Neurobiology of Stress 9 (2018) 9–21

Contents lists available at ScienceDirect

Neurobiology of Stress
journal homepage: www.elsevier.com/locate/ynstr

Chronic stress as a risk factor for Alzheimer's disease: Roles of microglia- T

mediated synaptic remodeling, inflammation, and oxidative stress
Kanchan Bishta, Kaushik Sharmaa, Marie-Ève Tremblaya,b,∗
a
Axe Neurosciences, CRCHU de Québec-Université Laval, Québec, QC, Canada
b
Département de médecine moléculaire, Université Laval, Québec, QC, Canada

A R T I C LE I N FO A B S T R A C T

Keywords: Microglia are the predominant immune cells of the central nervous system (CNS) that exert key physiological
Microglia roles required for maintaining CNS homeostasis, notably in response to chronic stress, as well as mediating
Stress synaptic plasticity, learning and memory. The repeated exposure to stress confers a higher risk of developing
Alzheimer's disease neurodegenerative diseases including sporadic Alzheimer's disease (AD). While microglia have been causally
Neurodegeneration
linked to amyloid beta (Aβ) accumulation, tau pathology, neurodegeneration, and synaptic loss in AD, they were
Neuroinflammation
also attributed beneficial roles, notably in the phagocytic elimination of Aβ. In this review, we discuss the
Synaptic remodeling
Microglial phenotypes interactions between chronic stress and AD pathology, overview the roles played by microglia in AD, especially
Dark microglia focusing on chronic stress as an environmental risk factor modulating their function, and present recently-
described microglial phenotypes associated with neuroprotection in AD. These microglial phenotypes observed
under both chronic stress and AD pathology may provide novel opportunities for the development of better-
targeted therapeutic interventions.

1. Introduction: microglia and Alzheimer's disease CX3CR1CreER/ROSA26iDTR-flox mice treated with tamoxifen to induce
expression of the diphtheria toxin receptor selectively in microglia, and
Microglia are known to rapidly respond to alterations in brain receiving diphtheria toxin to deplete these cells, showed decreased
homeostasis during stress, trauma, disease or pathology (Matcovitch- motor learning-induced dendritic spine formation, and reduced levels
Natan et al., 2016; Tian et al., 2017). They are the resident, pre- of synaptic proteins VGlut1 and GluA2 from glutamatergic synapses in
dominant immune cells of the CNS, which although initially thought to the motor cortex (Parkhurst et al., 2013).
be responsible for orchestrating neuroinflammation and causing neu- Reactive ‘microgliosis’ in terms of abnormal morphology (e.g. a shift
rodegeneration (Cartier et al., 2014), were also recently attributed from a ramified to an amoeboid morphology), exacerbated im-
important roles in the maintenance of CNS homeostasis and remodeling munoreactivity for ionized calcium-binding adapter molecule 1 (IBA1),
of neuronal circuits across development and experience-dependent and increased proliferation is a prominent feature of AD pathology,
plasticity (Derecki et al., 2014; Ransohoff and El Khoury, 2015; Tay especially observed around amyloid plaques in postmortem brain
et al., 2017). Microglial ability to sense neuronal activity allows them to tissue. Similarly, positron emission tomography scans of AD patients
regulate synaptic plasticity, learning and memory mechanisms, and using the TSPO tracer [11C]-PK11195 revealed exacerbated glial activity
hence determine cognitive abilities (Morris et al., 2013; Sipe et al., (Edison et al., 2008; Perlmutter et al., 1992; Rozemuller et al., 1992;
2016). For instance, brain derived neurotrophic factor (BDNF) pro- Serrano-Pozo et al., 2011b). Investigating microglial implication in AD
duced by microglia was shown to modulate motor learning-dependent onset and progression is becoming increasingly important given the
synapse formation in mice (Parkhurst et al., 2013). In addition, various roles that these immune cells can play. While microglia were

Abbreviations: Aβ, Amyloid beta; ABCA7, ATP-binding cassette transporter A7; AD, Alzheimer's disease; APOE, Apolipoprotein E; APP, amyloid precursor protein; BDNF, brain derived
neurotrophic factor; CD11b, cluster of differentiation molecule 11B; CD33, cluster of differentiation 33; CNS, central nervous system; CR, complement receptor; CRF, corticotropin
releasing factor; DAM, disease associated microglia; DAP12, DNAX-activation protein 12; FAD, Familial Alzheimer's disease; FCRLS, Fc receptor-like S scavenger receptor; GR, gluco-
corticoid receptor; HPA axis, hypothalamic pituitary adrenocortical axis; IBA1, ionized calcium-binding adapter molecule 1; IL, interleukin; LTP, long-term potentiation; MGnD, microglia
with a neurodegenerative phenotype; mPFC, medial prefrontal cortex; MR, mineralocorticoid receptor; NADPH, nicotinamide adenine dinucleotide phosphate; NFT, neurofibrillary
tangles; PS, presenilin; ROS, reactive oxygen species; TGFβ, transforming growth factor β; TLR, Toll-like receptors; TMEM119, transmembrane protein 119; TNFα, tumor necrosis factor-
α; TREM2, triggering receptor expressed in myeloid cells 2; TYROBP, TYRO protein tyrosine kinase binding protein
∗
Corresponding author. Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval, 2705 Boulevard Laurier, Québec, QC, G1V 4G2, Canada.
E-mail address: tremblay.marie-eve@crchudequebec.ulaval.ca (M.-È. Tremblay).

