MINI REVIEW

published: 30 August 2018

doi: 10.3389/fncel.2018.00282

Microglial Implication in Parkinson’s

Disease: Loss of Beneficial
Physiological Roles or Gain of
Inflammatory Functions?
Cynthia Lecours 1,2 , Maude Bordeleau 1,3 , Léo Cantin 1,4 , Martin Parent 5,6 ,
Thérèse Di Paolo 1,2 and Marie-Ève Tremblay 1,7*
1
Axe Neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Quebec, QC, Canada, 2 Faculté de
Pharmacie, Université Laval, Quebec, QC, Canada, 3 Integrated Program of Neuroscience, Faculty of Medicine, McGill
University, Montréal, QC, Canada, 4 Département de Chirurgie, Faculté de Médecine, Université Laval, Quebec, QC,
Canada, 5 CERVO Brain Research Centre, Quebec, QC, Canada, 6 Département de Psychiatrie et Neurosciences, Faculté
de Médecine, Université Laval, Quebec, QC, Canada, 7 Département de Médecine Moléculaire, Faculté de Médecine,
Université Laval, Quebec, QC, Canada

Microglia, often described as the brain-resident macrophages, play crucial roles

in central nervous system development, maintenance, plasticity, and adaptation to
the environment. Both aging and chronic stress promote microglial morphological
and functional changes, which can lead to the development of brain pathologies
including Parkinson’s disease (PD). Indeed, aging, and chronic stress represent
main environmental risk factors for PD. In these conditions, microglia are known to
undergo different morphological and functional changes. Inflammation is an important
Edited by: component of PD and disequilibrium between pro- and anti-inflammatory microglial
Jose Luis Venero,
Universidad de Sevilla, Spain functions might constitute a crucial component of PD onset and progression. Cumulated
Reviewed by: data also suggest that, during PD, microglia might lose beneficial functions and
Sheela Vyas, gain detrimental ones, in addition to mediating inflammation. In this mini-review, we
INSERM, France
aim to summarize the literature discussing the functional and morphological changes
Frank Kirchhoff,
Saarland University, Germany that microglia undergo in PD pathophysiology and upon exposure to its two main
*Correspondence: environmental risk factors, aging, and chronic stress.
Marie-Ève Tremblay
tremblay.marie-eve@ Keywords: aging, chronic stress, inflammation, microglia, phagocytosis, Parkinson’s disease
crchudequebec.ulaval.ca;
[email protected]
INTRODUCTION
Received: 31 May 2018
Accepted: 09 August 2018 Parkinson’s disease (PD) affects one to two individuals per 1000 (Tysnes and Storstein, 2017),
Published: 30 August 2018 making it the most common neurodegenerative movement disorder (Morin et al., 2014). The
Citation: diagnosis is based on four clinical cardinal signs: rigidity, bradykinesia, resting tremors, and
Lecours C, Bordeleau M, Cantin L, postural instability (Jankovic, 2008). PD is often preceded by a prodromal stage, which includes
Parent M, Di Paolo T and non-motor symptoms like mood and sleep disorders (Poewe, 2008). In PD, motor symptoms arise
Tremblay M-È (2018) Microglial
from the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra (SN)
Implication in Parkinson’s Disease:
Loss of Beneficial Physiological Roles
pars compacta. DA neurons innervate the striatum and their degeneration is associated with a
or Gain of Inflammatory Functions? significant decrease of DA striatal content (Morin et al., 2014; Tysnes and Storstein, 2017). DA
Front. Cell. Neurosci. 12:282. neurons loss is often associated with an accumulation of Lewy bodies (LB), which are formed by
doi: 10.3389/fncel.2018.00282 the aggregation of misfolded α-synuclein, mainly in the SN, but also across several brain regions

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Lecours et al. Microglial Implication in Parkinson’s Disease

