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© 2007 Nature Publishing Group
A growing body of evidence suggests that the genera-
tion of proteinaceous aggregates is a common patho-
logical process in numerous neurodegenerative diseases.
Indeed, not only is the defining characteristic of several
neurodegenerative diseases the accumulation of pro-
teinacious fibrillary substances (such as senile plaques
(SPs) made of β-amyloid (Aβ), or neurofibrillary tan-
gles (NFTs) made of tau), but significant circumstantial
evidence also clearly implicates these aggregates in the
onset and progression of most aging-related neuro-
degenerative disorders that manifest clinically with
progressive cognitive and/or motor impairments. In
the case of neurodegenerative tauopathies — a group of
disorders that includes Alzheimer’s disease (AD) and the
frontotemporal dementias (FTDs) — NFTs consisting
of aggregated straight or paired helical filaments (SFs
and PHFs, respectively), twisted ribbons or other con-
formations
1
of aberrantly phosphorylated forms of the
microtubule-associated protein (MAP) tau are the diag
-
nostic hallmark lesions in the CNS. Although the precise
role of these and other specific diagnostic lesions in the
different stages of neurodegenerative disease pathology
is not yet fully understood, it is increasingly evident
that tau-mediated neurodegeneration may result from
the combination of toxic gains-of-function acquired
by the aggregates or their precursors and the detrimental
effects that arise from the loss of the normal function(s)
of tau in the disease state. Elucidating the exact roles of
the different aggregates and their precursors in neuro-
degeneration is a challenging endeavor, but one that is
likely to remain the focus of future research efforts to
discover the mechanisms of disease pathology, as well as
to develop better diagnostics and therapeutics.
Thus far, several lines of investigation have suggested
different, and at times contradictory, cause-and-effect
relationships between various pathological species
of disease proteins and the aggregates that they form.
These apparent contradictions may reflect the limita-
tions inherent in each of the in vitro and in vivo model
systems that are used to study specific disorders, includ-
ing neurodegenerative tauopathies. For example, the
realization that the neurotoxic species that contribute
to disease onset and progression may be ‘hidden’ in one
or more of the pre-aggregated/pre-fibrillar forms of the
misfolded protein clearly complicates both experimental
design and the unambiguous interpretation of results.
Moreover, added complexity may come from the fact
that, aside from its well-established role in promoting
the stabilization of microtubules (MTs), tau may have
additional functions as a result of its interactions with
other structures and enzymes
1
(for example, with the
plasma membrane
2,3
, the actin cytoskeleton
4
and with src
tyrosine kinases such as FYN
5
(see below)). Such poorly-
defined interactions and functions of tau contribute to
the difficulty of understanding how pathologically altered
tau mediates neurodegeneration, and more studies
*Center for
Neurodegenerative Disease
Research, Department of
Pathology and Laboratory
Medicine, University of
Pennsylvania, 3600 Spruce
Street, Philadelphia,
Pennsylvania 19104-4283,
USA.
‡
Institute on Aging,
University of Pennsylvania,
3615 Chestnut Street,
Philadelphia, Pennsylvania
19104-2676, USA.
§
Department of Chemistry,
University of Pennsylvania,
231 South 34th Street,
Philadelphia, Pennsylvania
19104-6323, USA.
Correspondence to J.Q.T.
e-mail: trojanow@mail.med.
upenn.edu
doi:10.1038/nrn2194
Published online
8 August 2007
Senile plaque
A site of Aβ accumulation and
dystrophic neurites in the
brains of mouse models and
patients with Alzheimer’s
disease.
Tau-mediated neurodegeneration
in Alzheimer’s disease and related
disorders
Carlo Ballatore*
§
, Virginia M.-Y. Lee*
‡
and John Q. Trojanowski*
‡
Abstract | Advances in our understanding of the mechanisms of tau-mediated
neurodegeneration in Alzheimer’s disease (AD) and related tauopathies, which are
characterized by prominent CNS accumulations of fibrillar tau inclusions, are rapidly moving
this previously underexplored disease pathway to centre stage for disease-modifying drug
discovery efforts. However, controversies abound concerning whether or not the deleterious
effects of tau pathologies result from toxic gains-of-function by pathological tau or from
critical losses of normal tau function in the disease state. This Review summarizes the most
recent advances in our knowledge of the mechanisms of tau-mediated neurodegeneration
to forge an integrated concept of those tau-linked disease processes that drive the onset and
progression of AD and related tauopathies.
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Mechanisms possibly involved in
tau hyperphosphorylation
Direct events
• Upregulation or abberant
activation of tau kinases
• Downregulation of phosphatases
• Mutations
• Covalent modifications of tau
• Others?
Indirect events
• Aβ-mediated toxicity
• Oxidative stress
• Inflammation
• Others?