https://doi.org/10.1016/j.ynstr.2018.05.003
Received 18 January 2018; Received in revised form 23 February 2018; Accepted 14 May 2018
Available online 19 May 2018
2352-2895/ © 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
K. Bisht et al. Neurobiology of Stress 9 (2018) 9–21

causally linked to neuroinflammation, Aβ accumulation (see Box 1), model resulted in cognitive impairment, accompanied by increased
and tau pathology, as well as implicated in neuronal and synaptic loss expression levels of pro-inflammatory tumor necrosis factor (TNF)α and
(Fuhrmann et al., 2010; Morris et al., 2013), they were also shown to interleukin (IL)-6, and decreased expression levels of anti-inflammatory
actively participate in the phagocytic clearance of Aβ and protection of IL-10 (Jiang et al., 2014). The association of TREM2 with its binding
neuronal tissue (Ard et al., 1996; Grathwohl et al., 2009; Majumdar partner DAP12, an activating adaptor protein, is important for micro-
et al., 2011; Maphis et al., 2015). glial survival and proliferation in mice, especially through regulation of
AD is a debilitating, progressive neurodegenerative disease and the the Wnt/β-Catenin pathway (Poliani et al., 2015; Zheng et al., 2017).
most common cause of dementia worldwide (van der Flier and TREM2/DAP12 activity is essential for microglial innate immune re-
Scheltens, 2005). It is characterized by a slow, progressive cognitive sponses, including chemotaxis and phagocytosis (Kleinberger et al.,
dysfunction, memory decline, and gradual disturbances in reasoning, 2014; Takahashi et al., 2005; Zhong et al., 2017). TREM2 knockdown
language, and physical abilities (Holtzman et al., 2011). In AD, the using a lentiviral strategy reduced microglial ‘efferocytosis’ or phago-
presence of extracellular Aβ deposits and intracellular neurofibrillary cytosis of apoptotic neurons, while its overexpression increased mi-
tangles (NFTs) are main hallmarks that lead to neuronal dysfunction, croglial phagocytic activity in a mouse neuron-microglia co-culture
cell death, and loss of synaptic connections, notably due to ensuing system (Takahashi et al., 2005).
inflammation and oxidative stress (Zhao and Zhao, 2013). The im- Other genes expressed by microglia that were implicated in sporadic
balance in Aβ homeostasis, i.e. production versus clearance of Aβ pep- AD include the ABCA7 gene and its variants rs3764650, rs4147929, and
tides, leads to their accumulation, aggregation –in either fibrillary, rs3752246 (Cuyvers et al., 2015). The gene encodes a protein thought
oligomeric, or β-sheet conformations– and deposition within the ex- to regulate lipid homeostasis (as well as Aβ homeostasis possibly) and
tracellular space (Sadigh-Eteghad et al., 2015). The extracellular Aβ mediate the formation of phagocytic cups, critical for microglial pha-
deposits trigger active ‘gliosis’ that primarily consists in hyperactive gocytosis of apoptotic cells and Aβ (Abe-Dohmae et al., 2004; Jehle
astrocytes and microglia among the surrounding parenchyma (Hardy et al., 2006; Kim et al., 2013). Increased ABCA7 levels were measured
and Higgins, 1992; Kurz and Perneczky, 2011; Wildsmith et al., 2013). in AD postmortem brains, and also in an AD mouse model knockout for
The hyperphosphorylation of tau –a tubulin binding protein that ABCA7 (J20/Abca7−/− mice) showing significantly increased insoluble
functions to stabilize microtubules in the neurons (Kadavath et al., Aβ levels and plaque burden in the brain, thus suggesting that ABCA7
2015)– results in its dissociation from microtubules, and aggregation in exerts a neuroprotective role in AD (Kim et al., 2013; Li et al., 2015).
the form of NFTs inside of neuronal cell bodies and neurites, which also Through this review, we aim to discuss the consequences of chronic
triggers gliosis (Grundke-Iqbal et al., 1986; Kadavath et al., 2015; stress on the onset and progression of AD pathology, overview the roles
Serrano-Pozo et al., 2011a). Synaptic and neuronal loss as a result of tau played by microglia in AD, by focusing on chronic stress as an en-
pathology and Aβ deposition have been shown to best correlate with vironmental risk factor modulating their function, and present the re-
the cognitive impairment seen in AD (Spires-Jones and Hyman, 2014). cently-described microglial phenotypes associated with neuroprotec-
These pathological features may appear early in subcortical nuclei such tion in AD. These microglial phenotypes observed upon chronic stress
as the locus coeruleus, then affect the hippocampus and entorhinal and AD pathology may provide novel opportunities for the develop-
cortex, and eventually spread to other cortical areas as the disease ment of therapeutic applications across different contexts of neurode-
progresses (Braak and Del Tredici, 2011; Glenner and Wong, 1984; generation.
Grundke-Iqbal et al., 1986; Hardy and Higgins, 1992; Holtzman et al.,
2011; Raber et al., 2004). 2. Chronic stress as an environmental risk factor
AD is a multifactorial disease driven by a combination of genetic
and environmental factors, and can therefore be classified into familial Stress is our body's natural response to adverse or demanding
(FAD) and sporadic forms (Johns, 2014). FAD comprising about 5% of changes in our environment, developed as a measure to deal and
AD cases is due to mutations in APP, presenilin-1, or presenilin-2 genes overcome these challenges to our well-being (McEwen, 2005). Allos-
that result in the production of aggregation-prone Aβ peptides (Johns, tasis refers to such internal adaptive mechanisms that attempt to restore
2014; Lanoiselée et al., 2017). Sporadic forms have no familial history homeostasis to meet the perceived and anticipated demands posed by
of AD, but may be related to the expression of apolipoprotein E4 the stressful situations (McEwen and Seeman, 1999). Stress, therefore,
(APOE4) involved with the transport of lipids, cholesterol, and other is crucial for survival, but its response can become maladaptive (Ellis
hydrophobic molecules into the brain (Raber et al., 2004). In addition, and Del Giudice, 2014). Depending on the actual stressor and the se-
environmental factors that comprise psychosocial stress confer a high verity of its effects, stress can be either beneficial or detrimental, and
risk of developing neurodegenerative diseases and may play an im- the duration and chronicity of the stressors exposure also plays an
portant role in the etiology of sporadic AD (Alkadhi, 2012; Aznar and important role in determining its outcome (McCormick and Hodges,
Knudsen, 2011; Nation et al., 2011). Genetic risk factors for sporadic 2017).
AD also include mutations or polymorphisms in several genes expressed While the body can quickly resolve and normalize the effects of
by microglia and other myeloid cells (Dos Santos et al., 2017; acute stress, when it becomes chronic, stress may seriously perturb the
Efthymiou and Goate, 2017; Jonsson et al., 2013; Malik et al., 2015; physiological and psychological balance of an individual. Repetitive
Satoh et al., 2017; Sims et al., 2017), stressing the importance of these recruitment of the neuroendocrine response to chronic stress can lead to
immune cells. While the brain is home to perivascular macrophages, as a cumulative disturbance of the internal homeostatic mechanisms.
well as monocytes derived from the bone marrow that enter the CNS Chronic unpredictable and uncontrollable stressors are generally asso-
from the circulation, especially during brain injury or systemic in- ciated with a high risk of developing cardiovascular diseases, depres-
flammation (Guillemin and Brew, 2004; Schwartz et al., 2013; Wohleb sion, and neurodegenerative disorders that include AD, especially in
et al., 2015), microglia are the predominant immune cell population individuals susceptible to stress and its detrimental effects (Leonard,
within the CNS. 2010; Liu et al., 2017).
The genes associated with sporadic AD include TREM2 (Guerreiro In individuals that are susceptible to stress, due to the high allostatic
et al., 2013), which codes for a cell surface protein (Prokop et al., 2015; load, the once protective coping mechanisms become pathological,
Sessa et al., 2004). The particular R47H variant of TREM2 leads to a whereas in resilient individuals, the adaptive response is successfully
loss-of-function that impairs TREM2-mediated neuroprotection and used to maintain homeostasis (McEwen, 2000; McEwen and Wingfield,
increases the risk of developing AD by threefold (Guerreiro et al., 2013; 2007). The biological mechanisms that determine the individual re-
Jonsson et al., 2013; Melchior et al., 2010). Knockdown of TREM2 in sponse to stress is the subject of intense research with the aim of pro-
the brain of a senescence-accelerated mouse prone 8 (SAMP8) mouse moting stress resilience, given the severe impact that chronic stress has