(Tansey and Goldberg, 2010). PD pathogenesis is associated contribute to synaptogenesis, synaptic pruning, and myelination
with genetic variations and environmental risk factors that (Schafer and Stevens, 2015; Kaur et al., 2017; Li and Barres, 2017;
mainly comprise aging and chronic psychological stress, as Paolicelli and Ferretti, 2017; Tay et al., 2017; Low and Ginhoux,
well as infection, brain trauma, and exposure to pesticides or 2018). Microglia are also required for the adaptation of the brain
herbicides (Tansey and Goldberg, 2010; Schapira and Jenner, and behavior to the living environment (Tremblay et al., 2011;
2011; Vyas et al., 2016; Niraula et al., 2017). Levodopa (L- Schafer and Stevens, 2015; Tay et al., 2017, 2018). Upon injury
DOPA) is the gold-standard symptomatic treatment for PD, or infection, and even chronic psychological stress, microglia
as no DA agonist demonstrates an equal efficacy on motors undergo various morphological and functional changes often
symptoms. However, adverse effects limit its chronic use. designated as microglial “activation” or reactivity to pathological
Within 5–10 years of treatment, most patients experience motor or traumatic challenges (Nayak et al., 2014; Tay et al., 2017).
complications including L-DOPA-induced dyskinesia (LID), Morphological and functional changes of microglia also occur
abnormal involuntary movements that can be more debilitating during aging where these cells become “senescent,” i.e., impaired
than the disease itself (Mercuri and Bernardi, 2005). in their surveillance and response to injury (Streit et al., 2014).
Inflammation, among the central nervous system (CNS) Considering that changes in microglial density and morphology
and periphery, is also a main hallmark of PD (Vawter et al., profoundly impact on their functions (summarized in Figure 1),
1996; Nagatsu et al., 2000; Imamura et al., 2003; Mount et al., these findings indicate that microglia could play an important
2007; Litteljohn and Hayley, 2012; Doorn et al., 2014). In the role in PD.
CNS, microglia which are known as the resident immune cells
were proposed to mediate the inflammatory response in PD.
The two main environmental risk factors for PD, aging, and MICROGLIA IN PARKINSON’S DISEASE
chronic stress, are linked to increased levels of pro-inflammatory PATHOPHYSIOLOGY
mediators in the CNS and periphery (Vyas et al., 2016; Niraula
et al., 2017; Tian et al., 2017). Nevertheless, the implication of In macaque monkeys treated with the neurotoxin 1-methyl-
microglia in the development and progression of PD is still 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), microglia
unclear, and it remains undetermined whether their alterations immunopositive (+) for major histocompatibility complex
are a cause or consequence of DA neurons loss (Le et al., (MHC) class II were found to be highly heterogeneous. They
2016). Microglia were recently shown to exert throughout the showed ramified, amoeboid or multinucleated morphologies, in
lifespan crucial physiological roles (Tay et al., 2018), which could the SN, nigrostriatal tract, and globus pallidus. Of note, MHC
become compromised and contribute to PD pathophysiology. class II is considered a marker of antigen presentation (Weenink
Transcriptomic studies also shed light on the complex signature and Gautam, 1997). However, in the striatum of macaque
of microglia, defining several phenotypes across contexts of monkeys receiving MPTP, microglia mainly displayed a ramified
health and disease (Butovsky et al., 2014; Gosselin et al., 2017; morphology with little evidence of active phagocytosis associated
Hanamsagar et al., 2017; Wlodarczyk et al., 2017). In the present with the accumulation of fat granules in their processes (Hurley
mini-review, we aim to summarize microglial functions in health et al., 2003). By contrast, amoeboid microglia were observed in
and their potential implications in PD. both the SN and striatum of mice exposed to MPTP (Kurkowska-
Jastrzebska et al., 1999; Wu et al., 2002). Differences in MPTP
administration paradigms or between species could explain
DIVERSE ROLES OF MICROGLIA IN this apparent discrepancy (Hurley et al., 2003). In fact, PD
HEALTH progression in humans has been shown to be best recapitulated
in non-human primates (Table 1 summarizes different animal
The origin of microglia has long been a subject of debate until models used in PD research) (Grow et al., 2016).
elegantly designed in vivo lineage studies in mice identified Various brain regions (e.g., pons, basal ganglia, striatum,
erythromyeloid cells from the embryonic yolk sac as their frontal, and temporal cortices) of PD patients also showed
progenitors (Ginhoux et al., 2010; Schulz et al., 2012; Kierdorf increased binding of the radiotracer 11 C-(R)-PK11195
and Prinz, 2013; Gomez et al., 2015; Hoeffel et al., 2015). compared to age-matched healthy controls by positron emission
These progenitors colonize the brain during the first trimester tomography (Ouchi et al., 2005; Gerhard et al., 2006). The
of fetal development, in both rodents, and humans, then mature radiotracer 11 C-(R)-PK11195 binds to 18-kDa translocator
into microglia (Kierdorf and Prinz, 2013). Thereafter, microglial protein (TSPO) expressed mainly by microglia, in association
pools are maintained by self-renewal, at least under normal with inflammatory stimuli (Mondelli et al., 2017). In the SN
physiological conditions (Hashimoto et al., 2013; Askew et al., of post-mortem PD samples, MHC class II+ microglia were
2017). first described in 1988 (McGeer et al., 1988). Since then,
Mature microglia which display a ramified morphology, other studies confirmed the presence of reactive microglia
referred to as homeostatic microglia, constantly survey the CNS in the SN of PD patients (Hirsch and Hunot, 2009). Besides
environment and contribute to its maintenance and plasticity MHC class II, microglia were shown to express intracellular
through specific molecular pathways (Tremblay et al., 2011; adhesion molecule (ICAM)-1, integrin receptors CD11a, the
Kierdorf and Prinz, 2013; Nayak et al., 2014; Schafer and Stevens, lysosomal activity marker CD68, and the scavenger receptor
2015; Tay et al., 2017). In particular, homeostatic microglia TLR2 in the SN, putamen, and hippocampus of PD patients

