Astrocytes in Parkinson’s disease
Master Thesis Neuroscience & Cognition
October – December 2009
Supervisor: Simone van den Berge
Parkinson’s disease is a common neurodegenerative disorder with a high prevalence in people
over 65. Its main hallmark is progressive loss of dopaminergic neurons in the substantia nigra,
leading to characteristic motor symptoms such as tremor and bradykinesia. The pathology of
this disease is not yet fully understood. Recently it has been suggested that astrocytes might
play an important role in disease initiation and progression. In response to neuronal damage
astrocytes can enter a state called reactive astrogliosis, which is characterised by hypertrophy
and increased expression of glial fibrillary acidic protein. Though initially meant as a
protective reaction, this can have both beneficial and detrimental effects on surrounding
neurons. In this review the role that astrocytes might play in Parkinson’s disease is discussed.
Evidence of astrogliosis in animal models of Parkinson’s disease and post mortem studies of
patients is described, implicating the involvement of this process. Subsequently, several
factors are discussed that are important during the astrocytic response in Parkinson’s disease,
divided in neuroprotective and neurodegenerative effects. Based upon the astrocytic factors
that could contribute to disease pathology, some potential therapies for Parkinson’s disease
targeting astrocytes are suggested.
1. Introduction ............................................................................................................................4
1.1 Parkinson’s disease...........................................................................................................4
1.2 Animal models of PD .......................................................................................................5
1.3 Astrocytes .........................................................................................................................8
1.4 Astrocytes in the substantia nigra.....................................................................................9
2.1 Astrogliosis in animal models of PD..............................................................................12
2.2 Astrogliosis in PD patients .............................................................................................13
2.3 Remote astrocyte activation ...........................................................................................14
2.4 Activation pathway.........................................................................................................14
3. Neurodegenerative & proinflammatory factors in astrocytes ..............................................16
3.1 α-synuclein in astrocytes and Lewy bodies....................................................................16
3.2 ER stress and unfolded proteins .....................................................................................17
3.3 The role of astrocytes in oxidative stress-induced neuronal degradation.......................17
3.4 MAO-B expression in astrocytes and production of reactive oxygen species ...............19
3.5 Immune responses and the role of astrocytes in sustaining inflammation .....................20
3.6 Effect of hormones on astrocyte development and response to injury...........................21
4. Neuroprotective effects of astrocytes ...................................................................................22
4.1 Protective effects of PAR-1 activation...........................................................................22
4.2 Role of Nurr1 in protecting dopaminergic neurons........................................................22
4.3 Anti-inflammatory and neuroprotective effects of hydrogen sulphide ..........................23
4.4 The role of purines in regulation of the astrocytic response ..........................................23
4.5 Astrocyte influence on microglia ...................................................................................24
4.6 Protective effects of enriched environment....................................................................25
4.7 Astrocyte influence on neurogenesis..............................................................................25
4.8 Nrf2-mediated gene transcription inducing a large neuroprotective response...............26
5. Potential therapies for PD treatment targeting astrocytes ....................................................27
List of abbreviations .................................................................................................................32
Though Parkinson’s disease was first described in 1817 its pathology is still not fully
understood. Several factors are known to contribute to disease initiation and/or progression
(Gasser 2009; Weidong Le et al. 2009) but it is not known why certain people develop the
disease while others do not. This review focuses on a particular aspect of the disease: the
involvement of astrocytes. The importance of astrocytes in normal brain function and their
possible involvement in neurodegenerative disorders has only recently been discovered. In
response to certain signals, astrocytes can start an active inflammatory response called
reactive astrogliosis (Eddleston & Mucke 1993), which is implicated to be important in the
pathology of Parkinson’s disease. Here, an overview is given of how astrocytes and reactive
astrogliosis might be involved in Parkinson’s disease and different models of this disease.
First, an introduction is given explaining some background information on Parkinson’s
disease, different animal models for this disease, and normal astrocyte function. Subsequently,
the concept of astrogliosis will be explained and some detrimental as well as beneficial factors
are presented that might play a role in reactive astrogliosis in Parkinson’s disease. Finally,
some potential therapies targeting astrocytes are suggested.
1.1 Parkinson’s disease
Parkinson’s disease (PD) is a common neurodegenerative disorder with a prevalence of 1.8 %
in people over 65 (Rijk et al.
2000). It is characterised by
disabling motor abnormalities
such as tremor, muscle rigidity,
instability and other
accompanying symptoms such
as fatigue and speech problems
(Purves et al. 2001) . Overall,
PD is primarily idiopathic with
only a subset of cases (<15% of
cases) with a family history of
PD. In pedigrees with a patternFigure 1 In Parkinson’s disease neurons are lost in the substantia
nigra, which is located in the midbrain. (howstuffworks.com)
of inherited PD, genetic linkage studies have identified 13 PARK loci to date. Molecular
genetics studies have identified genes associated with 7 of 13 PARK loci (Harvey et al. 2008).
The primary neuropathological hallmark of PD is loss of pigmented dopaminergic neurons in
the substantia nigra pars compacta (SNpc), projecting to the striatum. This results in a deficit
in striatal dopamine levels, leading to most of the clinical symptoms. In figure 1 the neuronal
loss in the SN of a PD patient is shown compared to a healthy individual. Until now, the most
common treatment for this disease is administration of levodopa (L-dopa), a dopamine
precursor, which increases dopamine levels in the brain. However, especially after chronic
administration, this treatment has many side effects and loses its effectiveness (Schapira et al.
2009). Moreover, L-dopa administration does not interfere with disease progression but only
alleviates the symptoms. Therefore, it is important to require a deeper understanding of the
causes and pathology of PD. Not only to try to prevent the disease but also to develop new
therapies that might stop or slowdown disease progression.
PD is diagnosed pathologically by the loss of pigmented neurons in the SNpc and is
associated with widespread occurrence of Lewy bodies and dystrophic Lewy neurites
throughout the central and autonomic nervous system (Gelb et al. 1999). These are abnormal
intracellular aggregates of α-synuclein in respectively neurons and axons, that might
contribute to disease pathology. It has also been found that oxidative stress plays an important
role in disease pathology and might be the main cause of neuronal degradation. In post
mortem studies, evidence of increased oxidative stress in the SNpc of PD patients has been
observed (Hunot et al. 1996).
1.2 Animal models of PD
PD is a multifactorial disease with a complex etiology that results from genetic risk factors,
environmental exposures and most likely a combination of both. Rodent models of
Parkinsonism aim to reproduce key pathogenic features of the syndrome, including movement
disorder induced by the progressive loss of dopaminergic neurons in the substantia nigra,
accompanied by the formation of α-synuclein containing Lewy body inclusions. The two most
widely used models for PD are the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
model and the 6-hydroxydopamine (6-OHDA) lesion model, these and other rodent models
are reviewed in Melrose et al. 2006.
MPTP is a by-product of the chemical synthesis of a meperidine analogue with potent heroin-
like effects. It can induce a Parkinsonian syndrome in humans almost indistinguishable from
PD. MPTP is a potent and irreversible mitochondrial complex I inhibitor whose toxic
metabolite MPP+ is selectively transported by the dopamine transporter DAT (Watanabe et
al. 2005). The conversion of MPTP in astrocytes and the effect of MPP+ on neurons is shown
in figure 2. MPTP causes damage to the dopaminergic pathways identical to that seen in PD
with a greater loss of neurons in the SNpc than in the ventral tegmental area (Muthane et al.