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K. Bisht et al. Neurobiology of Stress 9 (2018) 9–21

on human health and the serious burden that it imposes on individuals AD in late-life stages (Johansson, 2014; Johansson et al., 2012, 2010;
as well as to the society (Schneiderman et al., 2005; Seib et al., 2014). Wang et al., 2012). These evidence indicate that chronic stressors
Stress is also a consequence of disease, especially when the normal confer an increased vulnerability to developing neurodegenerative
day-to-day activities of the affected individuals are being significantly diseases across the lifespan.
disrupted as a result of their underlying medical condition, thus causing Similarly, chronic stress was shown to ‘prime’ or sensitize microglia
psychological stress (Donovan et al., 2018). The resulting psychological to generate heightened, exaggerated responses to a second stimulus
stress may lead to exacerbated cellular stress due to inflammation and occurring later in life (Santos et al., 2016). Studies by our group and
oxidative damage (Hayashi, 2015; Miller and Sadeh, 2014). The mo- others have detailed the effects of chronic stress on microglia using a
lecular mechanisms by which stress leads to altered homeostasis and number of paradigms in rodents, including maternal separation, phy-
pathology will be discussed further in this review. sical restraint, tail suspension, forced swim or water immersion, social
A key physiological system that responds to psychological stress is defeat or isolation, and unpredictable modifications of the housing
the hypothalamic-pituitary-adrenocortical (HPA) axis, which comprises conditions (Calcia et al., 2016; Lehmann et al., 2016; Roque et al.,
a tightly regulated pathway of communication between the para- 2016; Sugama et al., 2011, 2007; Wang et al., 2017; Winkler et al.,
ventricular nucleus of the hypothalamus, the pituitary gland, and the 2017; Wohleb et al., 2018). Overall, these studies revealed that mi-
adrenal gland. Stressors exposure results in HPA axis activation that croglia are integral partners in mediating the response of the brain and
eventually leads to the secretion into the blood stream of glucocorticoid behavior to stress. In the absence of proper neuron-microglial crosstalk
stress hormones: cortisol in humans or corticosterone in rodents (Smith (as observed in Cx3cr1 knockout mice, which are deficient in frac-
and Vale, 2006). Blood glucocorticoids cross the blood-brain barrier talkine signaling) (see Box 1), chronic unpredictable stress failed to
and enter the brain to activate glucocorticoid receptors (GR) and mi- alter microglial morphology and phagocytic activity, as well as short-
neralocorticoid receptors (MR), two important signaling pathways and long-term synaptic plasticity, including long-term potentiation
having essential roles in mediating the brain response to stress (LTP, a cellular mechanism proposed to underlie memory formation)
(Scheuer, 2010). While GR is ubiquitously expressed by neurons, mi- (Milior et al., 2016). Cx3cr1 knockout mice also failed to develop an-
croglia, CNS-infiltrating monocytes, astrocytes, and oligodendrocytes, hedonia, which is a measure of depressive-like behavior (Milior et al.,
MR expression is restricted to mainly neurons showing limited ex- 2016). Similar findings of an increased resistance to stress in the Cx3cr1
pression by microglia and astrocytes (Madalena and Lerch, 2017). MR knockout mice were reported by other groups using different stress
is active in basal conditions, due to its high binding affinity and sen- paradigms (Hellwig et al., 2016; Rimmerman et al., 2017; Winkler
sitivity toward the low resting levels of corticosteroids (de Kloet et al., et al., 2017). In addition, microglial depletion, using systemic admin-
2000). It mediates the tonic functions of glucocorticoids, including their istration of a colony stimulating factor 1 receptor antagonist, in mice
circadian regulation of learning and memory (de Kloet et al., 2000). GR exposed to repeated social defeat stress, prevented anxiety (McKim
is mainly active during stressful conditions, due to its low binding af- et al., 2017). Similarly, treatment of rats with minocycline, a well-
finity for corticosteroids, allowing its response to high corticosterone/ known modulator of microglial activity, rescued working memory upon
cortisol levels (de Kloet et al., 2000; Groeneweg et al., 2012). GR and exposure to chronic restraint stress (Hinwood et al., 2012). These
MR also differ in their relative distribution across the brain; while MR is findings and those from other studies indicate that microglial response