Neurotoxicity
Compromised axonal
transport
Loss of function
Toxic gains-of-function
NFTs made of hyperphosphorylated
tau sequester normal tau
Hyperphosphorylated tau
Detachment from MTs;
loss of MT-stabilizing function
Changes in
MT dynamics
NFTs become physical obstacles to the
transport of vesicles and other cargoes
Alternative splicing
The process by which introns
are excised from RNA after
transcription and the cut ends
of the RNA are rejoined to form
a continuous message.
Alternative splicing allows the
production of different
messages from the same DNA
molecule.
are needed in order to elucidate these mechanisms. In
addition, because disease onset and progression are
dynamic processes that take place over time (often over
several years), it is conceivable that processes such as
the aggregation of altered tau may produce a range of
different effects at various stages of the disease.
Given the complexities of this research, it is timely to
critically analyse the progress made towards a mechanis-
tic understanding of tau-mediated neurodegeneration,
and to discuss the therapeutic strategies that target the
most severe toxic consequences of tau pathologies. To
that end, our goal is to summarize the current under-
standing of normal tau functions and the pathogenesis
of tau aggregates in AD and related neurodegenerative
tauopathies, as well as their significance to the onset and
progression of these disorders (FIG. 1). We also provide an
overview of the animal models of tau-mediated neuro
-
degeneration (BOX 1; TABLE 1), and discuss tau-directed
drug-discovery efforts (
BOX 2; TABLE 2).
Physiological functions of tau
The primary function of the MAP tau, which is par-
ticularly abundant in the axons of neurons, is to stabi-
lize MTs. As summarized in FIG. 2, there are six major
isoforms of tau expressed in the adult human brain, all
of which are derived from a single gene by alternative
splicing. From a structural stand-point, tau is character-
ized by the presence of a MT-binding domain, which
is composed of repeats of a highly conserved tubulin-
binding motif
6
and which comprises the carboxy-
terminal (C-terminal) half of the protein, followed by a
basic proline-rich region and an acidic amino-terminal
(N-terminal) region, which is normally referred to as the
‘projection domain’. The six tau isoforms differ from each
other in the number of tubulin-binding repeats (either
three or four, hence the isoforms are normally referred
to as 3R and 4R tau isoforms, respectively) and in the
presence or absence of either one or two 29 amino-acid-
long inserts at the N-terminal portion of the protein,
which is not instrumental for MT-binding
7
. Although
the six isoforms appear to be broadly functionally
similar, each is likely to have precise, and to some extent
distinctive, physiological roles. The various isoforms
appear to be differentially expressed during develop-
ment, however, the 3R and 4R tau isoforms are expressed
in a one-to-one ratio in most regions of the adult
brain, and deviations from this ratio are characteristic
of neurodegenerative FTD tauopathies
8
.
Several lines of investigation substantiate a model
whereby the tubulin-binding repeats bind to specific
pockets in β-tubulin at the inner surface of the MTs,
whereas the positively charged proline-rich regions are
Figure 1 | Direct and indirect pathological events that can contribute to tau-mediated neurodegeneration.
Pathological events that can contribute to tau-hyperphosphorylation and detachment from microtubules are shown in the
box on the left. The middle box shows the mechanisms that underlie the loss of normal function and toxic gain-of-function
of tau, which ultimately result in impaired axonal transport and lead to synaptic dysfunction and neurodegeneration (right
hand box). Aβ, amyloid-β; MT, microtubule; NFT, neurofibrillary tangle.
Box 1 | Animal models of tau pathology
The use of invertebrates and rodents in reproductions of
human neurodegenerative diseases that affect higher
cognitive functions over an extended period of time
(decades), although faced with numerous challenges, has
been undeniably instrumental in gaining insights into the
mechanisms that underlie these diseases
64,75-77
. Indeed,
although none of the available models is capable of
recapitulating all the features of tangle pathology that are
found in the human brain, various transgenic models
(TABLE 1) are capable of reproducing different features of
Alzheimer’s disease (AD) in humans, and triple-transgenic
mice can now reproduce multiple signature lesions such
as plaques and NFTs in the same animal model. As such,
these transgenic animal models comprise the most
effective tool available to date for studying AD and
related tauopathies. Some of the commonly used
transgenic animal models are typically associated with the
development of motor impairments, which can severely
limit the use of these models in behavioural tests.
However, recent lines of research
78
have led to the
development of transgenic tauopathy models that have
no overt signs of motor deficits. These particular models
will certainly be invaluable for evaluating the effects of
candidate drugs on cognitive decline.
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tightly bound to the negatively charged MT-surface,
and the negatively charged projection domain
branches away from the MT-surface, possibly owing to
electrostatic repulsion
9,10
. Interestingly, it was found
that the MT-binding domain of tau, and several
MT-stabilizing drugs, including paclitaxel, epothilone
and discodermolide, seem to share, either completely
or in part, the same binding pockets in the β-tubulin
9,11
.