1994) and greater loss of nerve terminals in the putamen than in the caudate nucleus
(Moratalla et al. 1992). Differences with PD are that MPTP damage has much faster effects
and no Lewy bodies are found after MPTP administration in humans, though there is
upregulation of α-synuclein expression in rodents and primates (Meredith et al. 2002).
Dopaminergic neurons in rats are relatively resistant to MPTP-induced toxicity and in mice
susceptibility of the nigrostriatal pathway to neurodegeneration is strain dependant (Muthane
et al. 1994).
6-OHDA administration causes nigrostriatal depletion when stereotaxically injected into the
SN, median forebrain bundle or striatum. It destroys catecholaminergic neurons through a
combination of reactive oxygen species and increased toxic quinones (reviewed by Bove et al.
Figure 2 Schematic representation of the conversion of MPTP in astrocytes and the effects of MPP+ on
neurons (Vila & Predborski 2003).
2005). After injection dopaminergic neurons in the SNpc die within 24 hours, show apoptotic
morphology and decreased α-synuclein mRNA (corresponding with neuronal degeneration),
creating a PD like situation. A difference with PD is that Lewy body formation has not been
observed in this model.
Models based on neurotoxins have enormous value in helping to understand the consequences
of nigrostriatal loss and to test symptomatic therapies and interventions. However, there is no
clear evidence that the mechanisms of action of these toxins are similar to neuropathological
processes occurring in PD. Furthermore, there is no evidence to date that effective
neuroprotection against these toxins translates into an effective neuroprotective therapy in
humans with PD. Another major limitation of the toxin-based models is that they do not
reproduce the pathology and cell loss observed in other brain regions and peripheral tissues of
patients, nor the broad range of non-motor symptoms seen in PD.
Next to models based on neurotoxicity, there are now also transgenic models available.
Genetic mutations identified in familial Parkinsonism have recently provided a new approach
to understand the molecular pathways affected. Transgenic models with knock-outs,
overexpression or mutations in single genes provide a powerful new set of molecular tools to
study etiology. Examples of genes that can be manipulated in PD models are recessively
inherited loss-of-function mutations in Parkin, DJ-1 and PTEN-induced putative kinase-1
(PINK1) (for review see Harvey et al. 2008). In the past decade these were found to cause
early-onset (< 50 years at onset), L-DOPA-responsive Parkinsonism. The slowly progressive
and predominant motor phenotype in these patients suggests a disorder largely restricted to
dopaminergic neuronal loss. The majority of patients with Parkin-linked disease demonstrate
neuronal loss restricted to the substantia nigra. In contrast, dominantly inherited, gain-of-
function mutations in α-synuclein and leucine-rich repeat kinase result in more typical, late-
onset, Lewy body Parkinsonism with multi-system involvement (Ross & Farrer 2005).
Presently, it is unknown whether genetic causes identified in rare, Mendelian forms of
Parkinsonism highlight pathways affected in idiopathic PD. Parkinson’s syndrome most likely
results from an intricate combination of gene and gene-environment interactions. The most
optimal model for studying PD pathology would be one more closely reflecting sporadic
forms of the disease. The only genetic abnormality to date for which good evidence exists in
favour of a link with sporadic PD, is overexpression of wild-type α-synuclein via duplication
or triplication of the gene (Lee & Trojanowski 2006). Furthermore, patients with sporadic
forms of the disease present with abnormal α-synuclein accumulation and aggregates in a
subset of central and peripheral neurons (Halliday et al. 2006). There are several transgenic
mice models overexpressing α-synuclein using various promoters and mutations. A problem
with choosing a promoter, is that this often restricts expression to a specific area or specific
neurons, while models should mimic the broad but regionally selective α-synuclein pathology
observed in patients. It has also been found that some modifications, such as double mutation
or truncation, are necessary to obtain cell loss and decrease dopamine levels in mice
(reviewed by Chesselet 2008). The relevance of these mechanisms of α-synuclein toxicity to
sporadic PD remains unclear because patients do not have doubly mutated α-synuclein and
the phenotype induced by the truncated protein so far does not mimic that of PD. However,
there is a reasonable likelihood that these models share mechanisms that occur in sporadic PD
(Chesselet 2008). Mutations accelerate the formation of abnormal forms of the protein that
can also be adopted by wild-type α-synuclein, and truncated forms of the protein are found in
patient brains (Follmer et al. 2007). Another approach is to overexpress α-synuclein using
viral vectors which produces a rapid degeneration of nigrostriatal neurons (Kirik & Bjorklund
2003). This revealed the ability of wild-type α-synuclein to induce nigrostriatal pathology.
The well controlled regional and temporal overexpression, and the lack of expression during
embryonic and post-natal development, which may better mimic disease conditions and avoid
the upregulation of defence mechanisms, are distinct advantages. However, only a subset of
neurons is transduced in these models, which again brings up the problem of multiple affected
neuronal systems in PD pathology (Chesselet 2004).
Of course the shortcomings of available models should not discourage their use and delay
progress in the field of therapeutic strategies for PD. Each model has its own advantages and
disadvantages and they can be used to test various aspects of the disease.
Astrocytes are the major cell population within the central nervous system (CNS), they make
up 55-60% of total brain cells. Astrocytes are complex highly differentiated cells that are
present throughout the entire CNS. They make numerous essential contributions to normal
functioning in the healthy CNS. Examples of their many functions are regulation of blood
flow, provision of energy metabolites to neurons, participation in synaptic function and
plasticity and maintenance of the extracellular balance of ions, fluids and transmitters. Other
active functions might be synchronisation of neuronal firing patterns through neurotransmitter
release (reviewed by Volterra 2005).
Astrocytes express glial fiblillary acidic protein (GFAP) which is an intermediate filament
involved in controlling the shape and movement of astrocytes and is important for astrocyte-
neuronal interaction. GFAP-mediated astrocytic processes play a vital role in modulation
synaptic efficacy in the CNS. GFAP is also essential for normal white matter architecture and
blood-brain barrier integrity (reviewed by Eng et al. 2000).
Not too long ago, it was believed that astrocytes were inactive elements just providing a
scaffold function in the CNS. Now, it is known that astrocytes express almost the same set of
ion channels and receptors as neurons and they can respond to activation and have active
modulatory roles in intercellular communication (Seifert et al. 2006; Volterra 2005). It was
also found that not all astrocytes are the same with respect to antigen profiles and functional
properties. However, not much is known yet about expression and function of these different
1.4 Astrocytes in the substantia nigra
It has been known for a long time that not all astrocytes in the brain are the same. Initially, a
difference was found between astrocytes in grey and white matter but later it was discovered
that there is also regional and even intraregional heterogeneity (Bachoo et al 2004). In the
brain, astrocytes have an ordered arrangement with minimal overlap, forming discrete
territories in parallel with neuronal and vascular territories (Bushong et al. 2002). Astrocytes
in specific brain areas might differ for example in the neurotransmitter receptors they express,
their immune response, opiod receptor expression or gap junction coupling (Yeh et al. 2009).
Astrocytes can also be divided in one half exhibiting high GFAP expression, low input
resistance, a typical irregular cell body with branched processes and low membrane potential
and another half with low GFAP expression, larger input resistance and lower glutamate
uptake that are not couple through gap junctions (Volterra et al. 2005).