restricted to the prefrontal cortex (PFC), amygdala, and hippocampus, to stress may be critical in determining its outcome on resilience or
GR shows an abundant brain-wide expression especially in the PFC, susceptibility, with consequences on the overall brain homeostasis.
amygdala, hypothalamic paraventricular nucleus, locus coeruleus,
hippocampus, and hindbrain (Fuxe et al., 1987; Meaney et al., 1985; 3. Consequences of chronic stress on AD pathology
Reul and de Kloet, 1986, 1985).
Glucocorticoid signaling through GR and MR ensures a tight control A complex interaction of genetic and environmental factors has
over the HPA axis during an acute stress response, requiring an in- been proposed to modulate the etiology and pathogenesis of AD. Meta-
tegrative and coordinated activity of neuroendocrine circuits among the analysis studies conducted by Ownby et al. provided strong correlations
forebrain, hypothalamic, and hindbrain systems in order to mediate between individuals’ histories of early-life depression and their risk of
adaptive changes at both the physiological and behavioral levels (Myers developing AD later in life (Ownby et al., 2006).
et al., 2014). However, in conditions of prolonged psychological stress, In animal studies, the exposure of male and female 5xFAD mice (in
when the adaptive changes are no longer sufficient to meet the en- pre-pathological stages; see Fig. 1 for additional information on the AD
vironmental challenges, the HPA axis is chronically activated due to a pathology mouse models mentioned in this review) to chronic restraint
loss of inhibitory feedback causing a dysregulation of glucocorticoid stress resulted in increased neurotoxic Aβ42 (see Box 1) levels and
signaling (Ellis and Del Giudice, 2014; Nicolaides et al., 2015; O'Connor plaque deposition in the hippocampus of females only, without changes
et al., 2017, 2016; Vyas et al., 2016). For instance, rats receiving in the cerebral cortex of both males and females (Devi et al., 2010). This
chronic subcutaneous administration of corticosterone showed a per- finding suggests a sex- and brain region-specific vulnerability to the
manent depletion of hippocampal corticosterone receptors, accom- detrimental effects of stress. The elevation of blood glucocorticoid le-
panied by loss of hippocampal neurons, similar to that seen during vels upon stress could adversely influence Aβ processing, by targeting
aging (Sapolsky et al., 1985). the amyloid precursor and amyloid precursor-like proteins as shown in
The sustained increase in glucocorticoid levels was also proposed to rats in vivo (Budas et al., 1999). Similarly, exposure of APP-PS1 mice
initiate Aβ accumulation and tau pathology in AD (Dong and (see Fig. 1) to chronic isolation stress resulted in increased Aβ42/Aβ40
Csernansky, 2009; Green et al., 2006). The glucocorticoid cascade hy- ratios (see Box 1) in the hippocampus while worsening spatial working
pothesis postulates that HPA axis dysfunction may represent a con- memory (Huang et al., 2011). Chronic immobilization stress to
tributing factor in the pathogenesis of AD and other neurodegenerative APPV717I-CT100 mice (overexpressing human APP-CT100 bearing the
diseases, but strong clinical evidence is currently lacking (Bao et al., London mutation (V717I), see Fig. 1) also resulted in impaired per-
2008; Franceschi et al., 1991; Swanwick et al., 1998). In support of this formance under the passive avoidance task, increased extracellular Aβ
hypothesis, AD patients present a ∼83% increase in cortisol levels in deposits, elevated tau phosphorylation levels, and increased Aβ and
their cerebrospinal fluid compared to healthy age-matched controls, APP carboxyl-terminal fragments (APP-CTFs; see Box 1) in the hippo-
thus indicating an association between stress and AD (Sapolsky et al., campus, entorhinal, and piriform cortex (Jeong et al., 2006). Also, 3xTg
1985; Swaab et al., 1994; Woolley et al., 1990). Several other human mice (see Fig. 1) subjected to social stress showed increased plasma
studies revealed that individuals with a life-long history of stress or corticosterone levels accompanied by heightened anxiety compared to
trauma are at higher risk of developing brain atrophy, dementia, and age-matched wild-types (Rothman et al., 2012). The 3xTg mice

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K. Bisht et al. Neurobiology of Stress 9 (2018) 9–21

Fig. 1. Overview of the AD pathology mouse models mentioned in the review. Data compiled from Alzforum Alzheimer's disease research model database (https://
www.alzforum.org/research-models/alzheimers-disease).

