what is the role of microglia in parkinson’s disease ... · microglia, when chronic, is...

What is the role of Microglia in Parkinson’s disease

Pathology?

Candidate Number: CC5M5

M.S.c Clinical Neuroscience

Library Project

Word Count: 4,797

Supervisor:

Dr. Mark Cooper

Institute of Neurology

University College London

London. 13th

December, 2013.

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Abstract

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder

(Schapira, 2009). It is mainly characterized by the progressive loss of dopaminergic

(DA) neurons in the substantianigra pars compacta (SNpc) in the midbrain, which

translates into typical motor symptoms collectively known as Parkinsonism (Gelb et

al., 1999).Just as in most chronic and acute neurodegenerative conditions, the

pathological features in PD are accompanied by inflammation and microglia

activation. Microglia function as the brain’s immune cells and thus are essential to the

proper functioning of the central nervous system (CNS). However the activation of

microglia, when chronic, is considered neurotoxic and can lead to neuronal

dysfunction and death (McGeer et al., 1988).For long it has been questioned whether

microglial activation in PD is a cause or consequence of the PD pathology, and

particularly of the loss of dopaminergic neurons in the SNpc.In this review, we

discuss the role of microglia in the pathological features characteristic of PD. We

propose that microglia constitute a secondary causal mechanism in PD and act

through a vicious cycle of inflammation. Mounting epidemiological and clinical

evidence indeed suggests that chronic microglial activation occurs early in the disease

and contributes to the demise of dopaminergic neuron. Furthermore, neurotoxin

animal models have helped elucidate several molecular mechanisms thought to

regulate this inflammation. If microglia do in fact contribute to the disease pathology,

then understanding these mechanisms can be valuable for therapeutic treatments in

PD.

Keywords: Parkinson’s disease, Microglia, Inflammation, Neurodegeneration

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Contents

Part I: Parkinson’s Disease ............................................................................................. 6

1.1. Symptoms .............................................................................................................................. 6

1.2. Pathology ............................................................................................................................... 7

1.2.1. Dopamine depletion ................................................................................................................. 7

1.2.2. Lewy Bodies ................................................................................................................................ 8

1.2.3. Braaks Staging ............................................................................................................................ 8

1.3. Cellular mechanisms implicated in PD ....................................................................... 9

Aims ...................................................................................................................................... 11

Methods ............................................................................................................................... 11

Part II: Microglia .............................................................................................................. 12

2.1. Resting microglia .............................................................................................................. 12

2.2. Activated microglia: morphological changes & secretions ............................... 12

2.3. Chronic microglial inflammation................................................................................ 14

Part III: Role of Microglial Activation in PD............................................................ 16

3.1. Postmortem studies: Evidence of microglial activation in PD ......................... 16

3.2. Epidemiological studies: Involvement of activated microglia in PD ............. 17

3.3. Animal Models of PD: cellular mechanisms of microglial action in PD ........ 18

3.3.1 MPTP ............................................................................................................................................. 19

3.3.2. 6-OHDA........................................................................................................................................ 20

3.3.3. LPS ................................................................................................................................................. 22

Conclusion .......................................................................................................................... 24

References .......................................................................................................................... 26

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Abbreviations

6-OHDA 6-hydroxydopamine

APC Antigen-Presenting Cell

AT1 Angiotensin II Type 1 Receptor

ATP Adenosine Triphosphate

BBB Blood-Brain Barrier

BDNF Brain Derived NeurotrophicFactor

cKO Conditional Knockout

CNS Central Nervous System

COX2 Cyclooxygenase 2

DA Dopamine

EPA Eicosapentaenoic Acid

ETC Electron Transport Chain

GBA Glucocerebrosidase

GDNF Glial Derived NeurotrophicFactor

IL Interleukin

iNOS Inducible Nitric Oxide

JEV Japanese Encephalitis Virus

KO Knockout

LB LewyBody

LN LewyNeurite

LPS Lipopolysaccharide

LRRK2 Leucine-Rich Repeat Kinase 2

MHC Major Histocompatibility Complex

MMP-3 Matrix Metalloproteinase-3

MPTP Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MPP+ 1-Methyl-4-phenylpyridinium

