trojanowski JQ, Zhukareva V, Bird T, Schellenberg G,Wilhelmsen KC (1998) Pathogenic implications of muta-tions in the tau gene in pallido-ponto-nigral degenerationand related neurodegenerative disorders linked to chro-mosome 17. Proc Natl Acad Sci USA 95: 13103-13107

4. D’Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM-Y, BirdTD, Schellenberg GD (1999) Missense and silent taugene mutations cause frontotemporal dementia withparkinsonism-chromosome 17 type, by affecting multiplealternative RNA splicing regulatory elements. Proc NatlAcad Sci USA 96: 5598-55603

5. Dumanchin C, Camuzal A, Campion D, Verpillat P,Hannequin D, Dubois B, Saugier-Veber P, Martin C, PenetC, Charbonnier F, Agid Y, Brice A (1998) Segregation of amissense mutation in the microtubule-associated proteintau with familial frontotemporal dementia and parkinson-ism. Hum Mol Genet 7: 1825-1829

6. Games D, Adams D, Alessandrini R, Barbour R,Berthelette P, Blackwell C, Carr T, Clemens J, DonaldsonT, Gillespie F, Giodo T, Hagopian S, Johnson-Wood K,Khan K, Lee M, Leibowitz P, Liebergurg I, Little S, MasliahE, McConlogue L, Montoya-Zavala M, MuckE L, PaganiniL, Penniman E, Power M, Schenk D, Seubert P, Snyder B,Soriano F, Tan H, Vitale J, Wadsworth S, Wolozin B, ZhaoJ (1995) Alzheimer-type neuropathology in transgenicmice overexpressing V717F �-amyloid precursor protein.Nature 373: 523-527

7. Giasson BI, Galvin JE, Lee VM-Y, Trojanowski JQ (1999)The cellular and molecular pathology of parkinson’s dis-ease. In: Clark CM, Trojanowski JQ (eds)Neurodegenerative Dementias: Clinical Features andPathological Mechanisms, McGraw-Hill, New York, inpress

8. Goedert M, Hasegawa M (1999) The tauopathies:Towards an experimental animal model. Am J Pathol 154:1-7

9. Goetz J, Probst A, Spillantini MG, Schaefer T, Jakes R,Buerki K, Goedert M (1995) Somatodendritic localizationand hyperphosphorylation of tau protein in transgenicmice expressing the longest human brain tau isoform.EMBO J 14:1304-1313

10. Grover A, Houlden H, Baker M, Adamson J, Lewis J,Prihart G, Pickering-Brown S, Duff K, Hutton M (1999) 5’splice mutations in tau associated with the inheriteddmeentia FTDP-17 affect stem-loop structure that regu-lates alternative splicing of exon 10. J Biol Chem 274:15134-15143

11. Hall GF, Yao J, Lee G (1997) Human tau becomes phos-phorylated and forms filamentous deposits when overex-pressed in lamprey central neurons in situ. Proc Natl AcadSci USA 94: 4733-4738

12. Hong M, Trojanowski JQ, Lee VM-Y (1999) Tau-basedneurofibrillary lesions. In: Clark CM, Trojanowski JQ (eds)Neurodegenerative Dementias: Clinical Features andPathological Mechanisms, McGraw-Hill, New York, inpress

13. Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z,Reed L, Miller BI, Geschwind DH, Bird TD, McKeel D,Goate A, Morris JC, Wilhelmsen KC, Schellenberg GD,Trojanowski JQ, Lee VM-Y (1998) Mutation-specific func-tional impairments in distinct tau isoforms of hereditaryFTDP-17. Science 282: 1914-1917

14. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S,Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A,Grover A, Hackett J, Adamson J, Lincoln S, Dickson D,Davies P, Petersen RC, Stevens M, de Graaff E, WautersE, van Baren J, Hillebrand M, Joosse M, Kwon JM,Nowotny P, Che LK, Norton J, Morris JC, Reed LA,Trojanowski JQ, Basun H, Lannfelt L, Neystat M, Fahn S,Dark F, Tannenberg T, Dodd P, Hayward N, Kwok JBJ,Schofield PR, Andreadis A, Snowden J, Craufurd D,Neary D, Owen F, Oostra BA, Hardy J, Goate A, vanSwieten J, Mann D, Lynch T, Heutink P (1998) Associationof missense and 5’-splice- site-mutations in tau with theinherited dementia FTDP-17. Nature 393: 702-705