additionally displayed increased levels of Aβ oligomers, intraneuronal memory may partly result from the decreased expression levels of dif-
Aβ, and decreased levels of BDNF in the hippocampus, but no change in ferent plasticity-related proteins, including calcium calmodulin kinase
hyperphosphorylated tau (Rothman et al., 2012). Tg2576 mice showed II and protein kinase C, and increased expression levels of protein
increased Aβ levels and reduced IBA1 immunoreactivity, as well as phosphatase 2B (calcineurin), which are known to inhibit LTP in the rat
deficits in spatial and fear memories, while the PS19 mice had elevated hippocampus (Gerges et al., 2004). Cytokines secreted by microglia
levels of hyperphosphorylated tau in the form of insoluble aggregates, such as anti-inflammatory IL-10 and TGFβ, and pro-inflammatory
with an impairment of fear memory upon chronic restraint and isola- TNFα, IL-1β, IL-6, IL-12 and IL-18, could also be implicated (Piirainen
tion stress (Carroll et al., 2011). These detrimental effects were pre- et al., 2017). For example, IL-1 regulates learning and memory me-
vented by pre-stress treatment with an antagonist of the corticotropin chanisms notably through its influence on LTP. The induction of LTP
releasing factor (CRF) (Carroll et al., 2011). Mice overexpressing CRF promotes IL-1 expression while blocking IL-1 impairs maintenance of
(without bearing any mutations associated with AD) similarly displayed LTP in the rat hippocampus (Balschun et al., 2003; Schneider et al.,
increased levels of hyperphosphorylated tau in this study (Carroll et al., 1998). Similarly, IL-18 positively regulates LTP maintenance, while IL-
2011) and others (Campbell et al., 2015), supporting the detrimental 6 negatively regulates LTP maintenance in the rat hippocampus (del
consequences of chronic stress-mediated HPA axis dysregulation on AD Rey et al., 2013). The contribution of inflammatory microglia to AD
pathogenesis. pathology (Sarlus and Heneka, 2017) will be discussed below.
Aside from affecting the hallmark features of AD, the exposure of Chronic stress additionally regulates the synthesis and secretion of
rodents to stress resulted in impaired adult neurogenesis and synaptic neurotrophins that play key roles in synaptic plasticity, learning and
plasticity. Tg2576 mice (see Fig. 1) undergoing chronic isolation stress memory. A decline in BDNF expression was measured in the hippo-
showed an accelerated age-dependent deposition of Aβ, accompanied campus of wild-type rats in response to chronic restraint stress (Chiba
by reduced hippocampal neurogenesis and decreased contextual et al., 2012; Smith et al., 1995) and of rodent depression models upon
memory, compared with their unstressed littermates (Dong et al., predator stress or repeated social defeat (Roth et al., 2011; Tsankova
2004). Tran et al. revealed significant alterations of LTP and spatial et al., 2006). A similar decline in blood BDNF levels was detected in
memory in rats chronically receiving subpathogenic doses of Aβ patients suffering from depression or showing predisposition to de-
(subAβ) that were also exposed to repeated social defeat stress. Un- pression, which could be reversed by antidepressant treatment (Karege
stressed rats receiving subAβ did not differ from the controls receiving et al., 2005; Sen et al., 2008; Shimizu et al., 2003; Trajkovska et al.,
vehicle (Tran et al., 2011). This effect of social stress on LTP and spatial 2008). A reduction in BDNF levels was also observed in AD patients at

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K. Bisht et al. Neurobiology of Stress 9 (2018) 9–21