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Lecours et al. Microglial Implication in Parkinson’s Disease

FIGURE 1 | Microglial phenotypes that could be differently implicated in PD. Schematized morphologies are represented and their main characteristics summarized.
The following symbols are used; ↑, increased; ↔, unchanged; ↓, decreased.

(Imamura et al., 2003; Doorn et al., 2014). Microglia also stained (Sherer et al., 2003). Microglia release neurotrophic and anti-
positively for pro-inflammatory cytokines such as tumor necrosis inflammatory factors that promote neuronal survival (Le et al.,
factor (TNF)α and interleukin (IL)-6 in the striatum of PD 2016). These cells can also modulate the formation of dendritic
patients (Imamura et al., 2003). Other investigators nevertheless spines through the release of brain-derived neurotrophic factor
failed to observe evidence of microglial reactivity in the same (BDNF) in mouse primary motor cortex, a role that was required
region of PD patients (Knott et al., 1999; Mirza et al., 2000). for motor learning and procedural memory (Parkhurst et al.,
Cytokines such as IL-1β, IL-2, IL-4, IL-6, TNFα, transforming 2013). In PD, BDNF levels were reduced in the nigrostriatal
growth factor (TGF)α, and TGFβ1 were also increased at the region and/or cerebrospinal fluid of PD patients and animal
protein level in the striatum, and in the ventricular and lumbar models, notably exposed to MPTP or 6-hydroxydopamine (6-
cerebrospinal fluid of PD patients (Vawter et al., 1996; Nagatsu OHDA) (Nagatsu and Sawada, 2005). Furthermore, glial-derived
et al., 2000). Additionally, high levels of interferon (IFN)γ were neurotrophic factor (GDNF) was shown to protect and rescue
measured in blood plasma from PD patients (Mount et al., DA neurons from degeneration in models, including rats exposed
2007). Taken together, this data suggests that PD patients possess to methyl-4-phenylpyridinium (MPP+ ), the active metabolite of
an increased brain inflammatory status. Neurotoxic reactive MPTP (Ding et al., 2004; Nam et al., 2015). Additionally, in a
species that microglia can produce, such as superoxide and mouse model overexpressing human mutant α-synuclein, within
nitric oxide, were proposed to induce cellular stress and, in neurons mostly of the spinal cord, an increase in ionized calcium
turn, contribute to neuronal loss in PD (Block et al., 2007; Le binding adaptor molecule 1 (IBA1)+ microglial staining was
et al., 2016). Moreover, the cerebrospinal fluid of PD patients measured in this region alongside an increased co-expression
was shown to be toxic to DA neurons in vitro due to the high of AXL (Fourgeaud et al., 2016). With TYRO3 and MER,
concentration of cytokines and auto-antibodies against quinone AXL is part of the TAM receptor family of tyrosine kinases
proteins altered by DA oxidation (He et al., 2002; Nagatsu and that regulates microglial phagocytic removal of apoptotic cells,
Sawada, 2005). notably during adult neurogenesis. In the α-synuclein transgenic
mouse, loss of both receptors modestly prolonged the lifespan
Loss of Beneficial Physiological (Fourgeaud et al., 2016). The authors speculated that microglia
Functions might remove distressed motor neurons in PD, through TAM
Signaling between the microglial complement receptor 3 (CR3) receptor-mediated “phagoptosis” of living neurons causing their
and its ligand, the complement component C3, enriched at death (Brown and Neher, 2012), thus accelerating PD progression
synapses, plays a key role in synaptic pruning during brain (Fourgeaud et al., 2016). In this case, a beneficial microglial
circuits refinement (Schafer et al., 2012). In rats chronically function was proposed to become detrimental upon disease.
receiving rotenone, a pesticide acting as a mitochondrial complex
I inhibitor, CR3+ microglia were more abundant in the striatum Gain of Detrimental Inflammatory
and the SN. They also possessed an enlarged cell body with Functions
shorter, stubby processes in these two regions, contrary to the Midbrain DA neurons may be particularly vulnerable to
cerebral cortex, suggesting an exacerbated phagocytic activity detrimental microglial functions due to the abundance of these

