Terapias para Doenças Neurodegenerativas

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April 7, 2001 15:58 Annual Reviews AR121-37
Annu. Rev. Neurosci. 2001. 24:1121–159

Copyright °
c 2001 by Annual Reviews. All rights reserved
NEURODEGENERATIVE TAUOPATHIES
Virginia M-Y Lee,1 Michel Goedert,2
and John Q Trojanowski1
1Center for Neurodegenerative Disease Research, Department of Pathology and
Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia,
Annu. Rev. Neurosci. 2001.24:1121-1159. Downloaded from www.annualreviews.org
Pennsylvania 19104; e-mail: vmylee@mail.med.upenn.edu,

trojanow@mail.med.upenn.edu
2Medical Research Council, Laboratory of Molecular Biology, Hills Road, Cambridge,
CB2 2QH, United Kingdom; e-mail: mg@mrc-lmb.cam.ac.uk

by Open University on 07/11/13. For personal use only.
Key Words Alzheimer’s disease, frontotemporal dementia, mutation,

neurodegenerative disease, filamentous deposits, pathology, tau protein
■ Abstract The defining neuropathological characteristics of Alzheimer’s disease
are abundant filamentous tau lesions and deposits of fibrillar amyloid β peptides.
Prominent filamentous tau inclusions and brain degeneration in the absence of
β -amyloid deposits are also hallmarks of neurodegenerative tauopathies exemplified by
sporadic corticobasal degeneration, progressive supranuclear palsy, and Pick’s dis-
ease, as well as by hereditary frontotemporal dementia and parkinsonism linked to
chromosome 17 (FTDP-17). Because multiple tau gene mutations are pathogenic
for FTDP-17 and tau polymorphisms appear to be genetic risk factors for sporadic
progressive supranuclear palsy and corticobasal degeneration, tau abnormalities are
linked directly to the etiology and pathogenesis of neurodegenerative disease. Indeed,
emerging data support the hypothesis that different tau gene mutations are pathogenic
because they impair tau functions, promote tau fibrillization, or perturb tau gene splic-
ing, thereby leading to formation of biochemically and structurally distinct aggre-
gates of tau. Nonetheless, different members of the same kindred often exhibit diverse
FTDP-17 syndromes, which suggests that additional genetic or epigenetic factors influ-
ence the phenotypic manifestations of neurodegenerative tauopathies. Although these
and other hypothetical mechanisms of neurodegenerative tauopathies remain to be
tested and validated, transgenic models are increasingly available for this purpose,
and they will accelerate discovery of more effective therapies for neurodegenerative
tauopathies and related disorders, including Alzheimer’s disease.
INTRODUCTION
The study of sporadic and familial neurodegenerative diseases over the past decade
has led to the realization that many of these disorders are characterized by distinct
hallmark brain lesions that have in common the formation of filamentous de-
posits of abnormal brain proteins. Thus, a group of heterogeneous dementias and
0147-006X/01/0621-1121$14.00 1121
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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-associated
protein tau appears to share common mechanisms of disease. They are collectively
known as neurodegenerative tauopathies (Table 1). Despite their diverse pheno-
typic manifestations, brain dysfunction and degeneration in tauopathies is linked
to the progressive accumulation of filamentous tau inclusions, and this, together
with the absence of other disease-specific neuropathological abnormalities, pro-
vided circumstantial evidence implicating abnormal tau in disease onset and/or
progression. However, this view remained unproven and highly controversial un-
til 1998, when multiple tau gene mutations were discovered in frontotemporal
dementia and parkinsonism linked to chromosome 17 (FTDP-17), thereby pro-

viding unequivocal evidence that tau abnormalities alone are sufficient to cause
neurodegenerative disease (Foster et al 1997, Hutton et al 1998, Poorkaj et al
1998, 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-Sträussler-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
a
Diseases 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 and

degeneration.
This review is designed to integrate and interpret the remarkable recent advances
that have led to new insights into the mechanistic role that tau abnormalities play
in neurodegenerative disease. It begins with a brief summary of our current under-
standing of the human tau gene and the functions of the six alternatively spliced
tau isoforms that are expressed in the normal adult human brain. What is known
about 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 novel
sporadic, tauopathies. This information provides the context and perspective in
which to present an update on the increasing number of pathogenic tau gene mu-
tations, as well as a summary of the neuropathological and biochemical profiles of
the tau pathologies in FTDP-17. Finally, the review concludes with an update of
the current status of efforts to develop transgenic (TG) and other animal models
of human neurodegenerative tauopathies.
STRUCTURE, FUNCTION, AND MOLECULAR

GENETICS OF TAU
Tau proteins are low Mr microtubule-associated proteins that are abundant in the
central nervous system (CNS), where they are expressed predominantly in axons.
They are also expressed in axons of peripheral nervous system neurons but are
barely 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). Human
tau proteins are encoded by a single gene consisting of 16 exons on chromosome
17q21, and the CNS isoforms are generated by alternative mRNA splicing of 11 of
these 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 generates
six tau isoforms ranging from 352 to 441 amino acids in length (Figure 1), which
differ by the presence of either three (3R-tau) or four (4R-tau) carboxy-terminal
tandem 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 splicing
of 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 adult
human brain, the ratio of 3R-tau to 4R-tau isoforms is ∼1, but the 1N, 0N, and
2N tau isoforms comprise about 54%, 37%, and 9%, respectively, of total tau
(Goedert & Jakes 1990, Hong et al 1998). In addition, the alternative splicing of
tau is developmentally regulated such that only the shortest tau isoform (3R/0N) is
expressed in fetal brain, whereas all six isoforms appear in the postnatal period of
the human brain (Goedert et al 1989a). In the peripheral nervous system, inclusion
of E4a in the amino-terminal half results in the expression of higher Mr proteins
termed 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 16
exons, 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 the
human CNS. E4a (striped box), which is also not transcribed in the human CNS, is expressed in
the peripheral nervous system, leading to the larger tau isoforms, termed big tau (see text). The
black 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 tau
protein have been discovered and extensively characterized (for review, see Buée
et al 2000). Most notably, tau binds to and stabilizes microtubules (MTs), in ad-
dition to promoting MT polymerization (Weingarten et al 1975, Cleveland et al
1977b). The MT binding domains of tau are localized to the carboxy-terminal half
of the molecule within the four MT binding motifs. These motifs are composed of
highly conserved 18–amino acid long binding elements separated by flexible, but
less conserved, interrepeat sequences that are 13–14 amino acids long (Himmler
et al 1989, Lee et al 1989, Butner & Kirschner 1991). The binding of tau to MTs
is a complex process mediated in part by a flexible array of weak MT binding sites
that are distributed throughout the MT binding domain delineated by these repeats
and their interrepeat sequences (Lee et al 1989, Butner & Kirschner 1991). In ad-
dition, sequences flanking the repeats contribute to microtubule binding (Gustke
et al 1994). 4R-tau isoforms are more efficient at promoting MT assembly and
have a greater MT binding affinity than do 3R-tau isoforms (Goedert & Jakes
1990, Butner & Kirschner 1991). It is interesting to note that the interrepeat se-
quence between the first and second MT binding repeats has more than twice
the binding affinity of any individual MT binding repeat (Goode & Feinstein
1994). This region is unique to 4R-tau and is believed to be responsible for the
higher 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 did
not have any overt phenotype (Harada et al 1994). However, a more recent study
has reported some subtle behavioral impairments in older knockout mice (Ikegami
et al 2000).
TAU PHOSPHORYLATION AND REGULATION