preclinical and clinical stages, within the hippocampus and temporal complement C1q protein in the brain (Fonseca et al., 2017).
cortex, where the diminished BDNF levels correlated with the pa- The exacerbated activity of microglial signaling through their CD33
thology severity (Connor et al., 1997; Michalski and Fahnestock, 2003; receptors was also linked to their deleterious effects in AD. Sialic acid is
Peng et al., 2005; Phillips et al., 1991). These data suggest that al- an important glycan typically found on the outer membrane of most cell
terations in neurotrophin signaling, particularly of BDNF, may underlie types. The interaction of sialylated residues on neurons with Siglec
some of the deleterious effects of chronic stress, and hence influence AD receptors on microglia is essential for a healthy neuron-microglial
onset and progression. BDNF expression is among other mechanisms communication in the brain (Varki, 2008; Wielgat and Braszko, 2012).
regulated by glucocorticoid signaling onto both GR and MR (Suri and CD33 (or siglec-3), a sialic acid-binding transmembrane receptor pro-
Vaidya, 2013). Since microglia express GR and MR, they were proposed tein, is largely expressed by microglia, and functions to inhibit auto-
to play important roles in facilitating the adaptive response to stress immune activation through its binding to sialylated self-association
and AD pathology, notably through their remodeling of neuronal cir- molecular patterns (Griciuc et al., 2013; Malik et al., 2013; Schwarz
cuits (Carrillo-de Sauvage et al., 2013; Chantong et al., 2012; Parkhurst et al., 2015; Varki and Angata, 2006). A modest increase in CD33
et al., 2013; Sierra et al., 2008; Tanaka et al., 1997; Vyas et al., 2016). mRNA and protein levels detected in postmortem human AD frontal
cortex was associated with a decrease in Aβ phagocytosis, and conse-
4. Roles of microglia in AD pathology quently, knockout mice lacking CD33 showed a reduced Aβ burden
(Griciuc et al., 2013). Sialic acid binding (from sialylated agents found
While microglia exert neuroprotection in AD, especially through in the vicinity of plaques, such as ApoE and ApoJ) to CD33 results in the
their phagocytic clearance of Aβ (ElAli and Rivest, 2016), a loss of their activation of SHP1 and SHP2 phosphatases inhibiting the TREM2/
beneficial functions can exacerbate amyloidosis, leading to subsequent DAP12 pathway. This mechanism was proposed to conceal the plaques
inflammation, synaptic loss, and neuronal damage (Gandy and from microglial immune surveillance and phagocytic clearance
Heppner, 2013; Heppner et al., 2015; Perry and Holmes, 2014; Rivest, (Linnartz and Neumann, 2013). TREM2 binding to its ligands such as
2015). Vice versa, microglial inability to clear abnormally aggregated ApoE, clusterin (CLU, or ApoJ), and low density lipoproteins, allows its
Aβ results in the activation of pro-inflammatory signaling pathways, association with the plaques (Atagi et al., 2015; Bailey et al., 2015).
furthering inflammation, oxidative stress, and neurodegeneration in AD TREM2-ApoE interaction is essential for the phagocytosis of apoptotic
(Lee and Landreth, 2010; Piirainen et al., 2017; Solito and Sastre, neurons and extracellular debris, from dying or dead neurons, as will be
2012). The following section aims at providing an overview of these discussed below when presenting novel microglial phenotypes. It also
various roles of microglia in AD, emphasizing the relationship to prevents escalation of neuroinflammation in mice treated with cupri-
chronic stress as an environmental risk factor. zone, a model of demyelination (Cantoni et al., 2015). TREM2 over-
expression in mouse primary microglial cells results in their cytoske-
4.1. Loss of beneficial physiological functions letal reorganization through the activation of DAP12 and
phosphorylation of extracellular signal-regulated kinases, and this step
The classical complement pathway is normally utilized by microglia is crucial for the phagocytosis of microsphere beads in vitro (Takahashi
to eliminate apoptotic or damaged neurons, microbial load and cellular et al., 2005). Furthermore, TREM2 is expressed by microglial processes
debris, as well as synaptic elements (Boulanger, 2009; Chung et al., in the immediate vicinity of the plaques. Plaque-associated microglia
2015). The cascade involves tagging of the targeted elements by C1q, surround amyloid deposits in postmortem human AD brain tissue, as a
their opsonization and subsequent phagocytosis via C3b complement- mechanism proposed to compact the deposits and inhibit any additional
CR3 microglial complement receptor (also known as CD11b) interac- deposition of Aβ peptides into the existing plaques, in order to prevent
tion. Its contribution to microglial pruning of synapses is now well further neurotoxicity and axonal dystrophy (Yuan et al., 2016). This
accepted during normal physiological conditions (Sasaki et al., 2014; neuroprotective barrier was not observed in Trem2 knockout mice, or
Schafer et al., 2012; Stevens et al., 2007) and was also proposed to in human AD postmortem brain bearing the TREM2 variant R47H, thus
underlie the pathological or traumatic remodeling of neuronal circuits supporting the implication of TREM2 in mediating microglial ability to
during stress by ‘dark’ microglia, a newly-defined microglial phenotype form neuroprotective barriers (Condello et al., 2017, 2015; Yuan et al.,
discussed below (Bisht et al., 2016). Complement pathway-mediated 2016).
microglial phagocytosis is a mechanism also recruited in diseases, im-
plicated in AD and in a number of neurodegenerative disorders such as 4.2. Gain of detrimental inflammatory functions
Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis
(Loeffler et al., 2006; Stevens et al., 2007). Zanjani et al. documented a A characteristic hallmark of stress, especially chronic, is the in-
progressive activation of complement proteins in human AD brain duction of pro-inflammatory mechanisms leading to oxidative stress
tissue, specifically of C1q, C3 and C4 around the plaques in both pre- (Hayashi, 2015; Miller and Sadeh, 2014), a condition resulting from the
clinical and clinical stages of the disease (Zanjani et al., 2005). This imbalance between antioxidant mechanisms and production of reactive
study revealed staining of NFTs and dystrophic neurites for the mem- oxygen species (such as H2O2, O2−, NO, ONOO−/ONOOH), eventually
brane attack complex C5b, which results from the cleavage of C5 upon triggering lipid peroxidation and DNA damage (Aschbacher et al., 2013;
binding of Cb3b to Aβ, in more advanced stages of pathology (Zanjani Bergamini et al., 2004; Epel, 2009). Oxidative stress induced neuronal
et al., 2005). Elevated C1q expression levels were also measured during damage is also a characteristic feature seen in Aβ and tau pathology,
aging in the human postmortem hippocampus, as well as in the hip- and often mediated by microglia and peripheral myeloid cells (Ghribi
pocampus and frontal cortex of J20 and APP-PS1 mouse models of AD et al., 2003; Giraldo et al., 2014; Kempuraj et al., 2016; Martin et al.,
(see Fig. 1), showing co-localization with synapses before the plaques 2017). Microglia engaged in inflammation are considered a major
could be detected (Hong et al., 2016; Stephan et al., 2013). Synaptic source of reactive oxygen species in the brain (Block and Hong, 2007).
loss was further prevented in the hippocampus of J20 and Tg2576 mice Aβ aggregates can mimic the damage-associated molecular patterns
with either C1q neutralizing antibodies or knocking out of C1q (Fonseca and stimulate Toll-like receptors (TLR; see Box 1) on microglia thereby
et al., 2004; Hong et al., 2016). The knockout or inhibition of C3 si- mounting an inflammatory response by the NRLP3 (NACHT, LRR and
milarly prevented synaptic loss in the hippocampus and cognitive de- PYD domains-containing protein 3) inflammasome complex (see Box 1)
cline in APPswe/PS1dE9 mice (see Fig. 1) still devoid of plaques, as (Heneka et al., 2013). As a consequence of the inflammasome activa-
well as during normal aging in wild-type mice (Shi et al., 2017). This tion, caspase-1 is recruited to the inflammasome, and a number of pro-
detrimental role of microglial complement-mediated phagocytosis is inflammatory mediators such as TNFα and IL-1β are released to induce
supported by the fact that microglia are the main cellular source of further pro-inflammatory responses by microglia and other brain