NGF NeurotrophicGrowth Factor

NO Nitric Oxide

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NRSF/REST RE1-Silencing Transcription factor / neuron-restrictive silencer transcription

factor

PBR Peripheral Benzodiazepine Receptor

PD Parkinson’s Disease

PEP Postencephalic Parkinsonism

PET Positron Emission Tomography

PINK1 PTEN Induced Putative Kinase 1

PPAR-y Peroxisome Proliferator-Activated Receptor Gamma

RNS Reactive Nitrogen Species

ROS Reactive Oxygen Species

SNCA Synuclein, Alpha

SNL Lateral SubstantiaNigra

SNm Medial SubstantiaNigra

SNpc SubstantiaNigra pars compacta

SP Substance P

SYN Synuclein

TLR Toll-Like Receptor

TNF Tumor Necrosis Factor

TNFR-1 Tumor Necrosis Factor Receptor-1

WT Wild Type

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Part I: Parkinson’s Disease

Parkinson’s disease (PD) was first described by Dr. James Parkinson in 1817,

in his small but famous publication “An Essay on the Shaking Palsy” (Parkinson,

1817, 2002; Alves et al., 2008). PD is the most common motor neurodegenerative

disorder, affecting 5 million people worldwide. The prevalence of PD is heavily age-

related; the disease is seen in 1% of those over the age of 60, and (Nussbaum & Ellis,

2003) and increases to 4-5% in those over 85 years old (Fahn, 2003). However, in the

rare instances of inherited PD which represent 4% of the affected population, the

disease does not seem related to aging as it tends to develop early on before 50 years

of age (Mizuno et al., 2001; Van Den Eeden et al., 2003).

Over the past ten years, a definitive link was established between familial forms

of PD and specific genetic mutations (Farrer, 2006). Indeed, mutations in DJ-1,

PINK1, GBA and Parkin were linked to recessive forms of inherited PD (Bonifati et

al., 2003; Valente et al., 2004a,b), and mutations in LRRK2 and -synuclein were

linked to dominant forms of inherited PD (Paisan-Ruiz et al., 2004; Zimprich et al.,

2004 ). However these mutations only account for a small percentage (~15%) of all

instances of PD (for a review on genetic factors in PD, see Shulman et al., 2010).

1.1. Symptoms

Clinically, PD is manifested by a variety of motor symptoms collectively

known as Parkinsonism. At the earliest stage, patients with PD usually experience a

slight tremor of a limb, and as the disease progresses, other symptoms arise including

resting tremor, rigidity, bradykinesia, and postural instability (Gelb et al., 1999; Fahn,

2003; Wolters, 2008; Stowe et al., 2009). Additionally, several non-motor symptoms

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are commonly experienced, including neuropsychiatric problems, and sensory and

sleep difficulties, and these arise as the disease pathology progresses to non-motor

areas in the brain (Gaenslen et al., 2011; Dickson et al., 2009; Reichmann et al.,

2009; Grinberg et al., 2010; Tysnes et al., 2010; Shulman et al., 2001; Aarsland and

Kurz, 2010; Halliday et al., 2011).

1.2. Pathology

1.2.1. Dopamine depletion

At first sight the brain of PD patients looks normal, however a sectioning of

the brain stem reveals several striking abnormalities, mainly the loss of pigmented

dopaminergic neurons in the midbrain, and the presence of Lewy bodies and pale

bodies in the remaining nigral neurons. The majority of clinical symptoms in PD have

been attributed the selective and massive reduction of dopaminergic neurons in the

midbrain from a normal count of 550,000 to the critically low level of 100,000

(Fearnley and Lees 1991; Pakkenberg, Moller et al. 1991). Neuronal loss in PD

affects many areas in the brain, including but not limited to the substantianigra pars

compacta, locus coeruleus, the nucleus basalis of Meynert, the dorsal motor nucleus

of the glossopharyngeal and vagus nerves and in advanced stages the neocortex.