Although the occupation of these pockets by tau, other
MAPs or MT-stabilizing drugs is thought to be sufficient
to maintain the tubulin conformations that promote the
polymerized state, MAPs, unlike MT-stabilizing agents,
may also contribute to MT-stabilization in other ways.
It is believed that the β-tubulin pockets of adjacent
protofilaments may be occupied by the different repeats
of the same MT-binding domain of tau, thereby causing
the crosslinking of three or four dimers
9
. In addition,
interactions of the proline-rich region of tau with the
surface of the MTs are likely to further contribute to
MT stabilization.
Interestingly, although the primary function of the
MT-binding domain of tau is the stabilization of MTs,
various lines of investigation have indicated that it may
also engage with other structures and enzymes, includ-
ing RNA
12
and presenilin 1 (PS1)
13
. Similarly, numerous
possible binding partners have been proposed for both
the proline-rich and the projection domains (the SH3
domains of src-family tyrosine kinases such as FYN
5,
and the plasma membrane
2,3
, respectively). Although
the importance of these specific interactions of tau
with partner structures other than the MTs is not yet
known in the context of tau-mediated neurodegenera
-
tion, collectively these findings support the notion that
tau might be a rather promiscuous binder that is prone
Table 1 | Commonly used transgenic mouse models of tau pathology
Gene Mutation/construct Promoter Tau pathology Refs
Mapt 4R/2N isoform Thy1 Hyperphosphorylated PHFs 82
Axonopathy without formation of neuronal NFTs 83
Axonopathy containing neurofilament- and
tau-immunoreactive spheroids, especially in the
spinal cord
84
Fetal tau (3R/0N isoform) Prion protein promoter NFTs in the brain at 18 months of age 56,85
P301L Prion protein promoter Tangle pathology detectable at 2.5 months of age 60,86
P301L Thy1.2 Tangle pathology detectable at 3 months of age 87
Inducible overexpression
of P301L
Ca
2+
–calmodulin-dependent
kinase II
Tangle pathology detectable at 2.5 months of age 13
Genomic tau Endogenous Tau-immunoreactive axonal swellings 88
G272V Prion protein promoter Oligodendroglial fibrillary lesions 89
P301S Thy1.2 Tau pathology detectable at 5 months of age 90
G272V P301L R406W Thy1 Tau pathology detectable at 1.5 months of age.
No motor impairment observed for up to 12 months
after birth
91
V337M
PDGF-β
Mutant tau induces neuronal degeneration,
associated with the accumulation of RNA and
phosphorylated tau
92
R406W Ca
2+
–calmodulin-dependent
kinase II
Hyperphosphorylated tau inclusions appear
in the forebrain at 18 months of age. No motor
abnormalities for up to 23 months after birth
93
G272V P301S Thy1.2 Hyperphosphorylated tau, tangles and PHFs.
No motor impairment for up to 18 months after birth
78
P301S Prion protein promoter This model recapitulates tauopathy, including early
indications of degeneration, such as synapse loss
and microglia activation
63
Apolipoprotein E (Apoe) ApoE4 Multiple Phosphorylated tau expression in the neocortex,
the hippocampus and the amygdala
94
Cdk5r1 p25 Neuron-specific enolase Phosphorylated tau expression in the cortex,
the amygdala and the thalamus
95
VKαD11HuCk and
VKαD11HuCγ
Anti-NGF IgH/Igk
Cytomegalovirus early region Phosphorylated tau expression in the cortex and
the hippocampus, with associated neuron loss
96
App, Psen1, and Mapt PS1 (M146V), APP (Swe),
tau (P301L)
Thy1.2
Both tau and Aβ pathology
97,98
All transgenic mice overexpressed their transgenic protein. VK
α
D11HuC
k
and VK
α
D11HuC
γ
carried the light and heavy chain genes of the chimeric antibodies
αD11, respectively. Aβ, amyloid-β; App, amyloid-b precursor protein; Ig, immunoglobulin; NFT, neurofibrillary tangle; NGF, nerve growth factor; PDGF-β, platelet-
derived growth factor-β; PHF, paired helical filament; PS1, presenilin 1.
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to heterogeneous interactions — particularly when
disengaged from the MT — which may lead to protein
misfolding and aggregation
14
.
The MT-binding ability of tau is post-translationally
regulated primarily by serine/threonine-directed phos
-
phorylation (FIG. 3), which can effectively modulate the
binding affinity of tau for MTs
15
. This is thought to be
the most prominent mechanism that regulates the affinity
of tau for the MTs
15
, although other post-translational
modifications, such as glycosylation
16–18
, may also have
a direct impact on the dynamic equilibrium of tau on
and off the MTs (see below). Notably, phosphoryla-
tion of tau appears to be developmentally regulated
— it is substantially higher during the development of
the fetal brain. On the other hand, in the adult brain,
neurons are normally characterized by a considerably
lower tau phosphorylation state. Furthermore, in the
course of tau-mediated neurodegeneration, aberrant tau
phosphorylation is always observed (see below).
