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Biochemical Society Transactions (2010) Volume 38, part 4
Insights from Drosophila models of Alzheimer’s
disease
Catherine M. Cowan, David Shepherd and Amritpal Mudher1
School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, U.K.
Abstract
AD (Alzheimer’s disease) is a neurodegenerative disorder characterized by the abnormal hyperphosphorylation and aggregation of the microtubule-associated protein tau and the misfolding and deposition of Aβ
peptide. The mechanisms by which tau and Aβ become abnormal is not clearly understood, neither is it
known what role either protein plays in the neurodegenerative process underlying AD. We have modelled
aspects of AD in Drosophila melanogaster to shed light on these processes and to further our understanding
of the relationship between tau and amyloid in this disease.
Introduction
Oligomeric and aggregated forms of the Aβ (amyloid βpeptide) and hyperphosphorylated and filamentous forms of
the microtubule-associated protein tau are the precursors
of neuritic plaques and neurofibrillary tangles, the pathological hallmarks of AD (Alzheimer’s disease). Since both Aβ
and tau are normal proteins found in healthy neurons, there
is a great deal of interest in understanding what triggers their
conversion into the abnormal and aggregated states that are
found in AD. Similarly, research efforts are directed towards
discerning how the pathological alteration of both proteins
affects their physiological function (which in the case of Aβ
is still not known). The relationship between tau and
Aβ is also a matter of debate, with the general consensus view
supporting the hypothesis that Aβ pathology lies upstream
of tau pathology in AD, but that the latter pathology is
responsible for the cognitive impairments that characterize
this disease [1].
Numerous cellular, ex vivo slice and in vivo animal model
systems have been established to answer these questions.
The earlier models emulated the amyloid pathology by
overexpressing mutant forms of APP (amyloid precursor
protein) and/or PS (presenilin) mutations in transgenic
rodent and invertebrate models (reviewed in [2,3]). After
the discovery of familial forms of tauopathies which are
linked to mutations in the tau gene, transgenic models
were generated which modelled aspects of the tau pathology
in rodents (reviewed in [4]) and invertebrates [5–9]. More
recently, transgenic rodent models have been created that
model both the amyloid and the tau pathologies by coexpression of mutant APP/PS and FTDP-17 (frontotemporal
dementia with parkinsonism linked to chromosome 17) tau
genes [10,11].
Key words: Alzheimer’s disease, amyloid, Drosophila, microtubule, tauopathy, wnt/wingless
signalling.
Abbreviations used: Aβ, amyloid β-peptide; AD, Alzheimer’s disease; APP, amyloid precursor
protein; FTDP-17, frontotemporal dementia with parkinsonism linked to chromosome 17; GSK3β,
glycogen synthase kinase 3β; PS, presenilin; UAS, upstream activating sequence.
1
To whom correspondence should be addressed (email [email protected]).
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Authors Journal compilation We have established various Drosophila models of
tauopathy in which we express either wild-type or mutant
forms of human 0N3R or 0N4R genes alone [5,7,8] or
in combination with Aβ 40 or Aβ 42 [12]. We have used
these models both to further our understanding of the
mechanisms by which hyperphosphorylated tau mediates
neuronal dysfunction and to probe the relationship between
the tau and amyloid pathologies.
Using Drosophila to model human disease
Drosophila has been used as a model organism for almost
a century and has been pivotal for the elucidation of a
plethora of biological processes in this time, ranging from
the rules of genetic inheritance [13] to an understanding of
complex processes such as circadian rhythms [14], learning
and memory [15], development [16] and aging [17], to
mention a few. Furthermore, the fruitfly genome has been
sequenced completely. As a result of all of these studies,
there is a wealth of genetic tools that can be employed
to study and manipulate almost any cellular process and
cell within this organism. The UAS (upstream activating
sequence)/GAL4 gene expression system is one example of
such a genetic tool that allows for experimental control over
both temporal and spatial transgene expression and has thus
been described as the fruitfly geneticist’s Swiss Army knife
[18]. Furthermore, Drosophila are small in size and have a
relatively simple well-studied anatomy which allows one to
carry out experiments at the level of single easily identifiable
cells (such as the well-characterized motor neurons and their
neuromuscular junctions [19]). Moreover, its short life cycle
makes it highly amenable to enhancer/suppressor studies
[20] that can shed light on novel modifiers of disease
processes. This is invaluable for the study of human diseases
such as tauopathies, where such knowledge will pave the
way for disease-modifying therapies. Another very important
attribute of Drosophila that make it particularly useful for
studying chronic and progressive human neurodegenerative
diseases is the transparent cuticle of the larvae which allows
the study of the progression of the disease process, and its
Biochem. Soc. Trans. (2010) 38, 988–992; doi:10.1042/BST0380988
The Biology of Tau and its Role in Tauopathies
impact on neuronal function, non-invasively in living intact
animals [7], [21]. All of these attributes of Drosophila make it
one of the most experimentally tractable model organisms.