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K. Bisht et al. Neurobiology of Stress 9 (2018) 9–21

immune cells like astrocytes (Heneka et al., 2013). Genetic deletion of details (Bisht et al., 2016). In electron microscopy, these cells showed a
NLRP3, caspase-1 and TLRs was shown to be neuroprotective by pre- condensed, electron-dense cytoplasm and nucleoplasm, a characteristic
venting the synaptic loss and cognitive decline, thereby confirming the giving them a ‘dark’ appearance. Dark microglia also displayed en-
pro-inflammatory contributions of CD11b-positive microglia in AD doplasmic reticulum and Golgi apparatus dilation, as well as mi-
(Heneka et al., 2013). Also, microglia were demonstrated to increase tochondrial alterations, considered the best-characterized signs of oxi-
the formation of Aβ oligomers and promote further their aggregation dative stress at the ultrastructural level. These cells seemed to be
due to the ability of Aβ to rapidly bind to ASC specks (see Box 1) re- extremely active at synapses, by means of their thin, elongated, rami-
leased by microglia, seeding further Aβ aggregation and spreading of fied processes strongly expressing complement receptor CR3 when
Aβ pathology, as observed in APPSwePSEN1dE9 mice (see Fig. 1) given contacting synaptic clefts and encircling synaptic elements. In mouse
intra-hippocampal injection of ASC specks (Venegas et al., 2017). Si- hippocampus, dark microglia were highly prevalent in conditions
milarly, co-application of an anti-ASC antibody did not exacerbate Aβ where normal homeostasis is disturbed: chronic stress, aging, AD pa-
pathology, as was also the case in ASC-deficient APPSwePSEN1dE9 thology (APP-PS1 mice; see Fig. 1), and where fractalkine signaling is
mice treated with brain homogenates derived from APPSwePSEN1dE9 disrupted (Cx3cr1 knockout mice; see Box 1). Especially in APP-PS1
mice (Venegas et al., 2017). These findings provide a direct evidence mice, dark microglia were frequently encountered around the plaques,
for the involvement of microglial inflammasome in the seeding and encircling dystrophic neurons, containing amyloid depositions in their
spreading of Aβ pathology in AD patients. processes, and showing a strong expression of TREM2, involved as
The pro-inflammatory C5a, which also results from the binding of discussed above in mediating microglial phagocytosis (Colonna and
C3b to Aβ, and is recognized by microglial CD88 receptors, leads to the Wang, 2016; Numasawa et al., 2011; Painter et al., 2015; Zheng et al.,
production of various pro-inflammatory cytokines, reactive oxygen 2017). Dark microglia showed a downregulated expression of homeo-
species (ROS), reactive nitrogen intermediates, and bioactive amines static markers, CX3CR1, IBA1 and P2RY12, but strongly expressed the
(Wilkinson and Landreth, 2006; Woodruff et al., 2010). Microglial ROS microglia-specific 4D4 in their processes (Bisht et al., 2016). They were
can be formed by the activities of nicotinamide adenine dinucleotide proposed to represent a subset of hyperactive microglia that become
phosphate (NADPH) oxidase, mitochondrial respiratory chain, xanthine stressed as a result of their hyperactivity under adaptive pressure,
oxidase, microsomal enzymes, cycloxygenase and lipoxygenase leading to exacerbated interactions with synapses. The increased pha-
(Wilkinson and Landreth, 2006). NADPH oxidase forms part of the in- gocytic activity of dark microglia also suggested that these cells might
tegral innate phagocytic immune system that utilizes superoxide (O2-) contribute to restricting the Aβ burden.
to mediate the destruction of invading microorganisms (Bergendi et al.,
1999; Wilkinson and Landreth, 2006). Other sources of ROS include 5.2. Disease associated microglia
hydrogen peroxide, hydroxyl radical, peroxynitrite and other oxidants
(Wilkinson and Landreth, 2006). In rat primary microglia, exposure to Keren-Shaul et al. identified a unique microglial population, the
Aβ activates NADPH oxidase and causes the release of ROS, which can disease associated microglia (DAM), using single-cell RNA-sequencing,
be terminated through the inhibition of upstream signaling partners by comparing microglia from wild-type versus 5xFAD mice (see Fig. 1)
such as the src-family tyrosine kinases or phosphatidylinositol-3 kinase (Keren-Shaul et al., 2017). Using the immune marker CD45+, myeloid
(Bianca et al., 1999; McDonald et al., 1997). Aβ induced NADPH oxi- cells were isolated from the brain and grouped into different clusters
dase activation in the rat hippocampus results in the formation of based on single-cell RNA-sequencing data. Three main microglial
peroxynitrite, a potent oxidant that oxidizes proteins, lipids, and DNA clusters emerged. Cluster I comprised cells expressing markers of
(Nam et al., 2012). Peroxynitrite mediated tyrosine nitration and ni- homeostatic microglia, which were present in both control and AD
trosylation of cysteines is extremely detrimental resulting in protein pathology animals, while clusters II and III microglia were only ob-
and enzyme dysfunction, leading ultimately to neuronal death in vitro served in AD pathology. The clusters II and III microglia showed an
(Bonfoco et al., 1995; Mander and Brown, 2005). The accumulation of upregulated expression of genes related to lipid metabolism, phagocy-
peroxynitrite in AD is supported by the presence of elevated levels of tosis, and AD pathology, such as CST7, APOE, LPL, CTSD, TYROBP, and
nitrated proteins in postmortem AD brain tissue, particularly within TREM2, and downregulated expression of homeostatic markers such as
regions containing NFTs (Castegna et al., 2003). Lipid peroxidation and transmembrane protein 119 (TMEM119, selective to microglia) and
DNA oxidative damage was also demonstrated in postmortem human CX3CR1, without changes in expression of inflammatory cytokines.
AD brains (Matsuoka et al., 2001; Nunomura et al., 1999; Sayre et al., They differed in their expression levels of phagocytic markers, sug-
1997; Wang et al., 2005). These findings indicate that pro-in- gesting an intermediate phenotype between homeostatic and cluster III
flammatory microglial activities may be detrimental in AD due to the (DAM) microglia. This transition was proposed to proceed in two steps,
formation of reactive oxygen and nitrogen intermediates resulting in with the complete transition into DAM requiring the expression of
oxidative stress-induced neuronal damage, which could be further ex- TREM2, highlighting again the importance of this receptor in mediating
acerbated by chronic stress. microglial response to AD pathology. The DAM phenotype was also
described in human postmortem AD brains, where it was found to
5. Newly-described microglial phenotypes contain intracellular Aβ, suggesting a neuroprotective role for the DAM
(Keren-Shaul et al., 2017).
The recent technical advancements, including in high-throughput
gene expression analyses distinguishing microglia from bone marrow- 5.3. Neurodegenerative microglial phenotype
derived myeloid cells, have allowed to start characterizing the diversity
of microglial phenotypes in the CNS, especially in the context of altered The complexity of the roles played by microglia in homeostasis as
brain homeostasis. Electron microscopy with immunostaining against well as diseased conditions is portrayed in another study by Krasemann
these recently identified markers was also used by our group to describe et al. where the authors described regulatory mechanisms underlying
‘dark’ microglia, a newly-defined phenotype associated with both the switch of microglia from a homeostatic to a neurodegenerative
chronic stress and AD pathology. phenotype: MGnD (microglia with a neurodegenerative phenotype)
(Krasemann et al., 2017). Microglia were isolated from the brain and
5.1. Dark microglia spinal cord using a specific Fc receptor-like S scavenger receptor
(FCRLS) antibody, in mouse models of AD (APP-PS1), multiple sclerosis
In 2016, we described the ‘dark’ microglia, which are strikingly (experimental autoimmune encephalomyelitis), and amyotrophic lat-
distinct from typical IBA1-positive microglia in their ultrastructural eral sclerosis (SOD1-G93A). Under normal physiological conditions,