However the pars nigracompacta (SNpc) region of the substantianigra is the most

severely affected as it has the highest count of dopaminergic neurons in the human

brain (Uhl et al., 1985; Moore et al., 2005). Neurons in the SNpc send their axons

through the nigrostriatal pathway to the caudate and putamen which are involved in

motor control. The degeneration of these neurons and subsequent dopamine depletion

in the ventral midbrain cause an increase in the inhibition of the thalamus and a

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subsequent reduction in the excitatory input to the motor cortex, which is clinically

manifested as bradykinesia amongst other motor symptoms (Obeso et al., 2008).

1.2.2. Lewy Bodies

Whilst most dopaminergic neurons in the PD brain are lost, those remaining

were found to contain in their cytoplasm numerous round eosinophilicproteinaceous

inclusions named Lewy bodies (LBs) after neurologist Frederick Lewy who was the

first to describe them in 1912 (Holdorff, 2002). LBs are considered by many the

hallmark of PD pathology, and are often associated with neuronal loss (Braak et al.,

2003). They are mainly constituted of -synuclein (Spillantini et al., 1997) and

ubiquitin (Lowe et al., 1988), in addition to more than 70 other molecules

(Wakabayashi 2006). LBs are thought to arise from the periphery of other inclusion

(pale bodies), which are located in the substantianigra and locus ceruleus, and formed

by aggregation of abnormal -synuclein. The latter appears to be influenced by a

number of factors including oxidation, phorsphorylation at serine 129, proteosomal

dysfunction and exposure to tau; however the mechanism of -synuclein aggregation

is not fully understood (Shults, 2006). The pathology of PD also includes

neuroaxonal spheroids and thread-like dysphoricLewyneurites (LN) which are seen in

neuronal processes.

1.2.3. Braaks Staging

In 2003, Braak et al. studied 110 cases of PD, and found that the disease’s

pathology progressed in the brain according to a predetermined sequence of six

stages, that have been since referred to as Braaks staging. The first two stages involve

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pathological changes in the medulla oblongata, the olfactory structures, and some of

the pontinetegmentum. Next, in stages 3 and 4 the pathology involves the SNpc in

addition to part of the proencephalic areas. Finally, stages 5 and 6 see the

degeneration of premotor areas as well as higher-order sensory areas of the

neocortex. As nonmotor areas are affected early on in the disease, including the

olfactory system, Doty et al. (2007) have proposed the use of olfactory testing for

early diagnosis of PD.

1.3. Cellular mechanisms implicated in PD

Although the etiology of PD remains unknown, several cellular mechanisms

have been suggested to underlie the disease onset and progression, including protein

aggregation, mitochondrial dysfunction, the ubiquitin proteasome system and

lysosomal dysfunction. A thorough discussion of these mechanisms is outside the

scope of this review, however we will briefly examine the ones relevant for the

purpose of the study (for a full review, see Cannon et al., 2013).

Recent evidence shows that aggregation of abnormal -synuclein actively

contributes to the degeneration of DA neurons. -Synuclein is encoded by the SCNA

gene, and alterations in the latter have been associated with familial cases of PD, and

linked to an increased risk in sporadic PD (Simon-Sanchez et al., 2009). Studies have

shown both in vitro and in vivo that neurons that overexpress this protein can

transmit it to other neurons, thus indicating that -synuclein can spread freely

between neurons (Olanow and Prusiner, 2009; Desplats et al., 2009).

Similarly, Pink1, DJ1 and Parkin have been linked to mitochondrial function

(Schon and Przedborski, 2011). The Pink1 gene encodes a kinase abundant in

mitochondria; a mutation in this gene can compromise mitochondrial function,

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thereby resulting in the intracellular buildup of reactive oxygen species (ROS) and

reactive nitrogen species (RNS) to which the brain, and specifically the

substantianigra, are especially sensitive (Marshall et al., 1999). However PINK1-null

mice were shown to have a normal count of DA neurons and receptors in the SN and

striatum. The role of mitochondrial dysfunction in PD is in part supported by the

MPTP animal model of PD, in which laboratory animals are exposed to the MPTP

neurotoxin which compromises the function of the mitochondrial complex 1;

subsequently, these animals develop PD-like pathologies.