Aside from phosphorylation and glycosylation, other
post-translational modifications of tau also occur
(see REF. 19 for a recent review), including glycation
20
,
ubiquitylation
21
, sumoylation
22,23
, nitration
24
and
proteolysis
25
. Although it is conceivable that most or all
of these post-translational modifications may take place
at various stages of tau pathology, their significance,
particularly in comparison to the well-established role
of phosphorylation, is yet to be fully characterized.
With its ability to modulate MT-dynamics, tau
contributes directly or indirectly to key structural and reg-
ulatory cellular functions. For example, the action of tau on
the MT network has great importance in maintaining an
appropriate morphology of neurons, the processes of which
typically extend over relatively great distances, making
neurons the most asymmetrical of all cells. Furthermore,
because the MT network is key to the sophisticated trans-
port machinery (FIG. 3) that allows signalling molecules,
trophic factors and other essential cellular constituents,
including organelles (for example mitochondria and
vesicles), to travel along the axons (axonal transport), then
tau clearly has profound effects on axonal transport and,
hence, on the function and viability of neurons and their
highly extended processes
26
. Importantly, under normal
physiological conditions, tau is in a constant dynamic
equilibrium, on and off the MTs. This equilibrium is
thought to be controlled primarily by the phosphorylation
state of tau, which in turn is determined by the actions
of kinases and phosphatases. Indeed, frequent cycles of
binding and detachment of tau from the MTs (corre-
sponding to phosphorylations and dephosphorylations,
respectively) may be needed to allow effective axonal
transport (FIG. 3).
Pathological aggregation of tau
Under pathological conditions, the equilibrium of tau
binding to the MTs is perturbed, resulting in an abnor-
mal increase in the levels of the free (unbound) tau
Table 2 | Therapeutic strategies targeting tau that are currently under investigation
Therapeutic approach Expected effect Current status Refs
Kinase inhibition Prevent the abnormal phosphorylation rate
or state of tau and consequent excessive
disengagement of tau from the MTs
Various stages of preclinical investigation 15,37
Inhibition of tau fibril formation or
dissolution of pre-existing aggregates
Prevent aberrantly phosphorylated
and/or misfolded tau from forming more
organized aggregates
Early stages of drug discovery 67–69,71,99
Activation of chaperone systems Facilitate the clearance of misfolded tau
and/or tau aggregates
Early stages of preclinical investigation 100,101
Stabilization of the MTs Compensate for the loss of tau’s
MT-stabilizing function, and thereby
sustain axonal transport
Different programmes are at various stages
of development, ranging from preclinical
investigations to Phase II studies
55,57,102
Aβ-directed therapies Prevent Aβ from contributing to
tau-mediated neurodegeneration
Several compounds in Phase I and Phase II
studies
75
Attenuation of inflammation Attenuation of inflammation might
contribute to a slowing of the progression
of the disease.
Different programmes are at various stages of
development, ranging from early preclinical
to Phase III studies
63,103–105
Aβ, amyloid-β; MT, microtubule.
Box 2 | The development of therapeutics
The need for therapies that are capable of modifying both amyloid-β (Aβ)- and tau-
mediated neurodegeneration cannot be overemphasized. Although a relatively large
number of Aβ-directed therapeutic approaches have been proposed, and although
many of these are at various stages of clinical investigation
79
, tau-directed therapies
have been lagging behind. Nonetheless, in light of the fact that two of the most
extensively studied cancer targets, namely kinases and MTs, are clearly involved in
tau-mediated neurodegeneration, the search for therapeutics that are capable of
modifying tau-pathology will be able to take advantage of past experience and,
importantly, of the relatively large number of biologically active compounds that have
already been developed. In addition, thanks to the recent development of various
in vitro tau fibrillization assays, high-throughput screening (HTS) of compound libraries
has been possible, and this has led to the identification of structures that are capable
of functioning as imaging ligands to detect aggregates in living patients, inhibiting
tau fibril formation and/or dissolving preformed fibrils
66–69,80
(TABLE 2). Although these
HTS efforts are clearly part of rather early-stage drug-discovery programmes, the hits
discovered thus far have promise as novel molecular tools to further investigate the
pathophysiology of tau. However, in order to conduct thorough evaluations of the
existing therapeutic agents, as well as of novel candidate compounds, in the context
of neurodegenerative diseases, key pharmacokinetic issues such as drug uptake in
the brain, which is notoriously hampered by the presence of the highly discriminating
blood–brain barrier
81
, remain to be resolved.