OF TAU FUNCTIONS
There are 79 potential serine (Ser) and threonine (Thr) phosphate acceptor residues
in the longest tau isoform, and phosphorylation at ∼30 of these sites has been
reported in normal tau proteins (reviewed in Billingsley & Kincaid 1997, Buée
et al 2000). Tau phosphorylation is developmentally regulated such that fetal tau is
more highly phosphorylated in embryonic compared with adult CNS (Kanemaru

et al 1992, Bramblett et al 1993, Goedert et al 1993, Watanabe et al 1993), and
the degree of phosphorylation of all six tau isoforms decreases with age, probably
because of the activation of phosphatases (Mawal-Dewan et al 1994). The tau
phosphorylation sites are clustered in regions flanking the MT binding repeats,
and it is well established that increasing tau phosphorylation negatively regulates
MT 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 MT
binding 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 role
in reducing the binding of tau to MTs (Biernat et al 1993). A similar role may be
considered for phosphorylation of Ser396, which is located adjacent to the carboxy-
terminal end of the fourth MT binding domain (Bramblett et al 1993), but other
data argue that phosphorylation of neither of these sites is sufficient to eliminate
the binding of tau to MTs (Seubert et al 1995). It is interesting that both sites are
phosphorylated in fetal tau and that they are hyperphosphorylated in all six tau
isoforms that form abnormal paired helical filaments (PHFs) in the neurofibrillary
tangles (NFTs) of the AD brain (Seubert et al 1995). The regulation of the binding
of 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 a
heptapeptide sequence (224KKVAVVR230) located within a proline-rich domain,
amino-terminal to the MT binding domains, promotes MT binding in combination
with the repeat regions (Goode et al 1997). Thus, it is likely that phosphorylation at
multiple sites, especially those flanking the MT binding repeats, but also additional
intra- and intermolecular interactions, regulate the MT binding function of tau.
Only little is known about the regulation of tau phosphorylation. One study has
reported increased phosphorylation of tau at Ser202/Thr205 in mice that lack
Reelin or both the very-low-density lipoprotein receptor and the apolipoprotein
E receptor 2 (Hiesberger et al 1999). It suggests that tyrosine phsophorylation
of 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 to

additional phosphorylation sites in tau and to mice mutant for other components
of this developmental pathway.
For the reasons discussed above, considerable research has focused on the
protein kinases and protein phosphatases that regulate tau phosphorylation, and a
large 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, Buée et al 2000, Hong et al 2000). These kinases include mito-
gen-activated protein kinase (Drewes et al 1992, Drechsel et al 1992, Goedert
et 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 also

phosphorylate 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 only
in vitro evidence to implicate specific kinases and that it remains unclear what role
they play in the in vivo phosphorylation of tau.
Recent data have implicated two protein kinases, GSK-3β and cdk5, in the in
vivo regulation of tau phosphorylation. GSK-3β is a Ser/Thr kinase that is abundant
in brain and associates with MTs (Mandelkow et al 1992, Ishiguro et al 1994, Singh
et al 1995, Takahashi et al 1995, Cohen 1999). Cotransfection of nonneuronal
cells with human tau and GSK-3β induces hyperphosphorylation of tau associated
with 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 a
phosphatidylinositol 3-kinase and protein kinase B–dependent signaling pathway
(Hong & Lee 1997). In addition, direct inhibition of GSK-3β by lithium salts or
ATP competitive inhibitors reduces tau phosphorylation and affects MT stability
(Hong et al 1997, Munoz-Montano et al 1997, Lovestone et al 1999, Takahashi
et al 1999, Leost et al 2000). Cdk5 is a Ser/Thr protein kinase highly enriched in
neurons that colocalizes to the cytoskeleton and contributes to the phosphorylation
of tau (Baumann et al 1993, Kobayashi et al 1993, Lew & Wang 1994). It is
activated by interaction with regulatory subunits, the best characterized of which
is 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 on
the 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 needed
to determine the relative contributions of individual kinases to tau phosphorylation
in vivo.
Because protein phosphatases are required for counterbalancing the effects of
tau protein kinases, they have also been an intense focus of research. A number
of studies have implicated several phosphatases in regulating tau phosphorylation,
including PP1, PP2A, PP2B, and PP2C (reviewed in Billingsley & Kincaid 1997,
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Buée 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 in
human brain tissue, and they dephosphorylate tau in a site-specific manner. Both
enzymes 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 the
major activity toward tau phosphorylated by a number of protein kinases (Goedert
et al 1992a, 1995a). PP1 and PP2A bind to tau, and this interaction is believed
to mediate an association with MTs (Sontag et al 1995, Liao et al 1998). PP2A
has also been demonstrated to bind directly to MTs, an interaction that regulates
its activity in vitro (Sontag et al 1999). Lastly, inhibition of PP1 and PP2A by
okadaic acid in cultured human NT2N neurons results in increased tau phospho-
rylation, accompanied by decreased tau binding to MTs, selective destruction of
stable MTs, and rapid degeneration of axons (Merrick et al 1997). As with the
kinases implicated in the phosphorylation of tau, further studies are necessary to

define the specific role of individual phosphatases in the in vivo regulation of the
phosphorylation state of tau.
AD NEUROFIBRILLARY PATHOLOGY IS MADE OF

ABNORMALLY PHOSPHORYLATED TAU
Filamentous neuronal or neuronal and glial tau inclusions associated with the de-
generation of affected brain regions are the defining neuropathological features of
tauopathies. In AD, NFTs and neuropil thread pathology are found in conjunction
with the deposition of β-amyloid (Aβ) fibrils in the extracellular space. By light
microscopy, the neurofibrillary lesions of AD are stained with anti-tau antibod-
ies (Brion et al 1985, Grundke-Iqbal et al 1986). Ultrastructurally, the dominant
components of neurofibrillary lesions in AD are paired helical filaments (PHFs)
and straight filaments (Kidd 1963). PHFs are composed of two strands of filament
twisted around one another with a periodicity of 80 nm and a width varying from
8 to 20 nm (Crowther & Wischik 1985) whereas straight filaments lack this helical
periodicity (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). Analysis
of PHFs purified from AD brains by sodium dodecyl sulphate–polyacrylamide
gel electrophoresis has revealed three major bands of approximately 68, 64, and
60 kDa, as well as a minor band of approximately 72 kDa (Greenberg & Davies
1990, Lee et al 1991) (Figure 2). Upon dephosphorylation, six bands are resolved
that correspond to the six isoforms of tau found in adult human brain (Lee et al
1991, Greenberg et al 1992, Goedert et al 1992b). The relative proportions of
the 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 (see
Trojanowski & 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 with
phosphorylation-independent anti-tau antibodies. Nondephosphorylated insoluble tau from the
brain 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 and
R406W), runs as three major bands of 68, 64, and 60 kDa and as a minor, variable band of 72
kDa. 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 with
the P301L mutation, the two prominent 68- and 64-kDa insoluble tau bands are detected (the
72-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 is
selective 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 is
deposited 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 isoforms
are expressed in the soluble fraction in PiD. Major tau proteins are depicted by solid bars and the
thickness of the bars correlates with the relative abundance of the specific tau isoform. A dashed
bar 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 isolated
from biopsies of normal human brain (Matsuo et al 1994), it is clear that PHFtau
is hyperphosphorylated and abnormally phosphorylated (Morishima-Kawashima
et al 1995, Hasegawa et al 1996, Hoffmann et al 1997, Zheng-Fischhofer et al
1998).
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Numerous protein kinases and protein phosphatases have been implicated in