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Lecours et al. Microglial Implication in Parkinson’s Disease

TABLE 1 | Summary of the main animal models used in PD research.

Animal models Symptoms

Motor Degeneration LID Others

Rodent
6-OHDA rat model ↓ Locomotion, modified ↑↑↑ SN loss, ↑↑↑ striatal DA AIM scale available to measure Not specific to DA neurons, not
behavior loss, no LB, unilateral lesion LID progressive, DA priming
needed for antiparkinsonian
effects
6-OHDA mouse model − − Poor LID −
MPTP mouse model ↓ Locomotion, bradykinesia ↑↑↑ SN neuron loss, ↑↑↑ Need high L-DOPA doses to −
striatal DA neuron loss, no LB induce AIM, poor LID
Rotenone rat model ↓ Locomotion ↑↑ SN neuron loss, ↑↑↑ − −
striatal DA loss, LB
α-synuclein transgenic Modified behavior, ↓ or ↑ SN neuron loss (variable), Poor LID −
mouse model motor activity striatal DA loss, LB (old
animals)
Non-human primate
MPTP cynomolgus and Modified behavior, tremor and ↑↑↑ SN neuron loss, ↑↑↑ LID (best model), LID First L-DOPA dose induces
rhesus macaque model rigidity, ↓ locomotion striatal DA loss, no LB (but reappearance after L-DOPA antiparkinsonian response, best
α-synuclein accumulation), withdrawal, different pattern of to test surgical treatments
bilateral lesion (if systemic) LID: stereotypic behaviors
MPTP marmoset model Modified behavior, tremor and ↑↑↑ SN neuron loss, ↑↑↑ LID Allows to test surgical
rigidity, ↓ locomotion, striatal DA loss, no LB (but treatments, not the best to test
movement indistinguishable, α-synuclein accumulation) anti-dyskinetic drugs
hyperkinesia
MPTP squirrel monkey Modified behavior, tremor and ↑↑↑ SN neuron loss, ↑↑↑ LID, have LID under unlesioned Limited for study of motor
model rigidity, ↓ locomotion striatal DA loss, possibility of conditions complication (no abnormal PD
LB (α-synuclein aggregates) movements observed)

The following symbols are used; ↑, increase; ↓, reduction; ↑↑↑, severe; ↑↑, moderate, summary of (Tieu, 2011; Blesa and Przedborski, 2014; Morin et al., 2014; Jagmag
et al., 2016; Morissette and Di Paolo, 2018).