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R1 R2 R3 R4
C terminus
4411
410
381
383
352
412
4R/2N
3R/2N
4R/1N
3R/1N
4R/0N
3R/0N
N terminus
N terminus
N terminus
N terminus
N terminus
N terminus
C terminus
C terminus
C terminus
C terminus
C terminus
1
1
1
1
1
fraction. It is likely that the resultant higher cytosolic
concentrations of tau increase the chances of patho-
genic conformational changes that in turn lead to the
aggregation and fibrillization of tau
14
(FIG. 4). Important
progress has been made in recent years in understand-
ing tau misfolding and fibril formation
14,27,28
. The path
from normal tau bound to the MTs to large aggregate
structures such as NFTs is thought to be a multi-step
phenomenon which begins with the detachment of tau
from the MTs. The key steps of tau fibrillization are
highlighted in FIG. 4. On abnormal disengagement of
tau from the MTs, which can be triggered by numer-
ous causes (including increased rate of phosphoryla-
tion and/or decreased rate of dephosphorylation),
the cytosolic concentration of unbound tau would
rise. This is likely to be a crucial step, one which may
render tau considerably more likely to undergo mis-
folding and may, as a result, make it more prone to
aggregation. Next, small nonfibrillary tau deposits
(normally referred to as ‘pretangles’) are formed, and
these, unlike NFTs, cannot be detected by β-sheet-
specific dyes
29–31
. This indicates that pretangles do not
contain β-sheets, and that a structural rearrangement
involving the formation of the characteristic pleated
β-sheet must occur during the transition from pre-
tangles to PHFs. Finally, PHFs further self-assemble
to form NFTs.
Causes of tau abnormalities in disease
It is believed that several pathogenic events might con-
tribute, either directly or indirectly, to tau hyperphos-
phorylation, misfolding and aggregation. Perhaps the
most direct cause-and-effect relationship was estab
-
lished by seminal genetic studies that demonstrated
that mutations of the tau gene (MAPT) are causative
of FTD with parkinsonism linked to chromosome-17
(FTDP-17)
32,33
. All cases of FTDP-17 are character-
ized by the presence of filamentous inclusions that
are composed of hyperphosphorylated tau. Such
mutations could lead to the expression of tau mutants
that are: predisposed to assembly into filaments and
therefore able to undergo rapid fibrillization
32,34
; more
readily phosphorylated and/or less prone to dephos-
phorylation
35
; or that show impaired MT binding
properties
8,36
. Furthermore, intronic MAPT muta-
tions, as well as most coding-region mutations in exon
10 (N279K, L284L,
∆N296, N296N, N296H, S305N
and S305S), may alter the alternative splicing of tau
to perturb the normal one-to-one ratio of the 3R to
4R tau isoforms, with the 4R isoform being overpro
-
duced in most, but not all, instances. Indeed, over 30
different tau gene mutations have been identified in
families with FTDP-17 (recently reviewed in
REF. 32).
Importantly, these genetic studies provide unam-
biguous evidence that tau malfunction is sufficient to
trigger neurodegeneration and dementia even in the
absence of other pathogenic insults.
Additional direct cause-and-effect links have been
established between tau malfunctions and an overall
imbalance in the activity levels or regulation of tau
kinases and phosphatases
15,37
. Under physiological
conditions, single tau molecules are typically phos-
phorylated at a subset of potential phosphate-acceptor
amino-acid residues. During late stage neurodegen
-
eration, the phosphorylation state of a single tau mol-
ecule can reach such high levels that many or most
of these residues are phosphorylated and, at the same
time, a higher proportion of tau molecules are in this
hyperphosphorylated state. Although several kinases
have been found to be capable of phosphorylating
tau in vitro, it is not yet clear whether all of them
participate in tau phosphorylation under physiologi-
cal or pathological conditions in vivo
1
. Nonetheless,
glycogen synthase kinase 3 (GSK3), cyclin-dependent
kinase 5 (CDK5) and the microtubule-affinity-regulating
kinase (MARK) have received particular attention as
potential targets for disease-modifying therapies using
inhibitory compounds
15
. For example, inhibition of
GSK3 by lithium not only reduced tau phosphoryla-
tion in vivo, but also lowered the level of aggregated
tau, compared with controls
38
. Other studies on the
effects of lithium in transgenic AD mice also suggested
a concomitant reduction in Aβ production, possibly
resulting from lithium-mediated inhibition of
GSK3α,
which is required for maximal processing of the pre-
cursor of Aβ, amyloid precursor protein (APP)
39
.
Similarly, a number of phosphatases
40
, including pro-
tein phosphatase (PP)1, PP2A, PP2B and PP2C, have
been identified that could potentially drive the reverse,
Figure 2 | The domain structure of the tau isoforms that are expressed in the adult
human brain.