the dysregulation of tau phosphorylation in the AD brain (for detailed reviews, see
Billingsley & Kincaid 1997, Buée et al 2000, Hong et al 2000). A recent study has
suggested 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 brains
of AD patients. The calcium-dependent cysteine protease calpain is believed to
generate 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 the
binding of p25 to cdk5 constitutively activated cdk5. Finally, the expression of the
cdk5/p25 complex in various cell lines increased tau phosphorylation and disrupted
the cytoskeletal network. Thus, it is possible that the cdk5/p25 complex may play
a mechanistic role in the conversion of normal tau into PHFtau in AD; however, it
will be important to confirm and extend these results in additional in vitro and in
vivo studies.
The mechanisms underlying PHF formation in neurons are still unclear, but it
is possible that hyperphosphorylation disengages tau from MTs, thereby increas-
ing the pool of unbound tau. Unbound tau may be more resistant to degradation
and more prone to aggregate than MT-bound tau. This suggests that an increased
ability of pathological tau to intereact with MTs may be beneficial. The organic
osmolytes trimethylamine N-oxide and betaine have been shown to increase
tau-promoted assembly of MTs (Tseng & Graves 1998). These compounds were
also shown to restore the ability of tau phosphorylated by cAMP-dependent protein
kinase or GSK-3β to promote MT assembly (Tseng et al 1999). Tau is a highly
flexible, 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 carrying
FTDP-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 MTs
generates some ordered structures, indicating that MTs can induce conformational
changes in tau (Woody et al 1983). Trimethylamine N-oxide and betaine probably
induce a tubulin and/or tau conformational change that favors assembly.
Along related lines, Lu et al (1999) demonstrated that the prolyl isomerase Pin1
binds to a single phosphothreonine residue (Thr231) in tau and that this restored
the ability of tau phosphorylated by cdc2 kinase to intereact with MTs. Pin1 was
reported to copurify with PHFs, resulting in a depletion of soluble Pin1 in AD
brain. Because depletion of Pin1 is believed to induce mitotic arrest and apoptotic
cell death, its sequestration in NFTs could contribute to neurodegeneration.
SYNTHETIC TAU FILAMENTS
Hyperphosphorylation is believed to be an early event in the pathway that leads

from soluble to insoluble and filamentous tau protein (Braak et al 1994). However,
it is unclear whether it is sufficient for assembly into filaments. Currently, there
is no experimental evidence that links hyperphosphorylation of tau to filament
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assembly. The availability of large quantities of recombinant human tau isoforms

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

More recently, experiments using sulphated glycosaminoglycans (GAGs) to
stimulate 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 isoforms

gave filaments with a typical paired-helical-like morphology, when incubated with
heparin or heparan sulphate, whereas assembly of individual 4R-tau isoform gave
filaments with a straight appearance. By immunoelectron microscopy, the paired-
helical-like filaments were decorated by antibodies directed against the amino
and 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-induced
filament assembly (von Bergen et al 2000).
Assembly of tau into filaments in the presence of sulphated GAGs occurs after
a 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 al
1996). However, it has been reported that phosphorylation at other sites, such as
Ser214 and Ser262, is strongly inhibitory toward assembly (Schneider et al 1999).
Subsequent to this work, RNA (Kampers et al 1996, Hasegawa et al 1997) and
arachidonic acid (Wilson & Binder 1997) were also shown to induce the bulk
assembly of full-length recombinant tau into filaments. This work has provided
robust methods for the assembly of full-length tau into filaments. Pathological
colocalization of sulphated GAGs (Snow et al 1990, Goedert et al 1996, Verbeek
et al 1999) and RNA (Ginsberg et al 1998) with hyperphosphorylated tau protein
suggests 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 the
deposition and fibrillization of Aβ peptides to form extracellular senile plaques is
the 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 than
AD, which share an abundant filamentous tau pathology and brain degeneration in
the absence of extracellular amyloid deposits (Table 1). Progressive supranuclear
palsy (PSP), corticobasal degeneration (CBD), and Pick’s disease (PiD) are three
such disorders. A recent consensus conference has classified them as disorders
belonging to a group of diseases known as frontotemporal dementia (FTD) (Pick’s
Conference 2001). Clinically, PSP is characterized by supranuclear gaze palsy as
well 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 is
a high density of fibrillary tau pathology, including neuropil threads, and NFTs that
are typically round or globose (Pollock et al 1986, Hauw et al 1994, Litvan et al
1996). 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 neurofibrillary
lesions has revealed 15- to 18-nm straight filaments, and filaments with a long
periodicity have also been observed (Tellez-Nagel & Wisniewski 1973, Roy et al
1974).
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 high Mr bands
(68 and 64 kDa) are present (the minor 72-kDa band is variably detected) (Flament
et 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 al
1999). They exhibit the same profile of phosphorylation-dependent tau epitopes
as 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 to
be increased in the brainstem but not in the cortex, which is consistent with the
distribution of the neurofibrillary pathology (Chambers et al 1999).
Polymorphisms in the tau gene may contribute to the risk of developing PSP
because a polymorphic dinucleotide repeat in the intron between E9 and E10 of the
tau gene has been linked to PSP (Conrad et al 1997). Subjects with the homozygous
tau allele A0, characterized by 11 TG repeats, were found to be overrepresented in
PSP 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, Morris
et al 1999a). Moreover, two extended tau gene haplotypes consisting of eight
common single-nucleotide polymorphisms in addition to the dinucleotide repeat
polymorphism have been described (Baker et al 1999). The haplotypes are in
complete linkage dysequilibrium and span the entire human tau gene. The more
common haplotype, H1, is significantly overrepresented in Caucasians with PSP.
In addition, two missense mutations in E4a are associated with the H1 haplotype
and 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 and
thus 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 haplotype
and the A0 allele to the pathogenesis of PSP are unknown, but it is possible that
the 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 the
cerebral cortex, deep cerebellar nuclei, and substantia nigra, in association with
prominent neuronal achromasia (Rebeiz et al 1967, 1968). Neuropathological ex-
amination shows depigmentation of the substantia nigra, as well as an asymmetric
frontoparietal atrophy that is often most severe in the pre- and postcentral regions.
In affected regions, there is neuronal loss with spongiosis, gliosis, and prominent
glial 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-immunoreactive