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Aims

Another mechanism that has been recently implicated in PD pathology is

microglial inflammation. Indeed, for over a decade, clinical data has supported the

presence of activated microglia in parallel with the other key pathological features in

the PD brain. We will first look at epidemiological and clinical studies to show that

these microglia do indeed play a role in PD by compromising the survival of

nigraldopaminergic neurons. Next, we will use evidence from experimental studies to

investigate various cellular mechanisms that may mediate this microglial action in

PD.

Methods

A preliminary search was performed on Elsevier B.V., Pubmed and Google

Scholarusing the keywords: microglia, parkinson and pathology. The search was

limited to publications from 1950 to the present (2013) and to the English language.

Additional articles were also provided courtesy of my project supervisor. Next, key

subjects were identified, and separate searches were conducted for Parkinson’s

disease, PD etiology, PD genetics, microglia, infections associated with PD,

postmortem PD studies, and neurotoxin and transgenic animal models.Articles that

were treating non-microglial inflammation were excluded. A complete list of all the

articles used is available in the references section.

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Part II: Microglia

Microglia are the resident immune cells of the central nervous system (CNS),

and have the ability to protect the brain in the event of injury and invasion of

pathogens. They were first described by psychiatrist Franz Nissl in 1899 as reactive

“Stabchenzellen” (rod cells) that could migrate, multiply and perform phagocytosis.

2.1. Resting microglia

Under physiological conditions, most microglia in the adult brain appear to be

in a “resting”, ramified state, characterized morphologically by small, rod-shaped

perikarya bearing long, elaborate processes(Li et al., 2012). At first glance, resting

microglia may seem to be static, dormant cells, with their soma being restricted to a

fixed territory in the brain parenchyma. However as demonstrated by Li et al. (2013)

in a study using time-lapse imaging in vivo in zebrafish, their processes are in fact

extremely dynamic, constantly extending and retracting through the territory as to

monitor surrounding neural tissue for pathogens. This is done at a speed that makes

resting microglia the fastest moving cells in the CNS.

2.2. Activated microglia: morphological changes & secretions

Upon activation, microglia undergo several morphological changes according

to a predetermined sequence of four stages defined by Kreuztberg in 1996 (Figure 1).

They proliferate, migrate, extend their processes to the site of injury and phagocyte

damaged cells and harmful molecules in an attempt to protect the CNS. They also

function as antigen-presenting cells (APCs), by presenting molecules from the

engulfed pathogens to T-cells, thereby initiating an immune response.

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Additionally, activated microglia upregulate their protein expression of iNOS

and their membrane receptors, and communicate with surrounding cells by secreting

a range of immunomodulatory molecules, including pro- and anti-inflammatory

cytokines, chemokines, neurotrophic factors and free radicals (Table 1; Tambuyzer et

al., 2009).

Figure 1: Stages of microglial activation (images adapted from Bonde et al., 2006).

Stage 1:Resting microglia.

Rod-shaped perikaryon, bearing thin,

ramified processes.

Stage 2: Activated ramified microglia.

Elongated perikaryon bearing long, thick

processes.

Stage 3:Amoeboid microglia.

Round perikaryon bearing short, thick

processes.

Stage 4:Phagocytic cells.

“Fried egg” morphology; round

microglia with vacuolated cytoplasm

and no visible processes.

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Table 1: Microglial secretions involved in inflammation

Secretions of activated microglia: Function:

Pro-inflammatory cytokines:

Interleukin (IL-1b); IL-6; IL-12; IL-16; IL-

23; Tumor necrosis factor (TNF-)

Initiate immune response

Anti-inflammatory cytokines:

IL-10; IL1-receptor agonist (IL1-ra);

transforming growth factor ß (TGF ß)

Downregulate immune response

Chemokine:

IL-8

Acts as chemoattractants to attract

microglia to site of injury

Neurotrophic factors:

Nerve growth factors (NGF); brain derived

neurotrophic factor (BDNF); glial derived

neurotrophic factor (GDNF)

Promotes the survival and regeneration

of neurons, and lengthen the life of

microglia to regulate their function.

Free radicals:

Reactive oxygen species (ROS); reactive

nitrogen species (RNS):

Highly reactive; can kill surrounding

pathogens; can also cause neuronal cell

death.

2.3. Chronic microglial inflammation

Microglial activation is important for the normal functioning of the brain, as it

allows to control the CNS environment and can be beneficial to the surrounding cells.