Though it is widely known that astrocytes form a heterogeneous population, not much is
known about specific properties of astrocytes in certain brain areas such as the substantia
nigra, which is important in PD. The reason for the specific loss of dopaminergic neurons in
the SN in PD might be based on special properties of the astrocytes in this area. These could
be more vulnerable to mutations or susceptible to environmental effects, and could have a
different response to injury than astrocytes in other brain areas. It is known, for example, that
there are lower numbers of astrocytes in the SN than in other brain areas (Mena & Yebenes
2008). If the dopamine neurons, which spontaneously generate abundant free radicals during
the metabolism of dopamine, are less protected by a smaller proportion of guardian cells with
high free radical scavenging properties, such as the astrocytes, then this could be an
explanation for the increased susceptibility of the nigral dopamine neurons. Astrocytes
support the differentiation, survival, pharmacological properties, and resistance to injury of
dopamine neurons (Mena & Yebenes 2008).
Astrocytes in the striatum have also been found to express relatively high levels of
intercellular adhesion molecule-1 (ICAM-1), an inflammatory mediator (Morga et al. 1998),
which might make this region more susceptible to inflammation. The SN appears to be
particularly vulnerable to inflammatory processes. For example, lipopolysaccharide (LPS), an
inducer of immune response, injected into the SN leads to loss of tyrosine hydroxylase(TH)-
cells, while there is no cell loss when it is injected into the hippocampus or cortex (Liu et al.
2006). This vulnerability could be due to the high level of oxidative action in dopaminergic
neurons or to the possible higher abundance of microglial cells.
Another factor making the SN more vulnerable is the high levels of MAO-B in this area in
neurons and astrocytes (Damier et al. 1996). MAO-B metabolises dopamine, which is present
in particularly high levels in the SN, because it is produced here, and is released by damaged
neurons. During conversion of its substrate, MAO-B produces ROS, which increases
oxidative stress and can be damaging to neighbouring neurons.
Reactive astrogliosis, whereby astrocytes undergo varying molecular and morphological
changes, is a poorly understood hallmark of all central nervous system pathologies. Reactive
astrogliosis can be induced by all forms and severities of CNS injury or disease including
subtle perturbations. It is not an all-or-nothing response but a finely gradated continuum of
progressive changes in gene expression and cellular changes that are subtly regulated by
complex intercellular and intracellular signalling. The changes undergone by reactive
astrocytes vary with the nature and severity of the injury and are regulated in a context
specific manner (Sofroniew 2009). Cellular changes include hypertrophy, and in severe cases,
proliferation and scar formation, as can be seen in figure 3 and 4. A very important aspect of
astrogliosis is the upregulation of GFAP, which is often used as a marker for reactive
astrogliosis (Eddleston & Mucke 1993). In figure 3 an immunohistochemical staining for
GFAP is shown in healthy tissue and different severities of astrogliosis, clearly showing
morphological changes during reactive astrogliosis. The changes undergone during reactive
gliosis have the potential to alter astrocyte activity both through loss and gain of functions
(Sofroniew 2009). These changes can have both beneficial and detrimental effects on
surrounding neural and non-neural cells. Several aspects of reactive astrogliosis might play a
role in PD pathology. Though astrogliosis might be beneficial in many ways, for example in
maintaining extracellular glutamate levels and homeostasis in the striatum after dopaminergic
neuronal loss, normal astrocytic functions might be compromised during astrogliosis. It has
been found for example that the number of glutamate transporters per astrocyte is reduced in a
model of chronic PD (Dervan et al. 2004). Changes in astrocyte ability to regulate glutamate,
Figure 3 Photomicrographs of immunohistochemical staining of glial fibrillary protein (GFAP) in astrocytes
in wild type mice. In healthy tissue and of different gradations of reactive astrogliosis and glial scar
formation after tissue insults of different types and different severity. (Sofroniew 2009)
and its associated synaptic functions, could be important for the progressive nature of the
pathophysiology associated with Parkinson’s disease.
Figure 4 schematic overview of changes undergone by astrocytes during reactive astrogliosis. (Buffo et al. 2009)
2.1 Astrogliosis in animal models of PD
In the MPTP model, the start of an astrocytic reaction is observed two days after MPTP
application (Kohutnica et al. 1998). This is one day later than the start of the microglial
reaction, suggesting that the astrocytic reaction depends on factors released by microglia, such
as interleukin-1, which is a known stimulator of astrogliosis (Giulian & Lachman 1985). In
the striatum the response is maximal after 5 days and in the SN 14 days after MPTP
administration (Kohutnica et al. 1998). Blocking conversion of MPTP into MPP+ with
pergyline, a MAO-B inhibitor, inhibits the astrocytic response to MPTP. Although the
conversion of MPTP to MPP+ occurs mainly in astrocytes, MPTP alone is not a factor
inducing the reaction of these cells. In MPTP induced reactive astrocytes, interleukin-6 (IL-6)
expression has also been detected (Kohutnica et al. 1998). It has been shown that IL-6 induces
the synthesis of neurotrophic factors, such as nerve growth factor, by astrocytes (Frei et al.
1989), and inhibits the production of neurotoxic agents like tumor necrosis factor α
(TNFα)(Aderka et al. 1989). Overexpression of this cytokine leads to an increase in the
number of GFAP positive astrocytes (Fattori et al. 1995). Furthermore, in the MPTP model,
astrocytic activation parallels the time course of dopaminergic cell death in the SNpc as well
as striatum and GFAP expression remains upregulated, even after most of dopaminergic
neurons have died due to MPTP intoxication. These findings implicate that astrocytic reaction
occurs after neuronal cell death and might play a role in the propagation of the
neurodegenerative process but not in its initiation (Liberatore et al. 1999).
In the 6-OHDA model, upregulation of GFAP is seen 24 hours after lesioning, and peaks at 4
days when GFAP levels are almost 4 times as high. This astrocytic response is transient and
returns to control levels after 28 days. When 6-OHDA is injected unilaterally a small
astrocytic response can be seen in the SN at the controlateral site as well. Furthermore, 6-
OHDA injection can induce GFAP changes over long distances in the striatum and even in the
cortex (Henning et al. 2008; Sheng et al. 1993). These results suggest that astroglial reaction
is triggered directly or indirectly by factors released from damaged neurons. However, it
might be that astroglial reaction is triggered only by the injection lesion and not specifically
by 6-OHDA damage (Depino et al. 2003).
2.2 Astrogliosis in PD patients
Though reactive astrogliosis can readily be found in animal models of PD, autopsy studies of
patients clinically and pathologically diagnosed with PD suggest that there might not be any
significant astrogliosis in the substantia nigra of PD patients. Some immunohistochemistry
experiments on the SN and putamen of PD patients did not find any alterations in the amount
of GFAP-immunoreactive astrocytes or in their morphology, compared to control brains.
Typical morphological characteristics of astrogliosis, such as hyperthrophy, shortening of
cytoplasmic processes and nuclear enlargement, were not found. Moreover, no difference in
the expression of metallothioneins was found, which are normally increased as protection to
increased oxidative stress (Mirza et al. 2000). However, others did find increased amounts of
reactive astrogliosis in PD patients, using GFAP-immunoreactivity (Miklossy et al. 2006).
This reactive astrogliosis was accompanied by high inter-cellular adhesion molecule 1(ICAM-
1) expression in the astrocytes and high expression of the counterreceptor Lymphocyte
function-associated antigen 1 (LFA-1) in microglia,which might be important for sustaining
inflammation (as explained in section 3.5).