inclusions 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 extensive
accumulation of tau-immunoreactive neuropil threads throughout gray and white
matter (Feany & Dickson 1995, Feany et al 1996). The tau filaments in CBD
include 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 in
that it consists of two major bands of 64 and 68 kDa and a variable, minor band
of 72 kDa (Ksiezak-Reding et al 1994, Buée-Scherrer et al 1996) (Figure 2).
However, the isoforms present in the tau pathology of CBD may differ from those
found in PSP. Antibodies specific for the insert encoded by E3 did not detect the
fibrillary tau pathology in CBD either biochemically or immunohistochemically in
studies 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 study
demonstrated that the fibrillary inclusions in CBD are composed predominantly
of 4R-tau isoforms that also contain the inserts encoded by E2 and to E3. Another
similarity between PSP and CBD was recently described by Di Maria et al (2000),
who showed that CBD is associated with the A0 allele of the tau gene, as well as
the H1 haplotype. Thus, the current biochemical and genetic data strongly suggest
that there is a substantial overlap between PSP and CBD. This is also apparent
with respect to the clinical (Hauw et al 1994) and pathological (Feany et al 1996)
features. Rather than representing two separate and distinct disorders, PSP and
CBD may be different phenotypic manifestations of the same underlying disease
process.
PiD, a variant of FTD, is defined neuropathologically by the presence of tau-
immunoreactive Pick bodies (Constantinidis et al 1974, Pollock et al 1986, Feany
et al 1996, Pick’s Conference 2001). Neuropathologically, it is characterized
by a frontotemporal lobar and limbic atrophy associated with marked neuronal
loss, spongiosis, and gliosis, with ballooned neurons and Pick bodies (Lund &
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Manchester Groups 1994, Dickson 1998). Pick bodies are detected by antibodies
to 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 of
wide, 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 distinct
from that in AD, CBD, and PSP in that it comprises two major bands of 60 and 64
kDa and a variable, minor band of 68 kDa (Buée-Scherrer et al 1996, Delacourte
et al 1996, Lieberman et al 1998) (Figure 2). Because the two major PiD tau
bands appear to lack the MT binding repeat encoded by E10, they are believed
to 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 detected
a signal in Pick bodies and PiD tau using an antibody specific for phosphorylated
Ser262 (Lieberman et al 1998). This may reflect heterogeneity of phosphorylation
at 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-specific
diagnostic 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 appropriate
nomenclature for this form of FTD (Mann 1998). However, this may change
soon because one study has defined this neuropathology more precisely using
quantitative morphometric methods (Arnold et al 2000). Moreover, recent evi-
dence suggests that FTLD (DLDH) may be a novel tauopathy that is caused by
a selective reduction or complete loss of all six brain tau isoforms in affected
and unaffected brain regions (Zhukareva et al 2001). The explanation for this is
enigmatic because there was no concomitant loss of tau mRNA compared with
control and AD brains. Although the majority of FTD patients with FTLD (DLDH)
neuropathology showed a dramatic loss of tau protein in brain regions with and
without neuronal degeneration, others showed less-substantial but still statistically
significant reductions in brain tau levels. Although the pathogenic mechanism un-
derlying this marked reduction in all six brain tau proteins in FTLD (DLDH) is not
known, the consequence of this loss may be similar to the losses of tau function
resulting from some of the tau gene mutations in FTDP-17.
FAMILIAL TAUOPATHIES—FTDP-17 SYNDROMES

The group of syndromes known as FTDP-17 consists of autosomal-dominantly
inherited neurodegenerative diseases with diverse, but overlapping, clinical and
neuropathological features (Foster et al 1997). Neuropathologically, they all show
the 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, Hong
et al 2000). The first such disorder was linked to chromosome 17 in 1994, when
Wilhelmsen et al (1994) described a familial disease they called “disinhibition-
dementia-parkinsonism-amyotrophy complex” and demonstrated genetic linkage
of this disease to chromosome 17q21-22. Subsequently, a number of related neu-
rodegenerative disorders were linked to the same region on chromosome 17 (Wijker
et al 1996, Bird et al 1997, Foster et al 1997, Heutink et al 1997, Murrell et al
1997, Lendon et al 1998). Clinically, they are characterized primarily by FTD and
parkinsonism (Foster et al 1997), but the different FTDP-17 syndromes appear to
reflect the burden of tau pathology and degeneration in brain regions known to
subserve specific cognitive, executive, or motor functions. Despite this pheno-

typic heterogeneity, the neuropathology of FTDP-17 is characterized by marked
neuronal loss in affected brain regions, with extensive neuronal or neuronal and
glial fibrillary pathology composed of hyperphosphorylated tau protein, but with-
out evidence of Aβ deposits or other disease-specific brain lesions in the majority

of the cases (Murrell et al 1999, Lippa et al 2000, Rizzini et al 2000, Spillantini
et al 2000).
Because the tau gene had been localized to chromosome 17q21-22, it was
an obvious candidate for the disease locus. In 1998, several groups identified
pathogenic mutations in the tau gene that segregated with FTDP-17 (Clark et al
1998, Dumanchin et al 1998, Hutton et al 1998, Poorkaj et al 1998, Spillantini
et al 1998c). To date, >20 distinct pathogenic mutations in the tau gene have
been identified in a large number of families with FTDP-17 (Table 2, Figure 3).
Eleven missense mutations in coding regions of the tau 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 al
2000), P301L (Clark et al 1998, Dumanchin et al 1998, Hutton et al 1998, Bird
et 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 al
1999), N296N (Spillantini et al 2000), and S305S (Stanford et al 2000)] as well
as a deletion mutation [1K280 (Rizzu et al 1999)] have also been identified. In
addition, five substitutions in six different positions of the intron following E10
have 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, Hutton
et 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, additional
pathogenic mutations may be present in other introns of the tau gene. Thus, a
mutation in the intron following E9 has been described in a patient with familial
FTD (Rizzu et al 1999). It disrupts one of the several (A/T)GGG repeats that may
play 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, personal
communication
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-like
CBD-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)
a
FTDP-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 frontotemporal

dementia and parkinsonism linked to chromosome 17. The longest human brain tau isoform is
shown with known coding region mutations indicated above. The gray boxes near the amino
terminus represent the alternatively spliced inserts encoded by exons (E)2 and E3, whereas the
black 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 and
the 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 support