The isoforms can differ from each other in the number of tubulin-binding
domains (three or four repeats located in the C-terminal half of the protein, shown in
red), and are referred to as 3R or 4R tau isoforms, respectively. They can also differ in the
presence or absence of either one or two 29-amino-acid-long, highly acidic inserts
(shown in yellow) at the N-terminal portion of the protein (the projection domain).
Between the projection domain and the microtubule-binding domain lies a basic
proline-rich region.
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Cargo moving
along the axon
Cargo moving
along the axon
Motor protein
Vesicle
Tau attached
to the MT
MT
Kinase-mediated phosphorylation
detaches tau from the MT
Dephosphorylation reaction by
phosphatases restores the
MT-binding ability of tau
Dephosphorylation
Phosphorylation
Phosphorylated tau
disengaged from the MT
Oxidative stress
A disturbance in the pro-
oxidant–antioxidant balance in
favour of the pro-oxidant,
leading to potential cellular
damage. Indicators of oxidative
stress include damaged DNA
bases, protein oxidation and
lipid peroxidation products.
Dystrophic neurites
The processes (axons and
dendrites) of neurons that are
damaged or degenerating in
AD.
dephosphorylation of tau; however, the exact role of
these phosphatases under physiological and pathologi-
cal conditions is not completely clear.
The overall effect of the increased rate and/or state
of phosphorylation appears to be the abnormal dis-
engagement of tau from the MTs. Furthermore, it is
likely that various other pathological events, includ-
ing Aβ-mediated toxicity, as well as oxidative stress and
inflammation, may be able to trigger or contribute
(independently or in combination) to an abnormal
detachment of tau from the MTs
41–45
. For example, it has
been suggested that oxidative stress could be responsi-
ble for detrimental covalent modifications of tau, which
include the formation of intermolecular disulphide
bridges
46
and tyrosine nitration
24
. Such modifications
are likely to cause misfolding, hyperphosphorylation and
aggregation, and thereby contribute to abnormal disen-
gagement of tau from MTs, as well as to the formation
of aggregates. However, despite the clear involvement of
these pathological processes in tau-mediated neuro-
degeneration, their relative positioning in the cascade
of events that leads to neuronal loss remains unclear. For
example, although oxidative stress is often regarded as an
upstream event relative to tau pathology, recent studies
have revealed that pathological tau may interfere with
mitochondrial function and induce oxidative stress
47
.
This raises the interesting possibility that although oxida-
tive stress is likely to be a relatively early event that could
lead to tau malfunction, it is equally possible that tau
malfunction, once initiated, may further exacerbate the
effects of this, and possibly other, upstream events.
Connections between Aβ-mediated toxicity and tau
pathology have repeatedly been proposed
48,49
; however,
the mechanism or mechanisms that link SPs and NFTs
have not yet been fully established, and this remains one
of the most challenging conundrums of AD research.
Nonetheless, new lines of investigation support the
notion that tau malfunction, in addition to being inde-
pendently capable of producing neurodegeneration
even in the absence of Aβ deposits or other pathological
events
32,33
, could be a key mediator of neurodegen-
eration in response to other upstream events, including
Aβ-induced toxicity
44
. An interesting and unexpected
development of the proposed pathological role of tau as a
common mediator of neurodegeneration is the hypoth-
esis that suppression of tau may potentially be beneficial.
In accordance with this hypothesis, a recent study
50
has
shown that reduction or elimination of endogenous tau,
in a mouse model of AD-like Aβ amyloidosis which
expresses human amyloid precursor protein (hAPP)
with a familial AD mutation that increases Aβ produc-
tion, is beneficial against Aβ-induced deficits. These
results appear to substantiate previous cell-based studies
which showed that cultured hippocampal neurons from
tau-knockout mice treated with fibrillar A
β were not
susceptible to Aβ-induced toxicity
44
. However, although
the most valid model for comparisons with tau suppres-
sion would be a tau-knockdown mouse, it is notable that
tau-knockout mice show behavioural impairments and
structural abnormalities with advancing age
51
, suggest-
ing that long-term suppression of tau as a therapy for
tauopathies might be fraught with complications.
Tau-mediated neurodegeneration
As described above, in AD and related neurodegen-
erative disorders that are collectively referred to as
tauopathies,
52,53
tau no longer binds to the MTs; instead
it becomes sequestered into NFTs in neurons, and into
glial tangles in astrocytes or oligodendroglia. In AD at
least, the largest burden of tau pathology (~95% of total
tau by morphometic analyses) is found in neuronal proc-
esses known as neuropil threads or dystrophic neurites
54
.
In broad terms, the pathological consequences of these
events could result from a loss of normal tau func-
tion combined with gains of pathological functions of
hyperphosphorylated tau, the filaments formed thereof,
and the aggregation of these filaments to form glial and
neuronal tangles in dystrophic neurites.