cells in this region (Lawson et al., 1990). This susceptibility is of DA neurons when added to human primary mesencephalic
also conferred by the enrichment of DA neurons with iron, a neuron-glia cultures (Zhang et al., 2011). The phagocytic
redox active element, associated with antioxidant glutathione clearance of NM by microglia also induced the production
deficiency and monoamine oxidase activity, which all contribute of superoxide, nitric oxide, hydrogen peroxide and pro-
to DA oxidation resulting in the production of reactive species inflammatory TNFα and IL-6, which could be prevented by
(Block et al., 2007; Tansey and Goldberg, 2010; Wang and genetic deletion of CR3 in vitro (Zhang et al., 2011). Besides
Michaelis, 2010). This susceptibility of the SN was further NM, matrix metalloproteinase 3 (MMP3) and α-synuclein, which
emphasized by the finding that local lipopolysaccharide (LPS; are released by degenerating DA neurons, promote microglial
a bacterial component) injection into the SN, hippocampus or production of reactive species (Block et al., 2007).
cerebral cortex of wild-type rats induced neuronal loss only
in the SN (Kim et al., 2000). Further in vitro characterization
of neuron-glial cultures identified a key role for microglia MICROGLIA IN AGING AND CHRONIC
in the regional sensitivity to LPS. Indeed, supplementation STRESS
of microglia into cortical neuron-glial cultures was sufficient
to promote LPS-induced neurotoxicity (Kim et al., 2000). Normal Aging and Microglial Alterations
Microglia might over-produce pro-inflammatory mediators and Aging is associated with an increased expression level of pro-
reactive species, notably when performing phagocytosis, which inflammatory cytokines (e.g., IL-1β, IL-6, and TNFα) as well
could lead to neuronal damage and in turn contribute to as decreased expression level of anti-inflammatory cytokines
sustaining inflammation in PD (Whitton, 2007; Tansey and (e.g., IL-10) and anti-oxidants (e.g., glutathione levels) in rodent
Goldberg, 2010). In rat primary neuron-glial cell cultures, brain (Frank et al., 2006; Sierra et al., 2007; Ritzel et al.,
the exogenous application of α-synuclein aggregates induced 2015). Furthermore, during aging, LPS-immune-challenged mice
microglial transformation into amoeboid cells, which produced display an exacerbated inflammatory response (Godbout et al.,
reactive species resulting in DA neurons loss (Zhang et al., 2005; Sierra et al., 2007; Njie et al., 2012). With relevance to PD,
2005). In vitro, neuromelanin (NM), a dark pigment formed by analyses of IBA1+ microglia in the SN and striatum of wild-type
melanin that is found in catecholaminergic neurons (containing mice, from birth until 24 months of age, revealed that cellular
DA or norepinephrine) (Fedorow et al., 2005), induced loss density is decreased while clustering is increased after 18 months

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Lecours et al. Microglial Implication in Parkinson’s Disease