in favor of the hypothesis that FTDP-17 mutations lead to tau dysfunction and
disease by one or more of three distinct mechanisms. Intronic and some exonic
mutations affect the alternative splicing of E10 and consequently alter the relative
proportion of 4R-tau and 3R-tau. The other exonic mutations impair the ability
of tau to bind MTs and to promote MT assembly. Some of these mutations also
promote the assembly of tau into filaments. Moreover, additional mechanisms
may 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 50 splice site of
E10, 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 of
these mutations, there is a relative increase in E10-containing tau mRNAs, and this
probably reflects increased utilization of the E10 50 splice site, as demonstrated in
exon trapping experiments. Biochemical analysis of insoluble tau extracted from
autopsied FTDP-17 brain tissue of patients with these mutations reveals exclusively
4R-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 unaffected
regions of FTDP-17 brains (Hong et al 1998, Spillantini et al 1998c, Goedert et al
1999b, Yasuda et al 2000).
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The regulation of splicing of E10 in the tau gene appears to be complex and may
involve multiple cis-acting regulatory elements that either enhance or inhibit the
utilization of the E10 50 splice site, many of which are affected by the mutations
identified in the tau gene (D’Souza et al 1999, Grover et al 1999, D’Souza &
Schellenberg 2000, Gao et al 2000, Jiang et al 2000). Splicing regulatory elements
within E10 appear to include an exon-splicing enhancer (ESE) and an exon splicing
silencer (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-rich
sequence, and an AC-rich sequence (D’Souza & Schellenberg 2000). Immediately
downstream of the ESE within E10 is a purine-rich ESS. The flanking exons of the
tau gene also appear to affect E10 splicing (Gao et al 2000). For example, it appears
that E9 and E11 exert opposite effects, i.e. E9 may promote E10 splicing, whereas
E11 may suppress it. Lastly, intronic sequences immediately downstream of E10
inhibit its splicing (D’Souza et al 1999, Grover et al 1999, D’Souza & Schellenberg
2000, Gao et al 2000, Jiang et al 2000). This inhibition may be secondary to the
formation of a stem-loop structure that sequesters the E10 50 splice site from
the 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 the
three-dimensional structure of a 25-nucleotide-long RNA from the E10 50-intron
junction by nuclear magnetic resonance spectroscopy has shown that this sequence
forms a stable, folded stem-loop structure (Varani et al 1999, 2000). The stem
consists of a single G-C base pair that is separated from a double helix of 6 bp by
an unpaired adenine (Figure 3). As is often the case with single-nucleotide purine
bulges, the unpaired adenine at position −2 does not extrude into solution but
intercalates into the double helix. The apical loop consists of six nucleotides that
adopt multiple conformation in rapid exchange. Known intronic mutations and
the mutations in codon 305 are located in the upper part of the stem and reduce
the thermodynamic stability of the stem loop (Varani et al 1999, 2000; Yasuda
et al 2000). Moreover, the relative proportions of 3R-tau and 4R-tau isoforms
from nonhuman species correlate with the predicted stability of this stem-loop
structure (Grover et al 1999). However, another study has concluded that this ESS
may function as a linear sequence that is independent of a stem-loop structure
(D’Souza & Schellenberg 2000).
Pathogenic FTDP-17 mutations in the tau gene may alter E10 splicing by af-
fecting several of the regulatory elements described above. Thus, the intronic
mutations, 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 al
1999) (Figure 3). The S305N mutation and the +3 intronic mutation may also
enhance E10 splicing by increasing the strength of the 50 splice site (Spillantini
et al 1998c, Iijima et al 1999). However, the finding that the S305S mutation that
weakens the E10 50 splice site also leads to a predominance of 4R-tau argues against
this effect of these mutations (Stanford et al 2000). The N279K mutation may
improve the function of the ESE by lengthening the purine-rich sequence within
this regulatory element (TAAGAA to GAAGAA), thus enhancing E10 splicing
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(D’Souza & Schellenberg 2000). Moreover, the thymidine nucleotide present in

the wild-type (WT) sequence may function as an inhibitor of splicing (Tanaka et al
1994). The observation that the 1K280 mutation, which deletes the three adjacent
purine residues (AAG), abolishes E10 splicing supports this hypothesis (D’Souza
et al 1999). The silent L284L mutation that enhances E10 splicing may do so
by disrupting a potential ESS (UUAG to UCAG) (Si et al 1998, D’Souza et al
1999). However, because mutation of this consensus sequence does not increase
E10 splicing (D’Souza & Schellenberg 2000), a second possibility is that the mu-
tation lengthens the AC-rich element within the ESE. Thus, the L284L mutation
may affect either an enhancing or an inhibiting regulatory splicing element. The
effect of the N296N mutation on splicing of E10 is probably due to disruption of

an 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-tau
and 3R-tau may bind to distinct sites on MTs (Goode & Feinstein 1994, Goode
et al 1997), and it is possible that a specific ratio of tau isoforms is necessary for
normal MT function. Thus, the altered ratio of 3R/4R-tau may directly affect MT
function. In addition, overproduction of 4R-tau may lead to an excess of free tau
in the cytoplasm, leading to its hyperphosphorylation and assembly into filaments.
In contrast to the FTDP-17 mutations discussed above, other mutations alter the
ability of tau to interact with MTs. Specifically, mutations K257T, G272V, 1K280,
P301L, P301S, V337M, G389R, and R406W reduce the binding of tau to MTs
and decrease its ability to promote MT assembly in in vitro assays (Hasegawa
et al 1998, Hong et al 1998, Bugiani et al 1999, D’Souza et al 1999, Murrell
et 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 al
1999). Similar effects on MT function are observed when tau is expressed in a
variety of cell lines, including SHSY5Y neuroblastoma cells (Dayanandan et al
1999), Chinese hamster ovary (CHO) cells (Dayanandan et al 1999, Matsumura
et al 1999, Vogelsberg-Ragaglia et al 2000), monkey kidney (COS) cells (Arawaka
et al 1999, Sahara et al 2000), and Sf9 insect cells (Frappier et al 1999). Expression
of 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 binding
and/or function, both in in vitro assays and in transfected cell lines (DeTure et al
2000, Sahara et al 2000). The discrepancies between these and other studies are
most likely due to the differences in the levels of expression, the methods used for
the quantification of tau levels, and the binding of tau to MTs. Nevertheless, even
if these missense mutations cause only a modest reduction in MT binding affinity,
this could have large cumulative effects on affected neurons over the human life
span. Furthermore, increased cytosolic concentrations of unbound mutant tau pro-
teins may facilitate aggregation of these abnormal proteins, with or without their
WT counterparts, into filamentous inclusions.
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A subset of missense tau gene mutations may cause FTDP-17, at least in part,
by promoting tau aggregation. Several studies have demonstrated that some of
these mutations, including K257T, G272V, 1280K, P301L, P301S, V337M, and
R406W, promote heparin- or arachidonic acid–induced tau filament formation in
vitro relative to WT tau (Arrasate et al 1999, Nacharaju et al 1999, Goedert et al
1999a, 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 the 1K280 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 the 1K280,
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-Ragaglia
et al 2000).
All known mutations in the tau gene lead to the formation of filaments made
of hyperphosphorylated tau protein (Crowther & Goedert 2000). However, the
fibrillary lesions observed with mutations in E10 or the intron following E10 are
biochemically and ultrastructurally distinct from the lesions caused by mutations
that are located outside E10. Coding region mutations located outside E10 affect all
six isoforms of tau. Thus, as one might predict, tau fibrillary lesions are composed
of all six tau isoforms (Hong et al 1998, Murrell et al 1999, Van Swieten et al
1999) (Figure 2). For some mutations (V337M and R406W), the morphologies
and biochemical characteristics of tau filaments are indistinguishable from those
of AD (Spillantini et al 1996, Hong et al 1998, Van Swieten et al 1999). Other
coding region mutations located outside E10 (K252T, G272V, E342V, and G389R)
give rise to a tau pathology that closely resembles that of PiD (Spillantini et al
1998b, 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 aggregation
of 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 filaments
observed in 4R-tau disorders, particularly CBD (Reed et al 1998, Spillantini et al
1998b, 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 disinhibition
dementia 2 (HDDD2), which appears similar to some of the syndromes seen in
FTDP-17 kindreds, has been reported to show linkage to 17q21-22 with a lod
(logarithm of odds) score of 3.68; however, no tau gene mutation or any other
genetic abnormality has been identified in this family (Lendon et al 1998). It is
surprising, however, that recent studies of three brains from affected members of
the HDDD2 kindred revealed that HDDD2 shares significant neuropathological
and biochemical abnormalities with sporadic FTD patients classified as FTLD
(DLDH) (Lendon et al 1998, Zhukareva et al 2001). As discussed above regarding
FTLD (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 may
be controlled posttranscriptionally, either at the level of tau mRNA translation or
through mechanisms that regulate mRNA stability. Thus, the HDDD2 kindred
appears to be the familial counterpart of sporadic FTLD (DLDH), both of which
may define a novel and distinct tauopathy caused by a reduction of brain tau.
Although the biochemical and structural characteristics of the tau aggregates
in 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 phenotypes
and topographical distributions of pathology is more enigmatic. For example, it
is not clear why the clinical and neuropathologic phenotype of individuals with
FTDP-17 mutations ranges from FTD (including subtypes thereof, such as PiD,
CBD, and PSP) to multisystem neurodegeneration. However, some tau gene mu-
tations cause a similar phenotype in different families or in different members of
the same family. For instance, the N279K mutation typically causes a phenotype
reminiscent of PSP with superimposed dementia (Reed et al 1998, Delisle et al