The fact that many insights into human diseases such as
Huntington’s disease [22], Parkinson’s disease [23] and AD
have come from Drosophila models of these diseases testifies
to the usefulness of this experimental system for elucidating
the mechanisms that underpin neurodegeneration (reviewed
in [24,25]).
We have employed the UAS/GAL4 system to induce
expression of human tau in either motor neurons alone or
in all neurons of Drosophila. We have then carried out studies
to investigate the effects of highly phosphorylated human
tau on aspects of neuronal function such as axonal transport
[7], microtubular cytoskeletal integrity [26] and synaptic
structure and function [8]. In some instances, these studies
were carried out in living intact animals, thus they provided
insights into the disease processes as they unfolded in vivo.
More recently we co-expressed the human tau with Aβ 40
and Aβ 42 to ascertain whether or not the presence of
the amyloid pathology in the same neurons as the highly
phosphorylated tau influences the tau-mediated neuronal
dysfunction [12].
Soluble highly phosphorylated tau disrupts
neuronal and synaptic function
Since the realization that hyperphosphorylated tau is the main
constituent of neurofibrillary tangle pathology in AD [27] the
pathological significance of tau hyperphosphorylation and
aggregation has been vigorously investigated. It has been
hypothesized that tau phosphorylation leads to a loss of
tau function (tau–microtubule hypothesis, reviewed in [28]),
whereas tau aggregation may lead to a toxic gain-of-function
[29]. Since tau hyperphosphorylation is evident before
filament formation in post-mortem AD-affected brains
[30], it has been hypothesized that hyperphosphorylation
primes tau for aggregation [31]. Thus it is conceivable
that a pathological cascade unfolds in tauopathies in which
hyperphosphorylation of tau is stimulated in the early
stages and this in turn leads to tau aggregation and tangle
formation in late stages. Neuronal dysfunction, mediated by
highly phosphorylated tau, may characterize the early stages,
whereas neuronal death mediated by toxic tau filaments may
be a feature of the late stages of disease.
One aim of our research is to test this hypothesis in
Drosophila. We employ Drosophila models of tauopathy
(i) to study the neuronal consequences of inducing tau
hyperphosphorylation and filament formation, and (ii) to
investigate the causal relationship between the development
of both tau aberrations. By investigating the neuronal
consequences of inducing tau hyperphosphorylation, we
have effectively been testing the tau–microtubule hypothesis
in vivo. This is a long-standing hypothesis that is based
primarily on evidence obtained from in vitro observations,
and our studies in Drosophila are the first to test all aspects
of this hypothesis in one in vivo experimental paradigm
(reviewed in [28]). We have shown that, following expression
of highly phosphorylated human 0N3R tau in Drosophila
motor neurons, there is a profound disruption of axonal
transport, leading to significant synaptic dysfunction and
behavioural impairments ([7,8] and reviewed in [28]). More
recently, we have shown that the molecular mechanism
by which highly phosphorylated human tau mediates
this neuronal dysfunction is 2-fold: first, as predicted
by the tau–microtubule hypothesis, highly phosphorylated
tau is unable to bind to microtubules effectively and
thus, in the presence of human hyperphosphorylated tau,
the microtubule cytoskeleton becomes destabilized and
disorganized [26]. Secondly, this highly phosphorylated
human tau exhibits another pathological property, one not
predicted by the tau–microtubule hypothesis: it binds to
and sequesters endogenous Drosophila tau, compromising its
microtubule-binding capacity [26]. Both the destabilization
of the cytoskeleton and the sequestration of normal
endogenous Drosophila tau could be reversed by treatment
of the human-tau-expressing larvae with LiCl, a drug
that has been shown to be capable of suppressing
tau phosphorylation [7]. These results demonstrate that
highly phosphorylated tau is pathogenic and exhibits both
a loss of normal function and also a gain of toxic function.