15. Iwatsubo T, Baba M, Lee VM-Y, Trojanowski JQ (1999)Purification of Lewy bodies and identification of �-synu-clein as a major component of Lewy bodies. In: Lee VM-Y, Trojanowski JQ, Buee L, Christen Y (eds) FatalAttractions within Neurons – Intracytoplasmic ProteinAggregates in Alzheimer’s Disease and RelatedDegenerative Diseases. IPSEN Foundation, Paris, inpress

16. Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, KoselS, Przuntek H, Epplen JT, Schols L, Riess O (1998)Ala30-to-pro mutation in the gene encoding alpha-synu-clein in Parkinson's disease. Nature Gen 18:106-108


17. Lee VM-Y, Trojanowski JQ (1999) Frontotemporal demen-tia with Parkinsonism linked to chromosome 17 (FTDP-17): Tau protein dysfunction and FTDP-17 phenotypescorrelate with loci of tau gene mutations. In: Lee VM-Y,Trojanowski JQ, Buee L, Christen Y (eds) Fatal AttractionsWithin Neurons – Intracytoplasmic Protein Aggregates inAlzheimer’s Disease and Related Degenerative Diseases.IPSEN Foundation, Paris, in press

18. Masliah E, Veinbergs I, Mallory M, Rochenstein E,Hashimoto M, Takeda A, Mucke L (1998) Role of synu-clein aggregation in neurodegeneration in Alzheimer’sand Parkinson’s disease. Neurobiol Aging 19: S71

19. Nakamura M, Saatman KE, Galvin JE, Scherbel U,Raghupathi R, Trojanowski JQ, McIntosh TK (1999)Increased vulnerability of NFH-LacZ transgenic mouse totraumatic brain injury-induced behavioral deficits and cor-tical damage. J Cereb Blood Flow Metab 19: 762-770

20. Perl DP, Olanow CW, Calne D (1998) Alzheimer’s diseaseand Parkinson’s disease: Distinct entities or extremes of aspectrum of neurodegeneration. Ann Neurol 44: S19-S31

21. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE,Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, BoyerR, Stenroos ES, Chandrasekharappa S, AthanassiadouA, Papapetropoulos T, Johnson WG, Lazzarini AM,Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997)Mutation in the alpha-synuclein gene identified in familieswith Parkinson's disease. Science 276: 2045-2047

22. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM,Anderson L, Andreadis A, Wiederholt WC, Raskind M,Schellenberg GD (1998) Tau is a candidate gene forchromosome 17 frontotemporal dementia. Ann Neurol 43:815-825

23. Schmidt ML, Lee VM-Y, Trojanowski JQ (1990) Relativeabundance of tau and neurofilament epitopes in hip-pocampal neurofibrillary tangles. Am J Pathol 136: 1069-1075

24. Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug,Ghetti B (1998) Mutation in the tau gene in familial multi-ple system tauopathy with presenile dementia. Proc NatlAcad Sci USA 95: 7737-7741

25. Spillantini MG, Schmidt ML, Lee VM-Y, Trojanowski JQ,Jakes R, Goedert M (1997) �-synuclein in Lewy bodies.Nature 388: 839-840

26. Tu PH, Robinson KA, de Snoo F, Eyer J, Peterson A, LeeVM-Y, Trojanowski JQ (1997) Selective degeneration ofPurkinje cells with Lewy body-like inclusions in agedNFHLACZ transgenic mice. J Neurosci 17: 1064-1074

27. Varani L, Hasegawa M, Spillantini MG, Smith MJ, MurrellJR, Ghetti B, Klug A, Goedert M, Varani G (1999)Structure of tau exon 10 spicing regulatory element RNAand destabilization by mutations of frontotemporaldementia and parkinsonism linked to chromosome 17.Proc Natl Acad Sci USA 96: 8229-8234


Documents

Transgenic Models of Tauopathies and Synucleinopathies