At post mortem examinations it has also been found that there are increased amounts of NO
radicals in brains of PD patients (Hunot et al. 1996). In addition to evidence for increased NO
production in PD, impairment of mitochondrial function is also evident (Heales et al. 2004). It
has also been shown that gluthatione, an important antioxidant enzyme, is downregulated in
the SN of PD patients (Pearce et al. 1997; Sian et al. 1994)
2.3 Remote astrocyte activation
In PD and animal models of PD, astrocytes are not only active at the site of
neurodegeneration, the SN, but also in other areas such as the subthalamic nucleus (STN) and
globus pallidus (GP)(Henning en al. 2008). It is hypothesised that communication links exist
between astrocytes, or between neurons and astrocytes, along neuronal pathways that transmit
activating signals in response to neuronal damage, but only if the neuronal pathways are at
least partially intact. Analysis of astrocyte activation in two 6-OHDA rat models of PD:
partial and complete SNc lesions, by injections of 6-OHDA in the striatum and medial
forebrain bundle, respectively, has led to the finding that astrocyte activation after partial
lesioning can spread to the GP and STN while complete lesioning results only in astrocyte
activation at the lesion site (Henning et al. 2008). Astrocytes can presumably propagate
information about neuronal damage or reduced activity through gap-junction linked astrocytic
networks. Complete degradation of a neuronal pathway might lead to breakdown of glial
communication, for example through loss of gap-junctions, which are no longer necessary for
uptake of excess ions or neurotransmitters.
2.4 Activation pathway
Though reactive gliosis is a very common phenomenon not much is known about the
molecular pathways leading to this reactive state in various neurodegenerative diseases.
Analysis of gene expression changes and protein phosphorylation in the MPTP model has
identified the JAK-STAT pathway to be involved in astrocyte activation in PD.
Administration of MPTP caused rapid phosphorylation by JAK2 and nuclear translocation of
STAT3 in striatal astrocytes, prior to the induction of GFAP mRNA and protein (Sriram et al.
2004). Phosphorylated STAT3 can enhance transcription of GFAP possibly via a STAT3
binding site in the GFAP promoter. This indicates that the JAK2/STAT3 pathway is involved
in induction of astrogliosis. The JAK2/STAT3 can be activated by several gp130-related
cytokines, such as IL-6, leukaemia inhibitory factor (LIF) and oncostatin-M (OSM).
Expression of these ligands can be induced by MPTP-mediated neuronal damage, which
could be the trigger for astrogliosis (Sriram et al. 2004). A schematic representation of this
pathway is given in figure 5.
Figure 5 Schematic diagram showing the involvement of gp130-mediated phosphorylation of
JAK2/STAT3 pathway inducing GFAP expression. Upon putative ligand (e.g. IL-6, LIF, OSM) binding,
JAK2 and STAT3 are recruited to the gp130-signal transducer,JAK2 phosphorylates the Tyr-705 residue on
STAT3. The phosphorylated STAT3 dimerize, translocate to the nucleus and mediates transcriptional
activation of astrocytic genes such as GFAP. (Sriram et al. 2004)
3. Neurodegenerative & proinflammatory factors in astrocytes
Reactive astrogliosis in response to injury is a mechanism to clean up damage and control its
spread. Part of this reaction is the stimulation of inflammatory processes which can help
attract other damage controlling cells. However, too much inflammation increases, instead of
restricts damage. In some situations, the immune system can start to attack healthy cells
instead of just cleaning up damaged ones. Astrocytes can stimulate such neurodegenerative
processes and sustain the inflammatory response, sometimes even after the initial trigger is
3.1 α-synuclein in astrocytes and Lewy bodies
α-synuclein (α-syn) is a 14 kDa acidic protein concentrated in presynaptic neuronal terminals
(Norris et al. 2004). Normal physiological functions are hypothesised to include synaptic
vesicle turnover, synaptic plasticity, ubiquitin-proteasome processing and molecular
chaperoning. Its mutations are a cause of autosomal dominant PD. Currently there are three
known point mutations in the α-syn gene: A30P, E46K and A53T; duplications and
triplications also play a role in PD development (Lee & Trojanowski 2006). WT and mutated
forms of α-syn can up-regulate ICAM-1 expression and IL-6 secretion in human astrocytes.
Mutated forms are more potent for this than WT forms, which might explain why they induce
autosomal dominant PD (Klegeris et al. 2006).
Aggregated α-syn is a major component of Lewy bodies, which are frequently found in PD
(Gelb et al. 1999), also in astrocytes. Astrocytic inclusions in other pathologies, such as
progressive supranuclear palsy and corticobasal degeneneration, usually contain tau and not
α-syn. Ultrastructurally astrocytic inclusions in PD are composed of a meshwork of randomly
arranged, loosely packed α-syn filaments, with diameters of 20-40 nm (Wakabayashi et al.
2000). The distribution of glial cells with inclusions in PD is similar to that of
catecholaminergic neurons in the midbrain. The amount of α-syn positive glial inclusions
correlates with nigrostriatal neuronal loss (Wakabayashi et al. 2000). Overexpression of α-syn
in astrocytes results in cell death (Stefanova et al. 2001) but α-syn aggregation in glial cells
takes a long time and degeneration of glial cells is much slower than that of neuronal cells
(Wakabayashi et al. 2000).
Unaggregated α-syn is an effective stimulator of astrocytes and inflammatory processes.
Leakage or excretion of this protein from normal or damaged neurons into the extracellular
space could potentially stimulate astrocytes into an inflammatory state. Monomeric and
aggregated α-syn may be secreted via a special endoplasmic/Golgi-independent exocytosis
pathway (Lee et al. 2005). Such secretion is enhanced by proteasomal and mitochondrial
dysfunction which have been found in PD.
α-syn could influence astrocytes through all three major MAPK pathways: ERK1/2, JNK and
p38, all of which have been associated with the actions of α-syn. Inhibitors of these MAPK
pathways lower IL-6 secretion and ICAM-1 expression in human astrocytes and α-syn
significantly increases phosphorylation of ERK1, ERK2, p47 JNK and p38 MAPK (Klegeris
et al. 2006).
3.2 ER stress and unfolded proteins
It has been recently found that endoplasmic reticulum (ER) stress and aberrant protein
degradation might also play an important role in the pathogenesis of neurodegenerative
disorders. Homocysteine-induced endoplasmic reticulum protein is a stress-response protein
located in the ER membrane of neurons and astrocytes that can help defend against ER stress.
In PD this protein is found in neurons and astrocytes in the SN and it is accumulated in Lewy
bodies, suggesting a role in their formation. Unfolded proteins in astrocytes could induce the
inflammatory response (Slodzinski et al. 2009).
3.3 The role of astrocytes in oxidative stress-induced neuronal degradation
When astrocytes are stimulated by inflammatory mediators such as cytokines and
lipopolysaccharides, induction of the Ca2+ independent isoform of inducible nitric oxide
synthetase (iNOS), leads to generation of nitric oxide (NO) (Bolanos et al. 1994). In situations
of neuroinflammation, such as PD, astrocytes might contribute to neuronal cell death by
increasing NO production. NO also induces damage to the electron transport chain of brain
mitochondria leading to mitochondrial impairment, resulting in more oxidative stress
(Bolanaos et al. 1994). NO reacts with O2- to form peroxynitrite and its reactive intermediates
which can react indiscriminately with proteins, DNA, and other cell constituents.
On the other hand, upon exposure to NO, astrocytes increase their cellular glutathione (GSH)
availability, which can react with reactive oxygen species such as NO, reducing NO levels.