In fact, microglia express a variety of receptors on their surface, and are activated

upon binding of a certain extracellular substance to these receptors. However some of

these substances may act to promote a chronic activation of microglia, which quickly

becomes neurotoxic by inappropriately killing otherwise healthy neurons.

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For instance, LPS is a bacterium that binds to microglia through the toll-like

receptor (TLR) 4. This induces microglia to secrete numerous chemokines and

cytokines, which have the ability to further activate microglia by binding to autocrine

receptors (Kim and de Vellis, 2005). As we will see later, LPS is a commonly used in

animal model of PD. Additionally, microglia can be activated by abnormal or

aggregated -synuclein, which binds to scavenger receptors on microglia and can

induce neuronal death (Floden et al., 2005; Zhang et al., 2005). Also, molecules

released by dying neurons, including ATP, the active form of MMP-3, and

neuromelanin, can further activate microglia, thereby creating a vicious cycle of

inflammation and exacerbating the damage in neurons. Similarly, healthy neurons

express on their surface the transmembrane glycoprotein CD200 which normally

maintains microglia in their quiescent form by binding to the microglial receptor

CD200R; therefore a decrease in CD200 is accompanied by an increase in microglial

activation.

Thus, although microglia activation may be initially triggered by a specific

insult, it can be perpetuated by a continuous positive feedback from dying neurons,

and as a result persist long after the original insult has ceased and exacerbate neuronal

degeneration. Chronic microglial inflammation is neurotoxic and has been implicated

in the pathology of various neurodegenerative diseases, and we suspect that it may

play a particular role in PD by promoting the death of dopaminergic neurons in the

SNpc.

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Part III: Role of Microglial Activation in PD

3.1. Postmortem studies: Evidence of microglial activation in PD

The earliest evidence for the presence of activated microglia in the PD brain

comes from postmortem studies. The first such study dates back to 1998, when

McGeer et al. discovered activated T-lymphocytes and microglia in the

substantianigra of a deceased PD patient. Later many other studies replicated this

finding (Orr et al. 2002; McGeer and McGeer, 2004; Tansey et al., 2007; Hirsch and

Hunot, 2009). Additionally, cyclooxygenase 2 (COX2) and inducible nitric oxide

synthase (iNOS) were also discovered in the PD brain; their presence is suggestive of

an ongoing inflammatory process (Hunot et al., 1996; Knott et al., 2000). Also

indicative of inflammation was the finding of pro-inflammatory cytokines at

markedly increased levels in the cerebrospinal fluid of patients diagnosed with PD;

these included IL-1b, IL-1, IL-2, IL-6 and TNF (see Table 1; Boka et al., 1994;

Mogi et al., 1994a, b; Stypula et al., 1996; Dobbs et al., 1999). TNFR-1, a death-

signaling receptor, also showed increased expression in DA neurons of the

substantianigra (Boka et al., 1994; Mogi et al., 2000). Moreover, genes that encode

sub-units of the electron transport chain (ETC) and pro-inflammatory cytokines were

found to have higher expression in the lateral substantianigra (SNL) compared to the

medial substantianigra (SNm). Indeed, the SNL region is affected earlier and to a

greater extent than the SNm in PD, and this could be due to glial dysregulation in that

area (Duke et al., 2007).

Although the mentioned postmortem studies strongly support the presence of

inflammation in PD, they should be interpreted with caution, as the disease is mostly

at its terminal stage and thus they cannot validate whether microglial activation was a

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cause or a consequence of other pathological mechanisms or the massive neuronal

loss in PD (McGeer and McGeer, 2008). Nevertheless, Gerhard and colleagues

(2006) conducted a positron emission tomography (PET) imaging study of microglial

activationusing PK11195, a selective ligand for the peripheral benzodiazepine

receptor (PBR); he found compared to age-matched healthy participants, patients

with sporadic PD had much higher microglial activation in various regions of the

brain, including the basal ganglia, the striatum, the pons, and the frontal and temporal

cortices. This indicates that increased microglial activation in the SNpc occurs early

in PD and in parallel with the death of nigral DA neurons. Additional data from

epidemiological studies, tissue culture and animal models further supports the idea

that inflammation occurs at an early stage in PD (Liu, 2006).