Furthermore, the highly phosphorylated tau does not need
to aggregate to mediate these effects because tau filament
formation was not evident when disruptions to microtubular
integrity or binding to Drosophila tau were seen. Moreover,
although the human-tau-expressing neurons exhibited all
of these structural and functional aberrations, there was
no evidence of neuronal loss or overt neurodegeneration.
Thus soluble hyperphosphorylated tau proteins evident
in neurons before tangle formation may cause significant
neuronal dysfunction and this may be responsible for the
early symptoms of dementia in tauopathies.
Aβ 42 exacerbates tau-mediated neuronal
dysfunction
The relationship between the tau and amyloid pathologies in
AD has been researched intensively and is highly debated.
The finding that mutations in the tau gene cause familial
forms of tauopathies (such as familial forms of FTDP17) wherein tangle pathology is evident in the absence
of amyloid pathology suggests that tangle pathology lies
downstream of amyloid pathology in AD. This is supported
by studies in rodent models that exhibit both the tau and
amyloid pathologies in which the co-existence of the amyloid
pathology accelerates and exacerbates the emergence of the
tangle pathology [32]. Moreover, in these models, it has
been noted by many that the accumulation of oligomeric
Aβ precedes the induction of the hyperphosphorylated
tau [10,33]. These findings imply that oligomeric Aβ 42
can stimulate hyperphosphorylation and accumulation of
tau. Indeed, results from various in vitro and in vivo
studies lend support to this hypothesis: exposure of
primary cells in culture to oligomeric Aβ 42 can induce
phosphorylation of tau [34–36], and intracerebroventricular
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Authors Journal compilation 989
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Biochemical Society Transactions (2010) Volume 38, part 4
infusion of Aβ oligomers into rodent brains also stimulates
tau phosphorylation [37].
We were interested in investigating whether co-expression
of amyloid with human tau in our Drosophila model of
tauopathy induced tau hyperphosphorylation and exacerbated the tau phenotypes. We demonstrated that expression
of Aβ 42 with human 0N4R tau in this model resulted in
greater phosphorylation of the human tau at some (AT8,
AT180) but not all (PHF-1) sites [12]. Furthermore, in the
presence of Aβ 42 , tau-mediated phenotypes in both larval
and adult fruitflies were significantly exacerbated (Figure 1)
[12]. In larvae expressing either Aβ 42 alone or human tau
alone within their motor neurons, there were conspicuous
morphological abnormalities in the neuromuscular junctions
[12]. This is to be expected since both proteins have been
shown to cause structural and functional dysfunction within
synapses in various models of AD [8,38,39]. It was therefore
not surprising that when both proteins were co-expressed
in larval motor neurons, there was an additive exacerbation
of the NMJ (neuromuscular junction) phenotype induced by
expression of either protein alone [12]. In contrast, expression
of Aβ 42 in larval motor neurons did not result in significant
axonal transport disruption, and yet co-expression of Aβ with
human tau resulted in a 3-fold exacerbation of the disruption
caused by expression of tau alone (Figure 1A) [12]. Similarly,
pan-neuronal expression of Aβ 42 in adults did not induce
significant locomotor impairment in an adult climbing assay,
whereas expression of human 0N4R tau led to a progressive
age-dependent impairment which was potentiated severalfold
by co-expression of Aβ 42 (Figure 1B) [12]. These results
demonstrate that, even when Aβ 42 does not by itself cause
detectable neuronal dysfunction, it significantly exacerbates
tau-mediated neuronal dysfunction.
In attempting to unravel the mechanism by which Aβ
interacted with tau in this model, we assessed the activity
of the tau kinase, GSK3β (glycogen synthase kinase 3β), in
Drosophila expressing either protein alone compared with
those expressing both. We hypothesized that Aβ exacerbated
the tau phenotypes by activating GSK3β because several
reports have demonstrated that exposure to cells in culture
to oligomeric Aβ results in increased activity of GSK3β as
well as tau hyperphosphorylation [35,36,40]. In line with
this, we found that treatment of tau/Aβ 42 co-expressing
larvae to LiCl, a well-known GSK3 inhibitor, ameliorated
the Aβ 42 exacerbation of the tau phenotype (Figure 1C) [12].
However, when we examined the actual activity of GSK3β
in these tau/Aβ 42 bigenic fruitflies using antibodies against
active and inactive phospho-epitopes of GSK3β, we found no
difference between any of the lines [12]. These results suggest
that although GSK3β may be the kinase that mediates the
interaction between tau and amyloid in this model, this does
not occur via an Aβ 42 -induced increased enzymatic activity
of GSK3β.