This can protect against oxidative stress induced neuronal degradation, which might be a
major cause of neuronal cell loss in PD. On top of this, increased astrocytic GSH levels lead
to increased GSH release, increasing neuronal protection. NO exposure leads to increased
GSH efflux from astrocytes, even after removal of NO. This is not caused by increased
permeability of the plasma membrane but is a regulated response (Gegg et al. 2003). Neurons
co-cultured with astrocytes approximately double their GSH concentration, protecting them
against NO damage (Gegg et al. 2003). Thus, astrocytes can be both protective against
oxidative stress by increasing their GSH production and increase oxidative stress via
production of NO, damaging neurons.
From post mortem brain studies it is known that NO overproduction is found in PD patients.
Glial cells marked for high NOS activity and NO radicals have been identified in the SN post
mortem examination (Hunot et al. 1996). Furthermore, nitrotyrosine (an index of reactive
nitrogen species formation) residues and elevated nitrosylated proteins have been reported,
and determination of nitrite in cerebrospinal fluid also implies increased formation of NO
within the CNS (Heales et al. 2004). This supports the damaging effects of astrocytes
Proof of the importance of astrocytic gluthatione for neuronal survival comes from a study
using astrocyte-coated dialysis membranes placed directly on top of neuronal cultures to
provide a removable astrocyte layer between the neurons and the culture medium (Chen et al.
2001). Using this technique, it was established that astrocytes can protect neurons against NO
induced damage. Furthermore, it was found that gluthatione-depleted astrocytes cannot
protect neurons against NO damage and the gluthatione content of astrocytes directly reflects
their protective potential. GSH has a special function in protection against NO, but does not
influence normal neuronal survival in the absence of NO. Because astrocyte processes form a
nearly continuous membrane around neuronal cell bodies and processes, they can reduce the
amount of NO reaching neurons by trapping it. GSH can also function as an exchange of
reducing equivalents between astrocytes and neurons.
Unfortunately, it is known that the protection afforded to neurons by astrocytes is finite,
possibly due to a decline in GSH trafficking with chronic iNOS induction (Heales et al. 2004).
Depletion of GSH may facilitate production of reactive oxygen species by astrocytes. GSH is
important in limiting and repairing the deleterious actions of NO, but GSH levels can be
depleted by too high concentrations of NO (Chen et al. 2001). In PD a 40% loss of GSH has
been reported in the SN (Sian et al. 1994). This is at odds with elevated GSH as a protection
mechanism, but could be explained by the mechanism being transient. This decrease in GSH
concentration precedes other hallmarks of PD and may be important in the early pathogenesis
The reason that mainly neurons are affected in PD could be that neurons seem to be more
susceptible to NO exposure. GSH concentration is normally higher in astrocytes than in
neurons and in neurons NO exposure leads to a decrease instead of an increase in GSH. There
is also a greater inhibition of the mitochondrial respiratory chain in neurons than in astrocytes
exposed to NO (Gegg et al. 2003). GSH is synthesised by glutamate-cysteine ligase (GCL),
which is the rate limiting enzyme. The increased GSH concentration in astrocytes might be
explained by increased GCL activity after NO exposure, while in neurons there is no change
in this activity. The high sensitivity of neurons to NO might be caused by low CGL activity
and the inability to increase this activity upon NO exposure, which leads to low GSH
concentrations and greater susceptibility to oxidative stress.
Increased iNOS expression by astrocytes, which produces excessive amounts of NO, could
also play a role in inducing increased GFAP expression, a hallmark of reactive astrogliosis.
Inflammatory mediators and inducers of NO production induce the expression of GFAP in
astrocytes via NO. This induction is inhibited by scavenging NO or inhibiting iNOS, while
NO alone is sufficient to stimulate the expression of GFAP in astrocytes, independent of
microglia. It has been found that the expression of GFAP in astrocytes can be increased via a
NO-GC-cGMP-PKG pathway (Brahmachari et al. 2006), which might be important under
neurodegenerative conditions, for example in PD, and could be a pharmacological target for
3.4 MAO-B expression in astrocytes and production of reactive oxygen species
Monoamineoxidase-B (MAO-B) is found in the brain primarily in non-neuronal cells such as
astrocytes and radial glia. The SN contains especially high levels of MAO-B positive
astrocytes, which might play an important role in PD pathology (Damier et al. 1996). MAO-B
levels are known to increase with age and in association with neurodegenerative diseases
(Kumar & Andersen 2004).
During oxidation of its substrate, this enzyme reduces oxygen to H2O2, which is a reactive
oxygen species (Cohen et al. 1997). It has been postulated that age-related increases in MAO-
B activity may contribute to cellular degeneration in the brain due to corresponding increases
in the production of this reactive oxygen species. Astrocytes themselves are protected against
the H2O2 they produce because they contain high levels of GSH and gluthatione peroxidase,
which can detoxify H2O2 within cells. Surrounding neurons however, are very vulnerable
because they contain lower levels of these protective agents, as explained in section 3.3. High
amounts of H2O2 produced in astrocytes, expressing high amounts of MAO-B, can diffuse to
neurons and contribute to mitochondrial damage and neuronal cell death. MAO-B activity
levels have been found to be doubled in the SN in Parkinson’s disease, and to correlate with
the percentage of dopaminergic SN cell loss (Damier et al. 1996). In vitro studies have shown
that induced increases in astrocytic MAO-B levels result in specific inhibition of
mitochondrial complex 1 activity in cultured dopaminergic cells (Kumar et al. 2003).
Selective reductions in complex 1 activity have also been associated with PD.
It has even been shown that elevations in astrocytic MAO-B result in a relatively selective
loss of dopaminergic neurons in the SN (Mallajosyula et al. 2008). This cell loss was
accompanied by increased mitochondrial oxidative stress and selective decreases in complex
1 activity along with local microglia activation. These pathological findings correlated with a
significant decrease in locomotor activity. Thus, increased MAO-B activity is able to induce
several pathological hallmarks of PD (Mallojosyula et al. 2008). This suggests that MAO-B
may be a common initiator for these events and provides a novel model for exploring the
mechanisms by which these events can occur in the context of the human condition.
3.5 Immune responses and the role of astrocytes in sustaining inflammation
Several lines of evidence suggest that inflammatory mediators such as TNFα, NO and
interleukin-1, derived from microglia and astrocytes modulate the progression of PD
(Teisman & Shulz 2004). Environmental factors, such as infection, may interact with common
but less penetrant susceptibility genes to influence the onset of most commonly observed
sporadic PD cases.
Neuroinflammation in the SN, once initiated, may be self-sustaining, and the SN seems to be
particularly vulnerable to inflammation (Klegeris & McGeer 2007). An important
contributing protein in inflammation of the SN in PD cases could be ICAM-1. ICAM-1 with
its counter receptor LFA-1, is known to play a key role in inflammatory processes. In patients
with neuropathologically confirmed PD, high numbers of ICAM-1 positive reactive astrocytes
were found (Miklossy et al. 2006). In the SN, these ICAM-1 positive astrocytes were
concentrated around residual neurons in areas of heavy neuronal loss. LFA-1 positive
microglia gathered in such areas of high ICAM-1 expression, and LFA-1 leukocytes
infiltrated the tissue (Miklossy et al. 2006). ICAM-1 and LFA-1 are known to play a key role
in setting the level of inflammation in many other inflammatory diseases, such as rheumatoid
arthritis, coronary heart disease, type 1 diabetes and Alzheimers disease (see Miklossy et al.
2006). It is possible that overexpression of ICAM-1 with its ligand LFA-1 in PD patients is
responsible for sustaining inflammation in the SN and that this process is responsible for
autodestruction of SN dopaminergic neurons (Klegeris et al. 2006).