1999, Yasuda et al 1999). In contrast, there are several clinical and pathologic
descriptions of families with the P301L mutation that demonstrate a highly vari-
able phenotype ranging from PSP to CBD to PiD (Spillantini et al 1998b, Bird
et al 1999, Mirra et al 1999, Nasreddine et al 1999). Even more perplexing is the
report of two brothers from one P301L family (Bird et al 1999), with frontal lobe
degeneration in one individual and PSP-like pathology in the other. Similarly, in
a family with the P301S mutation, one individual presented with FTD whereas
his son presented clinically with CBD (Bugiani et al 1999). Although only a few
reports 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 pathologic
distinctions between them may be due to other genetic and/or epigenetic factors
that modify the effects of the primary mutation. Currently, the specific genetic
and/or environmental modifiers that might determine the phenotype of a specific
individual remain unknown, but these are fields of active investigation, and the
generation of animal models of tau-mediated neurodegeneration may facilitate
this 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 of
a variety of neurodegenerative disorders. In addition, they may be useful models
for the development and testing of novel therapies. Early efforts to produce an-
imal models with tau pathology were largely based on the hypothesis that the
development 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 al
1996, Sturchler-Pierrat et al 1997). More recently, several animal models of tau
pathology 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 tau
gene in conjunction with environmental and additional genetic factors initiate pathogenic processes
that cause regional and cell type–specific tau pathology and neurodegeneration, thus leading to
specific clinicopathologic phenotypes. PiD, Pick’s disease; CBD, corticobasal degeneration; PSP,
progressive supranuclear palsy; FTDP-17, frontotemporal dementia and parkinsonism linked to
chromosome 17.
Initial reports described TG mouse lines expressing 4R2N or 3R0N human tau
utilizing cDNA constructs with either the Thy1 or the 3-hydroxy-3-methylglutaryl
coenzyme A reductase promoters (Götz et al 1995, Brion et al 1999). Both lines
developed 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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TABLE 3 Transgenic models of tauopathies

April 7, 2001
1142
Gene Promoter Tau Pathology Phenotype Reference
Tau, 4R/2N Thy1 Somatodendritic tau expression Normal Götz et al (1995)

LEE
15:58
Tau, 3R/0N HMG-CoA Somatodendritic tau expression Brion et al (1999)

reductase
Tau, 3R/0N Prion protein Somatodendritic tau expression; tau Axonopathy with Ishihara et al
immunoreactive spheroids in brain muscle weakness (1999, 2001)
GOEDERT
and spinal cord; neurofibrillary

¥
tangles in brain at 18 months or older

Tau, 4R/2N Thy1 Somatodendritic tau expression; tau Axonopathy with sensori- Spittaels et al
Annual Reviews
immunoreactive spheroids in brain motor dysfunction (1999)

and spinal cord
Tau, 4R/2N Thy1 Somatodendritic tau expression; tau Axonopathy with Probst et al (2000)
immunoreactive spheroids in brain muscle weakness
TROJANOWSKI
and spinal cord

AR121-37
Tau, 4R/0N, Prion protein Neurofibrillary tangles in brain and spinal Motor and behavioral Lewis et al (2000)
P301L cord; somatodendritic tau expression deficits; amyotrophy
Tau, 4R/2N, Thy1 Neurofibrillary tangles in brain and spinal Götz et al (2001)
P301L cord; somatodendritic tau expression
Tau, genomic Endogenous Axonal expression Normal Duff et al (2000)
ApoE4 Multiple Phosphorylated tau expression in Motor dysfunction Tesseur et al (2000)
neocortex, hippocampus, and amygdala and amyotrophy
p25 Neuron specific Phosphorylated tau expression in Increased loco- Ahlijanian
enolase cortex, amygdala, and thalamus motor activity et al (2000)
Anti-NGF Cytomegalovirus Phosphorylated tau expression in Spatial memory and Capsoni
IgH/Igκ early region cortex and hippocampus with object recognition et al (2000)
associated neuron loss impairment
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finding that massive overexpression of 4R/2N human tau in lamprey reticulospinal

neurons led to the formation of PHF-like tau inclusions with degeneration of a
subset of these neurons (Hall et al 1997, 2000). Subsequently, a series of papers
has described lines of TG mice expressing high levels of 3R/0N or 4R/2N human
tau 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 bodies
and dendrites and large numbers of pathologically enlarged axons containing tau-
immunoreactive spheroids. These changes were most prominent in spinal cord but
were also seen in brain. They were accompanied by histological and behavioral
signs of amytrophy. Mice doubly transgenic for 4R2N tau and GSK-3β showed
increased levels of tau phosphorylation and a marked reduction in the number of
spheroids 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 resembles
that observed in the amyotrophic lateral sclerosis/parkinsonism–dementia complex
(Matsumoto et al 1990), it differs in several respects from that found in human
diseases. 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 S
and do not bind Gallyas silver. However, a recent report has shown that as these
tau TG mice aged to over 18 months, modest numbers of filamentous tau tangles
with similar properties to those found in AD could be detected in hippocampus
and entorhinal cortex (Ishihara et al 2001). Moreover, like NFTs in AD, the tau
tangles in these aged mice were ubiquitinated, did not contain neurofilaments or
tubulin, and were detected by Congo red, Thioflavin S, and Gallyas silver staining
methods. It is interesting that mice transgenic for the entire human tau gene ex-
pressed all six tau isoforms but failed to develop significant pathology (Duff et al
2000).
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 tau
with and without the P301L mutation. In contrast to mice expressing WT tau, mice
expressing tau with the P301L mutation exhibited an age- and gene dose-dependent
accumulation of tau tangles in both brain and spinal cord, with associated nerve cell
loss and reactive gliosis. Similar results have been reported by Götz et al (2001)
in TG lines expressing 4R2N tau with the P301L mutation. The tau tangles found
in these mice appeared to comprise only the mutant human tau, which suggests
that the P301L mutation probably causes neurodegeneration by promoting the ag-
gregation of the mutant tau. This is supported by recent biochemical studies using
antibodies specific for P301L tau that demonstrated recovery of mutant but not
WT tau from the insoluble fraction isolated from brain tissue of individuals with
the P301L tau gene mutation (Rizzu et al 2000).
Other approaches to the development of tau pathology in TG mice have made
use 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 architecture