of age in both regions (Sharaf et al., 2013). Moreover, microglia encircling excitatory synapses and making direct contacts with
underwent dystrophic morphological changes in the SN (see synaptic clefts (Bisht et al., 2016) suggesting an involvement in
Figure 1), such as reduced ramifications, starting at 12 months synaptic remodeling under pathological or traumatic conditions.
(Sharaf et al., 2013). In aged rhesus monkeys, an increase in The involvement of dark microglia in PD still remains unknown,
human leukocyte antigen-DR (HLA-DR), a component of MHC however.
class II+ microglia, and similar morphological alterations were
observed in the SN, together with an increased prevalence of
amoeboid-shaped microglia, upon administration of the MPTP CONCLUSION
toxin (Kanaan et al., 2008).
Overall, various studies using in vivo and in vitro approaches
Chronic Stress and Pathological Aging have improved our knowledge of microglial involvement in
Aging can induce important alterations of brain homeostasis PD despite the differences in paradigms and species used.
notably through its effects on microglia. In addition, aging might Aging and chronic stress, two main environmental risk factors
become “pathological” under the influence of an environmental for PD, exacerbated inflammation and altered microglial
risk factor, such as chronic psychological stress, thus triggering functions. These changes might trigger pathological pathways
disease onset and progression (Streit et al., 2014). notably in vulnerable CNS regions, such as the SN. Microglia
Chronic psychological stress can accelerate cellular aging by produce both pro- and anti-inflammatory mediators, but upon
acting on both oxidative stress and inflammation (Tay et al., neurodegeneration this tight equilibrium might get disrupted
2017; Tian et al., 2017). Upon stress, microglia become “primed” and become mainly pro-inflammatory. The death of DA
and show exaggerated response to a subsequent challenge neurons and associated reactive species production lead to
(Cunningham et al., 2005; Frank et al., 2007). Other than the pro-inflammatory and “phagoptotic” microglial phenotypes.
neuroinflammation changes, chronic restraint stress in otherwise Considering the inflammatory component of PD, it is important
healthy rodents was associated with a loss of neurons expressing to study microglial implication with its onset, progression,
tyrosine hydroxylase (TH), the enzyme that converts L-DOPA and symptomatic treatment using L-DOPA for a translation to
into DA, in the SN (Sugama et al., 2016; Ong et al., 2017). human patients. A better comprehension of the roles of different
This TH+ neuronal loss correlated with an increase of insoluble microglial phenotypes in PD might one day help to find anti-
α-synuclein monomers leading to the formation of aggregates parkinsonian and/or anti-dyskinetic drugs targeting microglia.
and decreased numbers of IBA1+ microglia in the SN (Ong
et al., 2017). Furthermore, when MPTP was administered after
inducing stress, using the same paradigm, the loss of TH+
AUTHOR CONTRIBUTIONS
neurons in the SN was found to be more important in stressed CL, MB, and M-ÈT designed the review outline and wrote a
rats than in unstressed littermates, which also displayed motor first version of the manuscript. MP, LC, and TD revised the
learning deficits (assessed with the rotarod) (Lauretti et al., manuscript and contributed to the subsequent versions.
2016). However, different outcomes of stress on DA neurons
were reported according to the type of stressor used and the
brain region examined (Belujon and Grace, 2015). The overall FUNDING
evidence nevertheless suggests a close relationship between
chronic stress and PD, which highlights the importance of CL and MB are recipients of master and doctoral training awards,
investigating microglial changes as a contributing factor to PD respectively, from Fonds de Recherche du Québec – Santé
pathophysiology. (FRQS). MP, LC, TD, and M-ÈT are funded by the Canadian
Another subset of microglia, “dark microglia” identified Institutes of Health Research (CIHR; #341846). M-ÈT is a Canada
by electron microscopy, was observed in adult mice exposed Research Chair (Tier 2) in Neuroimmune plasticity in health and
to maternal immune activation (Hui et al., 2018), chronic therapy.
unpredictable stress, or aging (Bisht et al., 2016). Dark
microglia display several markers of oxidative stress including
a condensed cytoplasm and nucleoplasm, which led to their ACKNOWLEDGMENTS
name, accompanied by dilation of the endoplasmic reticulum and
Golgi apparatus, as well as mitochondrial alteration. They are We are grateful to Dr. Giamal Luheshi for his critical revision of
highly ramified (see Figure 1) with their processes extensively the manuscript.

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the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson Conflict of Interest Statement: The authors declare that the research was
disease. J. Neurosci. 22, 1763–1771. conducted in the absence of any commercial or financial relationships that could
Zhang, W., Phillips, K., Wielgus, A. R., Liu, J., Albertini, A., Zucca, be construed as a potential conflict of interest.
F. A., et al. (2011). Neuromelanin activates microglia and induces
degeneration of dopaminergic neurons: implications for progression of Copyright © 2018 Lecours, Bordeleau, Cantin, Parent, Di Paolo and Tremblay.
Parkinson’s disease. Neurotox. Res. 19, 63–72. doi: 10.1007/s12640-009- This is an open-access article distributed under the terms of the Creative Commons
9140-z Attribution License (CC BY). The use, distribution or reproduction in other forums
Zhang, W., Wang, T., Pei, Z., Miller, D. S., Wu, X., Block, M. L., et al. (2005). is permitted, provided the original author(s) and the copyright owner(s) are credited
Aggregated alpha-synuclein activates microglia: a process leading to disease and that the original publication in this journal is cited, in accordance with accepted
progression in Parkinson’s disease. FASEB J 19, 533–542. doi: 10.1096/fj.04- academic practice. No use, distribution or reproduction is permitted which does not
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