3.2. Epidemiological studies: Involvement of activated microglia in PD

Several cases of infection have linked with a higher incidence of

Parkinsonism. For instance, the 1918 influenza pandemic was associated with a

marked increase in the occurrence of postencephalic parkinsonism (PEP), also known

as von Economo encephalitis, in the two following decades (Dale et al., 2004). In

fact, PEP then accounted for half of the cases of Parkinsonism (Josephs et al., 2002).

Another such type of infection is that of the Japanese encephalitis virus (JEV) which

affects populations in China, India as well as Southeast Asia; it was found that people

who have been infected with JEV for more than 12 months were at risk of developing

PEP, which shares many locomotor and neuropahtological symptoms with those in

idiopathic PD (Shoji et al., 1993). Ogata and colleagues (1997) have used JEV

experimentally used to induce PEP in rats; these presented with catecholamine

depletion and they showed severe hypokinesia. More recently, Smeyne et al. (2007)

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induced encephalitis in mice by administration of the H5N1 influenza virus. The

infected regions in the mice’s brain displayed -synuclein protein aggregation, in

addition to microglial inflammation, which was chronic in that it remained long after

the infection was gone. The inflammation was associated with a subsequent death of

DA neurons. This study thus suggests that, in general, infection may play a role in the

etiology of PD. Thus, chronic neuroinflammation, as in the cases of viral encephalitis

mentioned above, may be involved in the aggregation of -synuclein and may

compromise the survival of dopaminergic neurons in the NSpc, thereby promoting

the development of Parkinson’s disease. Similarly to PD, patients with Alzheimer’s

disease and multiple sclerosis often experience periods where their symptoms

deteriorate after having an infection (Cunningham et al., 2005).

Perry and colleagues (2007) have suggested that prolonged exposure to pro-

inflammatory mediators during an ongoing infection could lead to a marked increase

in microglial activation that, instead of being neuroprotective, causes further demise

of dopaminergic neurons. Indeed, neurons, as discussed earlier, that are already

damaged or under stress release neurotoxic molecules such as ATP (Davalos et al.,

2005), Neuromelanin (Wilms et al., 2003), MMP-3 (Kim et al., 2005, 2007) and can

lead to -synuclein aggregation (Zhang et al., 205), thereby exacerbating the

activation of microglia (see Table 1).

3.3. Animal Models of PD: cellular mechanisms of microglial action in PD

Animal models are of a particular importance in PD as they have allowed the

study of specific molecular events associated with the disease process, by

reproducing some of the disease’s pathological features in neurotoxin animal models

such as MPTP, 6-OHDA and LPS. Furthermore, by knocking out certain genes

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supposed to regulate inflammatory processes in PD, researchers were also able to

determine some of the cellular mechanisms that may mediate microglia’s neurotoxin-

induced compromising actions on DA neuronal survival.

3.3.1 MPTP

Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that,

upon entry in the CNS, crosses the blood-brain barrier (BBB) and is converted into

MPP+ by monoamine oxidase (MAO)-B (Westlund et al., 1985, 1988; Przedborski

and Jackson-Lewis, 1998). Subsequently, MPP+ is taken up by the dopamine

transporter DAT into nigral dopaminergic cells, where it inhibits the mitochondrial

complex I. This results in the increase in ROS and decrease in ATP, ultimately

leading to the selective death of DA neurons (Przedborski and Jackson-Lewis, 1998;

Przedborski and Vila, 2003). Exposure to MPTP, as demonstrated by its accidental

injection in a group of illicit drug users, rapidly induces acute motor symptoms that

closely resemble those in PD. MPTP exposure is commonly used to model PD in

animal studies.

Activated microglia were found in the CNS of both mice (Liberatore et al.,

1999) and monkeys (McGeer et al., 2003) subsequent to MPTP exposure.