and behavioral alterations (Ahlijanian et al 2000). However, there was no biochem-
ical evidence of an accumulation of insoluble, hyperphosphorylated tau in these
mice. TG mice expressing apolipoprotein E4, an allelic risk factor for sporadic
AD (Corder et al 1993), showed an age-dependent increase in tau phosphorylation
that 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-dependent
neurodegenerative pathology, including neuronal loss and hyperphosphorylated,
insoluble tau in cortex and hippocampus (Capsoni et al 2000). However, as for

the apolipoprotein E4 TG mice described above, no evidence of fibrillary tau
pathology was presented. In summary, although several TG mouse models show
features of various tau-related disorders, they still fall short of demonstrating the
entire 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 distinct
topographic and cell type–specific distributions of inclusions. The biochemical
and ultrastructural characteristics of the tau abnormalities, which are frequently
related to the inclusion or exclusion of E10, also reveal a significant phenotypic
overlap. The discovery of multiple mutations in the tau gene that lead to the ab-
normal aggregation of tau and cause FTDP-17 demonstrates that tau dysfunction
is sufficient to produce neurodegenerative disease. The mutations lead to specific
cellular alterations, including altered expression, function, and biochemistry of tau
protein. The finding that specific polymorphisms and mutations lead to diverse
phenotypes raises the possibility that the clinical and pathological expression of
these 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 function
of MTs and interferes with axonal transport. It remains to be established whether
a protein kinase/phosphatase imbalance is an early mechanistic step leading to the
generation of filamentous tau in some tauopathies. Genetic and/or environmental
factors could initiate a cascade of events that leads to the abnormal phosphorylation
of tau through incompletely defined pathways (Figure 4). It also remains to be
seen whether the mere presence of tau filaments inside brain cells is sufficient to
cause them to die. Similarly, the precise mechanisms by which tau protein assem-
bles into filaments in human brain remain to be discovered. Further investigation
into the mechanisms of tau dysfunction, as well as the identification of potential
disease-modifying factors, will provide additional insight into novel strategies for
disease treatment and prevention. The development of additional animal models
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of tauopathies that more closely recapitulate human diseases will facilitate this
undertaking.
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 of
filamentous proteins. Abnormal protein aggregation is observed in a large number
of neurodegenerative disorders (Prusiner 1998, Goedert et al 1998, Trojanowski
et al 1998). Thus, besides tau pathology, AD is characterized by the extracellular
accumulation of Aβ fibrils in the form of amyloid plaques; Lewy body disorders
contain intracytoplasmic filamentous aggregates of α-synuclein; trinucleotide re-
peat disorders have intranuclear inclusions composed of fibrous polyglutamines;
and spongiform encephalopathies demonstrate aggregates of proteinase-resistant

prion protein. Aggregation of proteins in the brain is a common theme in a diverse
group of disorders, and insight into the pathogenesis of any one of these disorders
may have implications for our understanding of the mechanisms that underlie all
these diseases.
ACKNOWLEDGMENTS
VM-YL is the John H Ware third Chair of Alzheimer’s disease research at the
University of Pennsylvania. Work done in our laboratories is supported by grants
from the National Institute of Aging of the National Institutes of Health, the Dana
Foundation, the US Alzheimer’s Association, the UK Medical Research Council,
and the UK Alzheimer’s Research Trust. We thank Drs. MS Forman and V van
Deerlin for their input.
Visit the Annual Reviews home page at www.AnnualReviews.org
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Annual Review of Neuroscience
Volume 24, 2001
CONTENTS
PDZ DOMAINS AND THE ORGANIZATION OF
1
SUPRAMOLECULAR COMPLEXES, Morgan Sheng, Carlo Sala
THE ROLE AND REGULATION OF ADENOSINE IN THE CENTRAL 31

NERVOUS SYSTEM, Thomas V. Dunwiddie, Susan A. Masino
LOCALIZATION AND GLOBALIZATION IN CONSCIOUS VISION,
57
S. Zeki
GLIAL CONTROL OF NEURONAL DEVELOPMENT, Greg Lemke 87
TOUCH AND GO: Decision-Making Mechanisms in Somatosensation,
107
Ranulfo Romo, Emilio Salinas
SYNAPTIC MODIFICATION BY CORRELATED ACTIVITY: Hebb''s
139
Postulate Revisited, Guo-qiang Bi, Mu-ming Poo

AN INTEGRATIVE THEORY OF PREFRONTAL CORTEX
167
FUNCTION, Earl K. Miller, Jonathan D. Cohen
THE PHYSIOLOGY OF STEREOPSIS, B. G. Cumming, G. C.
203
DeAngelis
PARANEOPLASTIC NEUROLOGIC DISEASE ANTIGENS: RNA-
Binding Proteins and Signaling Proteins in Neuronal Degeneration, Kiran 239
Musunuru, Robert B. Darnell
ODOR ENCODING AS AN ACTIVE, DYNAMICAL PROCESS:
Experiments, Computation, and Theory, Gilles Laurent, Mark Stopfer,
263
Rainer W Friedrich, Misha I Rabinovich, Alexander Volkovskii, Henry
DI Abarbanel
PROTEIN SYNTHESIS AT SYNAPTIC SITES ON DENDRITES,
299
Oswald Steward, Erin M. Schuman
SIGNALING AND TRANSCRIPTIONAL MECHANISMS IN 327

PITUITARY DEVELOPMENT, Jeremy S. Dasen, Michael G. Rosenfeld
NEUROPEPTIDES AND THE INTEGRATION OF MOTOR
357
RESPONSES TO DEHYDRATION , Alan G. Watts
THE DEVELOPMENTAL BIOLOGY OF BRAIN TUMORS, Robert
385
Wechsler-Reya, Matthew P. Scott
TO EAT OR TO SLEEP? OREXIN IN THE REGULATION OF
FEEDING AND WAKEFULNESS, Jon T. Willie, Richard M. Chemelli, 429
Christopher M. Sinton, Masashi Yanagisawa
SPATIAL PROCESSING IN THE BRAIN: The Activity of Hippocampal
459
Place Cells, Phillip J. Best, Aaron M. White, Ali Minai
THE VANILLOID RECEPTOR: A Molecular Gateway to the Pain
487
Pathway, Michael J Caterina, David Julius
PRION DISEASES OF HUMANS AND ANIMALS: Their Causes and
519
Molecular Basis, John Collinge
VIKTOR HAMBURGER AND RITA LEVI-MONTALCINI: The Path to
551
the Discovery of Nerve Growth Factor, W. Maxwell Cowan
EARLY DAYS OF THE NERVE GROWTH FACTOR PROTEINS,
601
Eric M. Shooter
SEQUENTIAL ORGANIZATION OF MULTIPLE MOVEMENTS:
631
Involvement of Cortical Motor Areas, Jun Tanji
INFLUENCE OF DENDRITIC CONDUCTANCES ON THE INPUT-
653
OUTPUT PROPERTIES OF NEURONS, Alex Reyes
NEUROTROPHINS: Roles in Neuronal Development and Function, Eric
677
J Huang, Louis F Reichardt
CONTRIBUTIONS OF THE MEDULLARY RAPHE AND
VENTROMEDIAL RETICULAR REGION TO PAIN MODULATION 737
AND OTHER HOMEOSTATIC FUNCTIONS, Peggy Mason
ACTIVATION, DEACTIVATION, AND ADAPTATION IN
VERTEBRATE PHOTORECEPTOR CELLS, Marie E Burns, Denis A
Baylor 779
ACTIVITY-DEPENDENT SPINAL CORD PLASTICITY IN HEALTH
AND DISEASE, Jonathan R Wolpaw, Ann M Tennissen 807
QUANTITATIVE GENETICS AND MOUSE BEHAVIOR, Jeanne M
845
Wehner, Richard A Radcliffe, Barbara J Bowers
EARLY ANTERIOR/POSTERIOR PATTERNING OF THE
869
MIDBRAIN AND CEREBELLUM, Aimin Liu, Alexandra L Joyner
NEUROBIOLOGY OF PAVLOVIAN FEAR CONDITIONING, Stephen
897
Maren
{{alpha}}-LATROTOXIN AND ITS RECEPTORS: Neurexins and
CIRL/Latrophilins, Thomas C Südhof 933