Apart from phosphorylation to activate or inhibit GSK3β,
compartmentalization with its substrates is another cellular
mechanism by which its activity can be regulated. Such a
mode of regulation of GSK3β activity is utilized in the
C The
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Authors Journal compilation Figure 1 Aβ 42 exacerbates tau-mediated phenotypes
Co-expression of Aβ 42 results in an exacerbation of the axonal transport
dysfunction (A) and locomotor impairment (B) caused by the expression
of human tau (tauwt ) alone. Treatment of tauwt /Aβ 42 bigenic adult
fruitflies with LiCl to suppress tau phosphorylation leads to a greater
survival of adults when compared with those expressing either protein
alone (C). Reproduced from [12] with permission.
wnt or wingless signalling pathway which plays a pivotal
role in determining cell fate during development. In the
absence of a wnt signal, GSK3β forms a complex with its
substrate β-catenin and phosphorylates it, targeting it for
degradation. Upon activation of frizzled receptors by wnt
ligands, an intracellular effector protein dishevelled (Dsh)
is recruited to destabilize the GSK3β–β-catenin complex,
resulting in reduced phoshorylation and degradation of βcatenin. Apart from β-catenin, GSK3β has also been shown
to form a complex with tau [41] and it has been demonstrated
that components of the wnt signalling pathway can suppress
its phosphorylation of tau in vitro [42,43], presumably by
disrupting the complex it forms with tau as it does with βcatenin.
It has been shown by many that Aβ 42 can interact with
components of the wnt signalling pathway and antagonize
The Biology of Tau and its Role in Tauopathies
Figure 2 Hypothetical interaction between tau and amyloid via the wnt signalling pathway
its effects [44–46]. We therefore hypothesized that Aβ 42
could enhance GSK3β-mediated phosphorylation of tau by
suppressing endogenous wingless signalling in the tau/Aβ 42
bigenic fruitflies. We thus predicted that up-regulating
wingless signalling by overexpressing Dsh in tau-expressing
Drosophila should have the opposite effect to Aβ 42 coexpression, and lead to a suppression of the tau phenotypes.
Indeed, in transgenic animals that co-express both tau and
Dsh, there is a significantly improved axonal transport
and locomotor behaviour and a concomitant reduction of
tau phosphorylation [12]. Thus it is possible to speculate
that GSK3β activity towards its substrates such as tau
are regulated by a low level of wingless signalling in the
adult brain and that if this becomes deregulated (such
as may happen following Aβ accumulation in the aged
brain), tau hyperphosphorylation ensues, leading to neuronal
dysfunction and cognitive decline (Figure 2). Thus wingless
signalling may be the link between the tau and amyloid
pathologies although components of this developmental
signalling pathway need to be demonstrated in the adult brain
to validate this idea.
Conclusions
We have modelled aspects of AD in Drosophila to
further our understanding of the mechanisms by which
hyperphosphorylated tau and oligomeric Aβ 42 disrupt
neuronal function in vivo. Using these Drosophila models,
we have been able to gain an insight into these pathological
mechanisms as they unfolded in living intact animals. The
genetic tractability of Drosophila allowed for tight spatial and
temporal control over the human tau and amyloid expression
and thus enabled us to conduct these studies at the level of
individual easily identifiable neurons as well as facilitating the
functional consequences at the organismal level.
From these studies, we can conclude that hyperphoshorylated human tau exhibits a profound loss of function
(leading to destabilization of the microtubule cytoskeleton
and a disruption of axonal transport) as well as an unexpected
gain of toxic function (by sequestering normal tau and
functionally compromising it). Furthermore, aggregation of
tau is not required for it to mediate these effects. Our
studies also indicate that Aβ 42 acts synergistically with
human tau to exacerbate its pathological effects. Although
the cellular process that facilitates the interaction between
tau and amyloid is unclear, our results point to the wingless
signalling cascade as a potential pathway that may link the
two proteins in AD.
Our studies highlight the utility of Drosophila models for
enhancing our understanding of the pathological mechanisms
that underpin human neurodegenerative diseases.
Funding
This work was supported by the Alzheimer’s Society UK and the
Wessex Medical Trust.
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Received 26 May 2010
doi:10.1042/BST0380988