The loss of tau’s normal MT-stabilizing function
would invariably lead to a pathological disturbance
Figure 3 | The dynamic equilibrium of tau microtubule (MT) binding. A schematic representation of the normal
dynamic equilibrium of tau, on and off the MTs, which is primarily determined by the phosphorylation state of tau.
Although the presence of tau on the MTs presents a physical obstacle for vesicles and other cargoes that are moving along
the axon, MT-bound tau is essential to MT integrity. Thus, relatively frequent cycles of tau–MT binding (promoted by
dephosphorylation of tau) and detachment of tau from the MT (promoted by phosphorylation of tau) are needed in order
to maintain effective axonal transport.
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Nature Reviews | Neuroscience
Possible causes of tau aggregation
Tau gene
mutations
Covalent
modifications
of tau
Others?
Phosphorylation
(by kinases)
Dephosphorylation
(by phosphatases)
Misfolded tau
Pretangles
β-sheet
containing structures
(PHFs)
Filamentous inclusions
(NFTs)
a
b
c
d
e
Detachment of tau from the MTs. Increased unbound tau.
Microglia
A non-neuronal cell type that is
present in the spinal cord and
the brain (it is the resident CNS
macrophage) and is
characterized by its ramified
morphology.
in the normal structural and regulatory functions of
the cytoskeleton, which would compromise axonal
transport and thus contribute to synaptic dysfunction
and neurodegeneration
26,55
. Indeed, the importance of
the loss of the MT-stabilizing function of tau in neuro-
degeneration was recently validated by proof-of-concept
studies carried out in vivo, which demonstrated that the
MT-stabilizing drug paclitaxel can ameliorate the neuro-
degenerative phenotype of transgenic mouse models
of AD-like tau amyloid pathologies
56,57
. However, the
discovery that the total level of NFTs correlates with
the degree of cognitive impairment
58,59
provided the ini-
tial circumstantial evidence to suggest that toxic gains-
of-function by NFTs might play an important part in the
progression of the disease. Indeed, pioneering studies
that used immunohistochemical techniques to deter-
mine the level of both NFTs and SPs in different brain
regions of AD patients, as well as non-demented elderly
individuals, demonstrated that the number of NFTs, but
not the numbers of SPs, correlates with the degree of
cognitive impairment
58,59
.
It is possible that the toxic effects of NFTs may
partly arise from the relatively large size of the fibril-
lary material that accumulates inside the neurons,
as this material may pose a direct physical disrup-
tion to cellular functions such as axonal transport.
Furthermore, NFTs may also contribute to the disease
progression by effectively sequestering more tau and
other proteins, and thereby reinforcing and amplifying
the loss of normal tau function.
However, the notion that NFTs could have a promi-
nent role in the progression of the disease was recently
challenged by reports that suppression of transgenic tau
in a neurodegenerative tauopathy mouse model pro-
duced improvements in memory function, even though
NFTs continued to accumulate
60,61
. However, it should
be noted that in the model used, the degree of tau sup-
pression is relative to the fully activated state of tau: this
means that a 2.5-fold overexpression of tau (compared
with endogenous tau) would still be present. Another
significant observation was that, in a mouse model of
AD-like Aβ pathology, axonal defects that consisted
of swellings that contained accumulated abnormal
amounts of tau, other proteins and vesicles were found
to precede the appearance of Aβ deposits, including
SPs, by more than 1 year
62
. Furthermore, restoration of
impaired axonal transport in a tauopathy mouse model
rescued the disease phenotype
57
. In addition, studies in
a transgenic (P301S) tauopathy mouse model revealed
that synapse loss and microglial activation precede the
appearance of NFTs, presumably due to the impaired
transport that results from tau hyperphosphorylation
63
.
Collectively, these studies substantiate the notion that
axonal transport defects, synapse loss and neuroinflam-
mation may be among the earliest signs of neurodegen-
eration that results from tau hyperphosphorylation,
whereas fibrillary tau tangles may be late-stage manifes
-
tations that could contribute to the disease progression
by physically interfering with normal cellular functions.
At the same time, the tangles may sequester larger
quantities of other functionally significant proteins,
and thereby exacerbate and amplify upstream causes. It
should be noted that the possible relative contribution
to neurodegeneration from the toxic gains-of-function
versus the loss of normal function may be experimen-
tally difficult to discern, as the toxic gain may imply, at
least in part, an amplification of the loss of function. In
addition, a precise correlation between the size of the
NFTs and these toxic gains (that is, the putative criti-
cal mass that is required for an insoluble intracellular
deposit to become a physical obstacle) is not yet known.
Figure 4 | Pathological aggregation of tau. A schematic
representation of the different stages of the formation of
pathological tau aggregates. a | Abnormal disengagement
of tau from the MTs and a concomitant increase in the
cytosolic concentration of tau are likely to be the key
events that lead to tau-mediated neurodegeneration.