IMAGING AND CODING IN THE OLFACTORY SYSTEM, John S
963
Kauer, Joel White
THE ROLE OF THE CEREBELLUM IN VOLUNTARY EYE
981
MOVEMENTS, Farrel R Robinson, Albert F Fuchs
ROLE OF THE REELIN SIGNALING PATHWAY IN CENTRAL
1005
NERVOUS SYSTEM DEVELOPMENT, Dennis S Rice, Tom Curran
HUMAN BRAIN MALFORMATIONS AND THEIR LESSONS FOR
1041
NEURONAL MIGRATION, M Elizabeth Ross, Christopher A Walsh
MORPHOLOGICAL CHANGES IN DENDRITIC SPINES
ASSOCIATED WITH LONG-TERM SYNAPTIC PLASTICITY, Rafael 1071
Yuste, Tobias Bonhoeffer
STOPPING TIME: The Genetics of Fly and Mouse Circadian Clocks, 1091
Ravi Allada, Patrick Emery, Joseph S. Takahashi, Michael Rosbash
NEURODEGENERATIVE TAUOPATHIES, Virginia M-Y Lee, Michel
1121
Goedert, John Q Trojanowski
MATERNAL CARE, GENE EXPRESSION, AND THE
TRANSMISSION OF INDIVIDUAL DIFFERENCES IN STRESS 1161
REACTIVITY ACROSS GENERATIONS, Michael J Meaney
NATURAL IMAGE STATISTICS AND NEURAL
1193
REPRESENTATION, Eero P Simoncelli, Bruno A Olshausen
Nerve Growth Factor Signaling, Neuroprotection, and Neural Repair,
1217
Michael V Sofroniew, Charles L Howe, William C Mobley
FLIES, GENES, AND LEARNING, Scott Waddell, William G Quinn 1283

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P1: FUM

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

Annu. Rev. Neurosci. 2001. 24:1121–159

Pennsylvania 19104; e-mail: vmylee@mail.med.upenn.edu,

CB2 2QH, United Kingdom; e-mail: mg@mrc-lmb.cam.ac.uk

Key Words Alzheimer’s disease, frontotemporal dementia, mutation,

1122 LEE ¥ GOEDERT ¥ TROJANOWSKI

movement disorders that are characterized neuropathologically by prominent intra-

dementia and parkinsonism linked to chromosome 17 (FTDP-17), thereby pro-

TABLE 1 Diseases with tau-based neurofibrillary pathology

NEW INSIGHTS INTO TAUOPATHIES 1123

investigating the role of tau abnormalities in mechanisms of brain dysfunction and

of human neurodegenerative tauopathies.

STRUCTURE, FUNCTION, AND MOLECULAR

1124 LEE ¥ GOEDERT ¥ TROJANOWSKI

NEW INSIGHTS INTO TAUOPATHIES 1125

TAU PHOSPHORYLATION AND REGULATION

more highly phosphorylated in embryonic compared with adult CNS (Kanemaru

1126 LEE ¥ GOEDERT ¥ TROJANOWSKI

phosphorylation. It remains to be seen whether this finding can be extended to

Mandelkow et al 1992), cyclin-dependent kinase 2 (cdk2) (Baumann et al 1993),

In addition, several members of the family of stress-activated protein kinases also

NEW INSIGHTS INTO TAUOPATHIES 1127

kinases implicated in the phosphorylation of tau, further studies are necessary to

AD NEUROFIBRILLARY PATHOLOGY IS MADE OF

1128 LEE ¥ GOEDERT ¥ TROJANOWSKI

NEW INSIGHTS INTO TAUOPATHIES 1129

Numerous protein kinases and protein phosphatases have been implicated in

SYNTHETIC TAU FILAMENTS

Hyperphosphorylation is believed to be an early event in the pathway that leads

1130 LEE ¥ GOEDERT ¥ TROJANOWSKI

assembly. The availability of large quantities of recombinant human tau isoforms

of full-length tau protein (Goedert et al 1992b).

(Goedert et al 1996, Perez et al 1996). Assembly of individual 3R-tau isoforms

NEW INSIGHTS INTO TAUOPATHIES 1131

1991). Compelling evidence in support of a causative pathologic role of tau pro-

1132 LEE ¥ GOEDERT ¥ TROJANOWSKI

cytic plaques (Feany & Dickson 1995), as well as numerous tau-immunoreactive

NEW INSIGHTS INTO TAUOPATHIES 1133

FAMILIAL TAUOPATHIES—FTDP-17 SYNDROMES

1134 LEE ¥ GOEDERT ¥ TROJANOWSKI

subserve specific cognitive, executive, or motor functions. Despite this pheno-

out evidence of Aβ deposits or other disease-specific brain lesions in the majority

NEW INSIGHTS INTO TAUOPATHIES 1135

TABLE 2 Tau mutations identified in FTDP-17a

K257T E9, R1 No change Reduced PiD-like Pickering-Brown et al

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

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

1136 LEE ¥ GOEDERT ¥ TROJANOWSKI

Figure 3 Schematic representation of mutations in the tau gene identified in frontotemporal

Data emerging from several laboratories continue to add increasing support

NEW INSIGHTS INTO TAUOPATHIES 1137

1138 LEE ¥ GOEDERT ¥ TROJANOWSKI

(D’Souza & Schellenberg 2000). Moreover, the thymidine nucleotide present in

effect of the N296N mutation on splicing of E10 is probably due to disruption of

NEW INSIGHTS INTO TAUOPATHIES 1139

1140 LEE ¥ GOEDERT ¥ TROJANOWSKI

reminiscent of PSP with superimposed dementia (Reed et al 1998, Delisle et al

EXPERIMENTAL ANIMAL MODELS OF TAUOPATHIES

NEW INSIGHTS INTO TAUOPATHIES 1141

TABLE 3 Transgenic models of tauopathies

Gene Promoter Tau Pathology Phenotype Reference

Tau, 4R/2N Thy1 Somatodendritic tau expression Normal Götz et al (1995)

Tau, 3R/0N HMG-CoA Somatodendritic tau expression Brion et al (1999)