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K. Bisht et al. Neurobiology of Stress 9 (2018) 9–21

Fig. 2. Overview of microglial functions in response to stress and AD pathology.

homeostatic microglia expressed Olfml3, P2ry12, Tmem119, Mef2a, Jun, adapt the organism to the adverse challenges. An imbalance or overload
and Sall1, among other genes regulated by TGFβ, all of which were in the adaptive responses to conditions of prolonged stress especially by
downregulated by the MGnD phenotype. Similarly, these cells showed microglia may lead to altered physiological functions, becoming either
an upregulated expression of APOE, Axl, and Clec7a genes. Microglial maladaptive or pro-inflammatory, thus predisposing the brain to sec-
transformation into MGnD, identified by gene expression signature, was ondary insults in the form of trauma or disease. Hence, microglia were
only observed in contexts where neuronal apoptosis occurred. In APP- thus proposed to play an important role in linking the adverse effects of
PS1 mice, MGnD primarily encircled amyloid plaques and dystrophic chronic stress with the onset and progression of AD (Piirainen et al.,
neurites, blanketed by homeostatic microglia in the periphery. They 2017). Therefore, a better understanding of the roles and underlying
also expressed TMEM119, providing support to their microglial origin. mechanisms by which microglia may contribute to regulating brain
In APOE knockout mice, microglia still phagocytosed dying neurons, functions and behavior in response to changes in the environment
but did not show the expression patterns of MGnD, indicating the im- under both homeostatic and altered states is required.
portance of APOE for maintaining this phenotype. Similar findings were While microglia can exacerbate pathological damage during chronic
observed in TREM2 knockout animals, proposing that an APOE-TREM2 stress and AD pathology via dysregulated complement-mediated pha-
switch mediates the transformation of homeostatic microglia into gocytosis, release of inflammatory cytokines, and their mediation of
phagocytic MGnD during neurodegeneration. oxidative stress, they may also contribute positively to the restoration
The above three studies stress the importance of studying the of neuronal homeostasis (see Fig. 2). The recent description of novel
variety of microglial phenotypes in the CNS. Brain resident microglia microglial phenotypes associated with chronic stress and neurodegen-
and peripheral macrophages should not be combined into one category, erative diseases further supports the view that microglia represent a
neither should the brain resident microglia considered as a single cell heterogeneous cell population in which different phenotypes behave
entity, since they appear to comprise heterogeneous populations having differently depending on the context. Through this review, we have
distinct gene expression signatures, functions, and morphologies de- attempted to highlight the importance of studying individual microglial
pending on the homeostasis status. Future studies aiming to address the phenotypes and their distinct contributions to brain homeostasis and
roles of microglia in stressed and pathological states should take these disease, considering that their activities could be selectively targeted to
new findings into consideration. promote neuroprotection in various neurological and neurodegenera-
tive contexts.

6. Conclusion and perspective

Acknowledgements
The way the brain microglia react to homeostatic changes as in
stress and neurodegeneration determines the overall outcome of the We are grateful to Marie-Kim St-Pierre, Katherine Picard, and
brain's capacity to respond to these alterations. These responses con- Mathilde S. Henry for their critical revision of the manuscript. This
tribute to what is known as allostasis or the adaptive measures taken to work was supported by a CIHR Foundation Scheme grant to MET and

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K. Bisht et al. Neurobiology of Stress 9 (2018) 9–21

an excellence scholarship from Fondation du CHU de Québec to KB. Carroll, J.C., Iba, M., Bangasser, D.A., Valentino, R.J., James, M.J., Brunden, K.R., Lee,
MET is a Canada Research Chair (Tier 2) in Neuroimmune plasticity in V.M.-Y., Trojanowski, J.Q., 2011. Chronic stress exacerbates tau pathology, neuro-
degeneration, and cognitive performance through a corticotropin-releasing factor
health and therapy. receptor-dependent mechanism in a transgenic mouse model of tauopathy. J.
Neurosci. 31, 14436–14449. http://dx.doi.org/10.1523/JNEUROSCI.3836-11.2011.
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