Additionally, many genetic factors are thought to regulate both inflammation and

neuronal death following administration of MPTP, including the prodynorphin (Dyn)

gene (Wang et al., 2012), the NRSF/REST transcription repressor (Yu et al., 2012),

the Wnt/b-catenin pathway, eicosapentaenoic acid (EPA; Luchtman et al., 2012),

naphtazarin (Choi et al., 2012) and curcuminoids (Ojha et al., 2012). However these

were found to regulate inflammation in general, and the specific role of microglia was

not determined. Nevertheless, the Angiotensin II peptide was recently found to be in

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part responsible for MPTP-induced microglial activation. Indeed, Labandeira-Garcia

and colleagues found that the binding of Angiotensin II to AT1 receptors increases

microglial activation in response to MPTP exposure in the mouse midbrain, both in

vitro and in vivo (Joglar et al., 2009). More recently, the group of Garrido-Gil (2012)

engineered AT1 knockout (KO) mice; subsequent to MPTP exposure, the KO mice

showed reduced microglial activation and microgliosis, along with lower DA

neurotoxicity subsequent, relative to WT mice. Thus, MPTP neurotoxicity could be in

part mediated by the increased microglial activation that occurs upon activation of the

AT1 receptors.

3.3.2. 6-OHDA

6-hydroxydopamine (6-OHDA) is a neurotoxic synthetic dopamine derivate,

which similarly to MPTP, is taken up by DAT into dopaminergic neurons, and kills

the latter by generating ROS (Cohen and Heikkila, 1974; Simola et al., 2007).

Treatment with 6-OHDA induces degeneration of DA neurons in the SNpc and DA

depletion, and is in fact the most commonly used model of PD (Simola et al., 2007).

However, unlike MPTP, 6-OHDA cannot cross the BBB, and as a result must be

administered by direct injection into the CNS at the site of the nigral DA neurons.

In a study using 6-OHDA-lesioned rats, Crotty and colleagues (2008) identified

activated microglia in the SNpc using MHC Class II antibodies, and found that

microglial activation was markedly increased, 10 and 28 days after 6-OHDA

treatment. Increased microglial activation was also reported by other researchers

using the 6-OHDA model (Akiyama and McGeer, 1989; He et al., 2001; Depino et

al., 2003). Additionally, Derpino and colleagues also found an increase in IL-1b

mRNA, and McCoy et al. (2006) noted a decrease in nigral DA loss in mice treated

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with 6-OHDA upon blocking the soluble form of the TNF- receptor.

However it should be noted that with this neurotoxin model, the resulting

nigrostriatal inflammation is not uniform across the various CNS regions, as shown in

a recent imaging study by Maia et al. (2012). The researchers imaged microglial

activation in the rat striatum and SNpc at several intervals after a unilateral,

intrastriatal 6-OHDA lesion. They found that microgliosis was delayed in the SNpc

by 14 days after the lesion, relative to the striatum, although by day 14 the extent of

microglial activation was simiar in both regions of the CNS. This indicates a

retrograde neuroinflammatory response is initiated at the site of the lesion in the

striatum and subsequently extends to the SNpc. Thus in PD, it could be that the death

of DA cell bodies in the SNpc is caused by axonal degeneration that starts in the

striatum.

As for MPTP, several factors were found to regulate 6-OHDA-induced

microglial activation. Indeed, agonists of the nuclear receptor PPAR-y were found to

decrease microglial activation following 6-OHDA treatment in rats, relative to

control rats that were not administered the PPAR-y agonists. This suggests that

PPAR-y has neuroprotective effects against 6-OHDA neurotoxicity (Sadeghian et al.,

2012). However, as PPAR-y is mainly expressed in neuronal cells (Moreno et al.,

2004), we hypothesize that PPAR-y agonists may attenuate toxicity through direct

interaction with neurons, and that their effects on microglial activation could be

secondary.

In contrast to PPAR-y agonists, agonists for the neuropeptide Substance P

(SP) was found to exacerbate DA neurotoxicity following 6-OHDA lesion. SP

antagonists, however, reduced the number of activated microglia and showed slight

neuroprotective effects against 6-OHDA-induced toxicity.