3.6 Effect of hormones on astrocyte development and response to injury
Exposure to hormones is another factor that could influence disease predisposition and
severity, possibly through an effect on astrocytes. Differences in hormone exposure might
also explain differences in PD prevalence between males and females. Alterations in
developmental programming of neuroendocrine and immune system function may critically
modulate vulnerability to Parkinson’s disease. It was found that hormonal programming has
an important effect on glial response to inflammation and oxidative stress. Studies using
glucocorticoid-deficient and estrogen-deprived mice showed that endogenous glucocorticoids
and the female hormone estrogen inhibit the aberrant neuroinflammatory cascade, protect
astrocytes and microglia from programmed cell death, and stimulate recovery of dopamine
neuron functionality, thereby triggering the repair process (Marchetti et al. 2005). In figure 6 a
schematic overview can be seen of the effects of estrogen and glucorticoids on activated
Figure 6 Schematic overview of the effects of estrogen and glucocorticoids on neurons and
astrocytes (Marchetti et al. 2005)
4. Neuroprotective effects of astrocytes
Of course, reactive astrogliosis does not happen without a reason. Initially, it is meant to have
a protective instead of a neurodegenerative effect. Just like astrocytes support neurons during
normal brain function, they continue to offer this support in situations of neuronal damage.
Moreover, they can stimulate repair via neurotrophic factors and control the inflammatory
response, preventing it from becoming excessive.
4.1 Protective effects of PAR-1 activation
A factor that is increased in reactive astrocytes in the SNpc of PD patients is protease
activated receptor 1 (PAR-1), a thrombin receptor. Thrombin-mediated activation of human
astrocytes results in morphologic changes and increased proliferation characteristic of reactive
astrogliosis. Moreover, this results in an increase in glial cell line-derived growth factor and
gluthatione peroxidase but not in inflammatory cytokines. Gluthatione peroxidase release
from these activated astrocytes has a protective effect on surrounding neurons (Ishida et al.
2006). Increased expression of PAR-1 seems to be a restorative move to protect against
4.2 Role of Nurr1 in protecting dopaminergic neurons
Nurr 1 belongs to the nuclear receptor (NR)4 family of orphan nuclear receptors and is known
to function as a constitutively active transcription factor by binding to target genes as a
monomer, homodimer or heterodimer with other receptors (Wang et al. 2003). It has an
essential role in development and/or maintenance of dopaminergic neurons. Human mutations
resulting in reduced expression of Nurr 1 are associated with late-onset familial PD,
indicating that normally Nurr 1 may play a protective role (Le et al. 2003).
Indeed it was found that Nurr 1 plays a previously unexpected role in protecting dopaminergic
neurons from inflammation-induced neurotoxicity (Saijo et al. 2009). It functions as an
inhibitor of inflammatory gene expression in microglia and astrocytes. Astrocytes can act as
amplifiers of microglia-derived mediators in the production of neurotoxic factors. Nurr 1
protects the CNS from amplification of inflammatory signalling via microglia-astrocyte
communication. Anti-inflammatory activity is mediated by a Nurr1/CoREST transpression
pathway that operates in a feedback manner to restore transcription of NF-κB target genes to a
basal state. NF-κB target genes include many pro-inflammatory proteins. Nurr1 is recruited to
NF-κB on inflammatory gene promoters via several mediators. It is suggested that the
CoREST transpression pathway might be widely used by members of the NR4A family.
Reduction of most of the well-established components of the CoREST complex severely
compromises the anti-inflammatory activity of Nurr1. Defects in the expression or activity of
these proteins could predispose individuals to PD (Saijo et al. 2009).
4.3 Anti-inflammatory and neuroprotective effects of hydrogen sulphide
Hydrogen sulphide (H2S) is a physiological product generated by all the tissues in the body
and a high production in the brain. It has anti-inflammatory and neuroprotective effects and is
also a powerful antioxidant, both directly and indirectly, by keeping other antioxidants such as
GSH in a reduced state. It can also react with nitrite ions, neutralising iNOS activity. Both
iNOS activity and oxidation products are known to be important in PD pathogenesis,
suggesting possible involvement of H2S.
In the brain, H2S is synthesised from L-cyteine, via cystathionine-b-synthase (CBS).
Astrocytes are the most powerful producers of H2S in the brain, and most strongly express
CBS, as was found in post mortem brain tissue (Lee et al. 2009). Inflammatory stimulation
causes a reduction in this CBS expression, and thus in H2S anti-inflammatory activity.
Endogenous H2S production has a protective effect against release of inflammatory mediators
by stimulated astrocytes, this can be stimulated by exposure to SH ions (from H2S in
solution). NaSH treatment and endogenous H2S have neuroprotective effects through
reduction of toxic materials secreted by glial cells subjected to inflammatory stimuli, and
reduce production of inflammatory mediatiors including NO (Lee et al. 2009). Externally
supplied SH can also reduce activation of NF-κBwhich is normally induced by inflammatory
stimulation of astrocytes, and suggested to be involved in PD (Saijo et al. 2009).
4.4 The role of purines in regulation of the astrocytic response
Purines also play a significant role in the pathophysiology of numerous acute and chronic
disorders of the central nervous system and might play a role in PD. This hypothesis is
supported by the protective effect of adenosine 2A receptor antagonist in PD models and
epidemiological studies (Jenner et al. 2009). Astrocytes are the main source of cerebral
purines (Cicarelli et al. 1999). They release either adenine-based purines, e.g. adenosine and
adenosine triphosphate, or guanine-based purines, e.g. guanosine and guanosine triphosphate,
in physiological conditions and release even more of these purines in pathological conditions.
Astrocytes express several receptor subtypes of types for adenine- and guanine-based purines
(Cicarelli et al. 2001). Specific enzymes metabolise both adenine- and guanine-based purines
after release from astrocytes. This regulates the effects of nucleotides and nucleosides by
reducing their interaction with specific membrane binding sites. Adenine-based nucleotides
stimulate astrocyte proliferation via an increase in intracellular [Ca2+] and specific effects on
proteins. Adenosine also may stimulate astrocyte proliferation, but mostly inhibits astrocyte
proliferation, thus controlling excessive reactive astrogliosis. The activation of certain
adenosine receptors also stimulates astrocytes to produce trophic factors, which contribute to
protect neurons against injuries. Guanosine stimulates the output of adenine-based purines
from astrocytes and in addition it directly triggers these cells to proliferate and to produce
large amount of neuroprotective factors. These data indicate that adenine- and guanine-based
purines released in large amounts from injured or dying cells of CNS may act as signals to
initiate brain repair mechanisms widely involving astrocytes (Ciccarelli et al. 2001).
4.5 Astrocyte influence on microglia
Although inflammation is an indispensable defense mechanism against pathogens, it often
damages surrounding tissues. Therefore, the extent of inflammation should be tightly
controlled to maximize the antipathogenic effect, while minimizing tissue damage. Astrocytes
might play an important role in this because they can modulate the activity of microglia,
which are responsible for the biggest part of the inflammatory response in PD.
Reactive oxygen species (ROS) are one of the major signalling molecules capable of
modulating microglia activation (Min et al. 2003). Therefore, microglial activation could be
regulated by modulating intracellular ROS level. A candidate molecule to regulate
intracellular ROS is the antioxidant enzyme heme oxygenase-1 (HO-1), which also has anti-
inflammatory effects. Min et al. (2006) demonstrated that astrocyte culture conditioned
medium (ACM) enhance HO-1 expression and activity in microglia. Furthermore, treatment
with ACM suppressed interferon-γ-induced ROS production, leading to reduced iNOS
expression and NO release.