Direct causes of abnormal disengagement of tau from the
MTs include an imbalance of tau kinases and/or
phosphatases, mutations of the tau gene, covalent
modification of tau causing and/or promoting misfolding,
and possibly other causes such as other post-translational
modifications. b | Once tau is unbound from the MT it
becomes more likely to misfold. This is thought to be a
stochastic phenomenon that is more likely at higher
cytosolic tau concentrations. c | Early deposits of tau,
called ‘pretangles’, are not stained by congo red or
thioflavine-T, indicating that these intermediate forms
of aggregated tau do not exhibit the pleated β-sheet
structure typically found in amyloid aggregates.
d
| A structural transition leads to this more organized
aggregate and the eventual development of neurofibrillary
tangles (e). Such transitions may be facilitated by
heterogeneous interactions with membranous
structures
14,29
. MT, microtubule; NFT, neurofibrillary tangle;
PHF, paired helical filament.
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Furthermore, with the existence of pre-fibrillary tau spe-
cies
30,31
, toxic gains-of-function by abnormal tau could be
ascribed to one or more of these ill-defined intermediate
species. Thus, although loss of tau function and the toxic
gain-of-function by PHFs or other abnormal species of
tau, in addition to the toxic properties acquired by NFTs
as they enlarge, may contribute to neurodegeneration to
different extents, it is highly plausible that both types of
mechanism contribute to the onset and progression
of AD and other tauopathies, especially at different
stages of the pathology.
Conclusions and future directions
Despite significant recent advances in our under-
standing of tau-mediated neurodegeneration, which
substantiate the notion that tau may act as a common
mediator of neurodegeneration for various upstream
pathological events, a detailed picture of causes and
effects has not yet emerged. Thus, although it is increas-
ingly clear that the disengagement of tau from MTs is
likely to comprise a cardinal step that sets the stage for
tau-mediated neurodegeneration, the links between
this and other upstream events such as Aβ-mediated
toxicity and oxidative stress remain less clear. Likewise,
although tau-mediated neurodegeneration probably
results from the combination of losses of function and
toxic gains-of-function, the specific roles played by the
various forms of misfolded and aggregated tau are not
fully understood. It should be noted, however, that the
onset and progression of the disease may not necessarily
be best represented by an unequivocal linear sequence
of causes and effects, where one single ‘root’ cause is
responsible for the entire cascade of events. With the
recognition that amplification mechanisms exist that
could effectively short-circuit cause and effect and
thereby exacerbate each-others’ detrimental effects,
it is plausible that disease progression may lie in the
ability to set in motions such self-sustaining cycles.
Thus, continuing efforts should be made to further
characterize the precise mechanism(s) by which differ-
ent pathological events may influence and amplify each
other. With a wide range of animal models that partially
recapitulate the key phenotypic features of AD and
related tauopathies already developed
64
(BOX 1; TABLE 1),
further insight into the mechanistic roles of the different
species of tau aggregates in neurodegenerative disease
relies on the discovery of a wider set of molecular tools.
These tools must be capable of selectively modulating
and/or imaging
65
putative pathogenic and pathologi-
cal steps. To this end, functional genomics and drug
discovery efforts aimed at some of these targets will
be instrumental (BOX 2; TABLE 2). For example, agents
that are capable of slowing down, blocking or reversing
protein tau aggregation in vitro
66–74
have been identified;
however, issues such as lack of selectivity and/or toxicity
have limited their use in vivo. In addition, several agents
that could compensate for the loss of tau function, such
as paclitaxel and other MT-stabilizing agents
55
that have
been part of the medical armamentarium for several
years, are hampered by limited CNS uptake and tox-
icities. Drug discovery and lead optimization efforts
that could succeed in making these and other agents
available for in vivo testing will greatly facilitate further
understanding of the tau pathway, as well as of the
pathogenic significance of specific events, whose exact
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Acknowledgements
We thank our colleagues for their contributions to the work
summarized here, which has been supported by grants from
the US National Institutes of Health (P01 AG09215, P30
AG10124, P01 AG11542, P01 AG14382, P01 AG14449,
P01 AG17586, PO1 AG19724, P01 NS-044233, UO1
AG24904), and the Marian S. Ware Alzheimer Program.
Finally, we are indebted to our patients and their families,
whose commitment to research has made our work possible.
Competing interests statement
The authors declare no competing financial interests.
DATABASES
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
APP | CDK5 | FYN | GSK3α | GSK3β | MAPT | MARK | presenilin 1
OMIM: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=OMIM
Alzheimer’s disease
FURTHER INFORMATION
John Q. Trojanowski’s homepages:
http://www.med.upenn.edu/aging
http://www.uphs.upenn.edu/ADC
http://www.uphs.upenn.edu/cndr/
ALL LINKS ARE ACTIVE IN THE ONLINE PDF.
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