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3.3.3. LPS

Lipopolysaccharide (LPS) is a bacterium, which upon intranigral injection in

rats, causes progressive degeneration of DA neurons and can be used to model the

pathology in PD (Castano et al., 1998). Interestingly, it was found that rats exposed to

LPS prenatally developed fewer nigral DA neurons (Ling et al., 2004). Furthermore,

in vitro cell culture studies from the rat midbrain show DA neurons to be twice as

vulnerable to LPS-induced toxicity as other neurons, and that LPS toxicity is

mediated by the activation of microglia (Bronstein et al., 1995; Gayle et al., 2002).

Several in vitro studies implicate nitric oxide (NO) in microglia’s effects on

DA neurons following exposure to LPS (Chao et al., 1992; Gibbons and Dragunow,

2006), however other studies do not support this finding (Castano et al., 1998; Gayle

et al., 2002). Similarly, McCoy and colleagues (2006) found IL-1b to play a role in

LPS-induced toxicity. Specifically, they found this cytokine to be released in a dose-

dependent manner in microglial cultures from rats after exposure to LPS, and they

noted that blocking the soluble TNF- receptor decreased microglial activation.

More recently, Koprich et al. (2008) injected a low, non-toxic dose of LPS

into the rat SNpc, and they reported an increase in microglial activation and in IL-1b;

however DA neurons were not affected. But when they later followed with 6-OHDA

treatment, the resulting loss of DA neurons was significantly exacerbated compared

to neurons that were not previously exposed to LPS. Similar findings combining LPS

and 6-OHDA were obtained by another group (Godoy et al., 2008). This suggests that

the initial insult from the LPS treatment primed the microglia, while the subsequent

insult lead to fully activated microglia.

of 36

Lately, Cui’s group (2012) treated rats with LPS by injecting it unilaterally

into the striatum, and they administered the experimental group with the

polysaccharide fucoidan. Although LPS caused DA neuronal loss, the group of rats

that received fucoidan had this loss reduced by 25-30%, suggesting that fucoidan

could be used as a therapeutic agent in PD; however, further research should be done

in order to elucidate the mechanisms underlying the protective function of fucoidan.

Finally, Trojanowski and colleagues (2006) conducted a study in which they

administered LPS in the SNpc of three groups of mice;-synuclein (SYN)-null mice,

mice overexpressing human SYN, and mice overexpressing mutant SYN. Although

all mice had similar extents of inflammation, only those overexpressing human SYN

also displayed inflammation and aggregation of insoluble -synuclein in parallel with

the neuronal degeneration. This suggests that protein aggregation in PD may cause

increased microglial activation, thereby further exacerbating neurodegeneration in the

SNpc.

of 36

Conclusion

Parkinson’s disease is mainly characterized by the massive loss of nigral DA

neurons and the presence of -synuclein-containing Lewy bodies. As revealed by

postmortem studies of the PD brain, these are also accompanied with inflammation,

to which the DA neurons in the SNpc are especially vulnerable. Indeed, it has now

become evident in many epidemiological, clinical and animal studies that microglial

activation in PD is not a mere epiphenomenon or an end-result of neuronal death;

rather, it is chronic, neurotoxic and occurs early in the disease process, thereby

exacerbating the death of dopaminergic neurons. It can thus be concluded that

microglial activation constitutes a secondary causal mechanism of Parkinson’s

disease, initiated by a combination of genetic predispositions and environmental

triggers. Throughout the disease, a vicious cycle of microglial inflammation is

perpetuated and reinforced by various molecular events (see Figure 2)

of 36

.

Figure 2 – Molecular events that trigger and maintain microglia activation thereby

contributing to DA neuron degeneration

a. In PD, the degeneration of nigral DA neurons is thought to be triggered by an interaction between

genetic predispositions and environmental factors.

b. The damaged neurons release molecules that increase microglial activation, including ATP, the

active form of MMP3 and neuromelanin.

c. Additional molecular mechanisms were found to mitigate microglial activation. Some of these can

be traced back to genetic mutations, such as -synuclein protein aggregation which is associated with

the SNCA gene. Others are influenced by epigenetic factors that can significantly modify the risk of

PD, such as infection and aging.

d. When microglia are activated, they secrete pro-inflammatory cytokines (TNF-, IL-1b) and

chemokines, and increase the production of oxidative stress thereby compromising neuronal survival.

The cycle is maintained as more neurons die and activate additional microglia.

of 36

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