4.6 Protective effects of enriched environment
It has been found that enriched environment (EE) has protective effects against
neurodegeneration (Anastatasia et al. 2009). EE is defined as a sustained and progressive
increase in cognitive and sensorimotor stimuli, with aggregated voluntary physical activity
and complex social interactions. EE significantly reduces 6-OHDA degeneration of
dopaminergic neurons in the SNpc of adult rats, preserves nigrostriatal projections, and most
importantly, improves the dopaminergic function. EE resulted in a marked increase in GFAP
expression in the SN after 6-OHDA lesioning (Anastasia et al. 2009). This suggests that an
early post-lesion astrocytic reaction may participate in the neuroprotective mechanism. It
appears that animals exposed to an EE have an increased ability to respond to the toxic injury
in the anterior SNpc, where the most susceptible neuronal population is located. Reactive
astrocytes probably participate in endogenous cell repair or neuroprotective mechanisms
triggered at very early times following exposure to the toxin, possibly involving release of
brain-derived neurotrophic factor, glial cell-line derived neurotrophic factor, and nerve
growth factor, among many others.
From epidemiological data it is suggested that lifestyle might influence PD etiology and
progression. The risk of PD might be influenced, for example, by educational achievement or
occupation as well as by exercise (Frigerio et al. 2005; Thacker et al. 2008). The use of
enriched environments in experimental situations can model both intellectual stimulation and
4.7 Astrocyte influence on neurogenesis
It is known that there are progenitor cells in the SN, from which new neurons can be formed
(Lie et al. 2002). Stimulating proliferation and differentiation would be very useful to replace
the neurons that are lost in PD. Finding the optimal conditions for this would also help in
potential stem cell replacement therapies. Astrocytes might help in this process by producing
various neurotrophic factors, synthesising extracellular substrates for axonal outgrowth and
synaptogenesis, and providing structural support and guiding migration. They can even act as
astrocytic progenitors during long-term recovery after brain injury (Liberto et al. 2004).
Astrocytes might need to become reactive to induce these properties. It has been found that
mesencephalic progenitor cells survive and differentiate better in rat PD models, than in
normal rats (Sun et al. 2003), and extracts from dopamine-depleted striatum show a stronger
trophic activity (Nakajima et al. 2001). Reactive astrocytes might mediate increased basic
fibroblast growth factor and glial cell-line derived neurotrophic factor levels, or other
neurotrophic factors. This can create an environment in which proliferation and differentiation
of progenitor cells is stimulated which can potentially be modulated to create new therapies
(Chen et al. 2005).
4.8 Nrf2-mediated gene transcription inducing a large neuroprotective response
As discussed before, it is known that oxidative stress might be an important cause of neuronal
degradation in PD. An endogenous cellular defence mechanism against oxidative stress is the
binding of the transcription factor nuclear factor E2-related factor 2 (Nrf2) to the antioxidant
response element (ARE) enhancer sequence. This activates many antioxidant and anti-
inflammatory genes as well as growth factors, inducing a large neuroprotective response.
Nrf2-ARE activated genes include HO-1, NAD(P)H quinone oxidoreductase-1 and
glutathione S-transferases as well as glutathione-synthesizing enzymes glutamate-cysteine
ligase catalytic subunit and glutamate-cysteine ligase modifier subunit (resulting in increased
GSH levels). Inflammatory mediators that are downregulated by Nrf2 include iNOS and
COX-2. Nrf2 is normally bound to its cytosolic suppressor Keap1, which dissociates in
response to oxidative stress, allowing Nrf2 to translocate to the nucleus and induce
transcription. Nrf2 is a very general defense mechanism but in the brain it is believed that this
response is mainly activated in astrocytes, since over expression of Nrf2 in astrocytes is
sufficient to prevent MPTP-induced neuronal cell death (Chen et al. 2009). Induction of this
pathway has also been found to reduce astrogliosis (Kanninen et al. 2009). Moreover, Nrf2
translocates to the nucleus after microglial exposure to astrocyte cultured medium, indicating
that reactive astrocytes might be able to induce this pathway in other cells (Min et al. 2006).
5. Potential therapies for PD treatment targeting astrocytes
Some of these findings about the role of astrocytes in PD can be used to design new PD
therapies, targeting astrocytes. The neuroinflammatory hypothesis implies that drugs with an
anti-inflammatory mode of action should either arrest, or effectively slow down the
neurodegenerative disease progression. The pursuit of novel molecular and cellular targets
could be used for future anti-inflammatory drug development. Establishing which of the
inflammatory mechanisms are the most powerful in sustaining inflammation, and finding
methods to reduce their effects, might be the key to developing truly effective therapy.
It has been found that non-aspirin NSAID use is associated with lower risk of PD, though
there might be gender differences in this protective effect (Hernan et al. 2006). This clearly
indicates that inflammation is involved, and reducing inflammation can have a positive effect.
This effect could be due to classical NSAID action on cyclooxygenases (COXs) or their effect
on other COX independent targets such as transcription factors NF-κB, NO synthase, and
others (Asanuma & Miyazaki 2007).
Lee et al. (2009) found that H2S can reduce production of inflammatory mediators by
astrocytes and had neuroprotective effects through its antioxidant activity. This indicates there
is a considerable therapeutic potential for H2S releasing drugs in the treatment of
neurodegenerative disorders characterised by inflammatory processes, such as PD. Damaging
effects of inflammation could be reduced by supplementary H2S provided by drugs. H2S
releasing NSAIDS such as S-aspirin and S-diclofenac attenuate the neuroinflammation
induced by activation of astrocytes. However, consequent actions on blood vessels, where
H2S is also synthesised, must be taken into account.
Min et al. (2006) showed that astrocytes can regulate microglia activity by inducing HO-1.
They also found that mimickers of HO-1 products, such as bilirubin, ferrous iron, and a
carbon monoxide-releasing molecule, reduced interferon-γ-induced iNOS expression and/or
NO release in microglia. Such components could be used as potential therapies to control the
microglial inflammatory response. It has been found for example that overexpression of Nrf2,
which induces HO-1, can protect again 6-OHDA (Jakel et al. 2007) as well at MPTP induced
damage (Chen et al. 2009) possibly through HO-1 antioxidant and microglia regulatory
Another factor that can modulate astrocyte activity,, and could be a potential therapeutic
agent, is ONO-2506 (Kato et al. 2003). This substance inhibits the expression of COX-2 or
iNOS mRNA, induced in activated astrocytes. In the MPTP-mouse model, ONO-2506
treatment prevented reduction in striatal dopamine and loss of loss of dopaminergic neurons
in the SN. Pre-treatment with this drug has no effect, indicating that is does not influence
MPTP toxicity but acts on astrocytes which are active later. ONO-2506 acts selectively on
astrocytes and modulates their activation or prevents too much activation that may be harmful
to neighbouring neurons. Interestingly, in ONO-2506 treated mice there is no reactive
astrogliosis peaking at 7 days after MPTP-treatment, as in normal situations, but there is a
moderate activation of astrocytes 3 days after MPTP treatment. This suggests that astrocytic
activation is facilitated, but to a limited degree, promoting only protective effects (Kato et al.
A very promising therapeutic target is the Nrf2-ARE pathway, which can induce many
different protective genes at once. Increased Nrf2-mediated gene transcription can be
achieved by overexpression of Nrf2 via injection of lentiviral or other vectors containing this
gene, into the SN (Kanninen et al. 2009). This can be done specifically in astrocytes using an
astrocyte promoter, or in all cells. Transgene expression then induces specific protection
against oxidative stress and reduces inflammation, which might help prevent neuronal
degradation in the SN. Another possibility is the oral administration of synthetic triterpenoids
which reduce Keap1 binding to Nrf2, increasing Nrf2 translocation to the nucleus, thus also
increasing expression of Nrf2-ARE regulated antioxidant and anti-inflammatory genes (Yang
et al. 2009).
There are many more factors involved in astrogliosis that could be manipulated to control the
astroglial reaction, an overview of these is given in Buffo et al. 2009. Of course, manipulation
of astrogliosis remains tricky, as astrocyte response is different in different neuropathologies
and certain effects might be beneficial as well as detrimental depending on the specific
Astrocytes play an important role in neurodegenerative diseases. In situations of neuronal
damage they can become reactive, a process which is called reactive astrogliosis (Eddleston &
Mucke 1993). This can be both beneficial, helping with neuronal repair or it can help sustain
inflammation, which could lead to more damage. Astrocytes react differently to different
types of damage and signals from neighbouring glial or neuronal cells. On top of this,
astrocytes form a heterogeneous population and can have different characteristics in different
brain areas, influencing their response to damage.
From post mortem studies and studies in animal models of PD, it is suggested that astrocytes
also play a role in PD (Kohutnica et al. 1998; Sheng et al. 1993). However, not much is
known about the specific mechanisms involved. It might be that astrocytes in the SN are
particularly vulnerable to certain types of damage or specific mutations, triggering neuronal
cell death in this area and inducing PD (Mena & Yebenes 2008; Morga et al. 1998). Or, once
astrogliosis is started, astrocytes can sustain and propagate inflammation (Liberatore et al.
1999; Miklossy et al. 2006). On the other hand, the reactive state of astrocytes might help
There are several factors that might have detrimental effects in PD. Mutated α-syn in
astrocytes can induce inflammation and aggregated forms of this protein cause neuronal cell
death (Klegeris et al. 2006; Stefanova et al. 2001; Wakabayashi et al. 2000). ER stress and
abberant protein folding are two more factors implicated in PD that can lead to cell death
(Slodzinksi et al. 2009). In their reactive state, astrocytes might also loose functions that are
important for normal neuronal survival such as the ability to regulate extracellular glutamate
levels (Dervan et al. 2004). Increased MAO-B levels in astrocytes due to age or disease result
in increased production of reactive oxygen species, contributing to neuronal cell loss (Damier
et al. 1996; Mallajosyula et al. 2008). ROS production can also be induced by inflammatory
mediators (Bolanos et al. 1994). Normally this is counteracted by increased GSH expression
and efflux but this might be a transient mechanism providing only limited protection (Chen et
al. 2001; Heales et al. 2004). Upregulation of ICAM-1 in the SN of PD patients indicates that
inflammation in this area might be self sustaining (Miklosssy et al. 2006). It is not known why
neurodegenerative effects are sometimes larger than protective effects but this could have
something to do with early exposure to hormones, programming astrocytes for a certain
response (Marchetti et al. 2005).
Protective effects might be mediated through upregulation of PAR-1 which increases GSH
expression and secretion of neurotrophic factors (Ishida et al. 2006). Nurr 1 reduces
inflammation via communication with microglia (Saijo et al. 2009). Antioxidants such as H2S
can help clean up ROS produced during inflammation (Lee et al. 2009). Adenosine might
have protective effects through its stimulation of astrocyte proliferation (Ciccarelli et al. 2001;
Jenner et al. 2009). Enriched environment in animal models or possibly lifestyle in patients
can also protect against neuronal damage presumably via induction of an early protective
astrocytic response (Anastasia et al. 2009). Finally, astrocytes can stimulate neurogenesis via
various neurotrophic factors (Chen et al. 2005) and protect against oxidative stress via
induction of Nrf2-mediated transcription of antioxidant genes (Chen et al. 2009; Kanninen et
Many of the factors increase reactive astrogliosis but this can have negative as well as positive
effects. Potential new PD therapies aimed at astrocytes have to find a way to distinguish
between these two effects. Inhibiting astrogliosis will suppress neurodegenerative but also
many protective effects and necessary homeostasis maintaining functions of astrocytes.
Protective effects should be stimulated without simultaneously stimulating degenerative
effects, or degenerative effects should be blocked without inhibiting protective effects. This
requires specific targeting of receptors and pathways involved in these processes. Some
examples are given of potential therapies aimed at astrocyte functioning. However, much
better understanding of the role of astrocytes in PD and the molecular mechanisms underlying
their effects is needed to find specific therapies that can inhibit the induction or progression of
this disease. Especially important would be to find what triggers or initiates the disease so the
disease can be recognised more early, and treated from the start, before too many neurons are
lost. A promising treatment is also the stimulation of neurogenesis, which might even be able
to repair neuronal networks to some extent. A possible way to achieve this would be to
manipulate astrocytes in such a way that they favour the survival and differentiation of stem
cell transplants and/or natural progenitor cells in the SN (Chen et al. 2005).
A very promising treatment is also the induction of Nrf2-mediated gene transcription (Chen et
al. 2009; Kanninen et al. 2009; Yang et al. 2009). This activates a large general
neuroprotective response through the regulation of antioxidant and anti-inflammatory genes
and growth factors. Instead of targeting single molecules and genes this is a relatively easy
way to influence many genes at the same time. Activation of Nrf2 gene transcription has
already been shown to protect against neuronal cell loss in the MPTP model (Yang et al.
2009). Increasing the neuroprotective and antioxidant potential of astrocytes, via induction of
the Nrf2-ARE pathway seems to be a very effective way to prevent neuronal degradation in
the SN and halt PD progression.
Astrocytes are a very promising target for the treatment of PD. Conventional therapies which
are mostly aimed at neurons, are still not able to stop the progression of the disease or reduce
the symptoms for a longer period of time. A problem with therapies targeting neurons is that
as long as neuronal death is not prevented, eventually there are not enough neurons left to
manipulate. Astrocytes on the other hand only increase their numbers when neuronal cell
death increases, and remain in the area. Astrocytes can be manipulated to stop or slow down
disease progression and possibly even stimulate repair at later stages of the disease, when
many neurons have already died, and other treatments loose effectivity. Therefore, it is very
important to continue research into astrocyte function in PD pathology, to get a better
understanding of the mechanisms underlying the disease and find possible therapeutic targets.
List of abbreviations
ACM astrocytic culture medium
ARE antioxidant response element
CNS central nervous system
DAT dopamine active transporter
EE enriched environment
GABA γ-aminobyturic acid
GCL glutamate-cysteine ligase
GP globus pallidus
HO-1 heme oxygenase 1
IFN-γ interferon γ
ICAM-1 intracellular adhesion molecule 1
iNOS inducible nitric oxide synthetase
LFA-1 lymphocyte function-associated antigen 1
MAO-B monoamine oxidase B
MAPK mitogen activated protein kinase
NF-κB nuclear factor κ B
Nrf2 NF-E2-related factor 2
NO nitric oxide
NSAID non steroidal anti inflammatory drug
NQO1 NADPH quinone oxidoreductase 1
PAR-1 protease activated receptor 1
PD Parkinson’s disease
SN(pc) Substantia nigra (pars compacta)
STN subthalamic nucleus
TH tyrosine hydroxylase
TNFα tumor necrosis factor α
WT wild type
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