Psychosocial stress on neuroinflammation and cognitive dysfunctions in Alzheimer's disease: the emerging role for microglia?

Neuroscience and Biobehavioral Reviews 77 (2017) 148–164

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Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

Review article

Psychosocial stress on neuroinflammation and cognitive dysfunctions in Alzheimer’s disease: the emerging role for microglia? Sami Piirainen a , Andrew Youssef a , Cai Song b,c , Allan V. Kalueff b,d,e,f , Gary E. Landreth g , Tarja Malm h , Li Tian a,i,j,∗ a

Neuroscience Center, HiLIFE, University of Helsinki, Viikinkaari 4, FIN-00014, Helsinki, Finland Research Institute of Marine Drugs and Nutrition, Key Laboratory of Aquatic Product Processing and Safety, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China c Department of Psychology and Neuroscience, Dalhousie University, 1355 Oxford St, Life Sciences Centre, Halifax, Nova Scotia B3H4R2, Canada d Institute of Translational Biomedicine, St Petersburg State University, St Petersburg 199034, Russia e Ural Federal University, Ekaterinburg 620002, Russia f ZENEREI Research Center, Slidell, LA 70458, USA g Department of Neurosciences, Alzheimer Research Laboratory, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA h A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70150, Kuopio, Finland i Zhejiang University-University of Edinburgh Joint Institute, 718 East Haizhou Rd., Haining, Zhejiang 314400, China j Psychiatry Research Centre, Beijing Huilongguan Hospital, Peking University, Beijing 100096, China b

a r t i c l e

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Article history: Received 18 August 2016 Received in revised form 20 January 2017 Accepted 31 January 2017 Available online 6 February 2017 Keywords: Late-onset Alzheimer’s disease Psychosocial stress Microglia Amyloid clearance Dementia

a b s t r a c t Chronic psychosocial stress is increasingly recognized as a risk factor for late-onset Alzheimer’s disease (LOAD) and associated cognitive deficits. Chronic stress also primes microglia and induces inflammatory responses in the adult brain, thereby compromising synapse-supportive roles of microglia and deteriorating cognitive functions during aging. Substantial evidence demonstrates that failure of microglia to clear abnormally accumulating amyloid-beta (A␤) peptide contributes to neuroinflammation and neurodegeneration in AD. Moreover, genome-wide association studies have linked variants in several immune genes, such as TREM2 and CD33, the expression of which in the brain is restricted to microglia, with cognitive dysfunctions in LOAD. Thus, inflammation-promoting chronic stress may create a vicious cycle of aggravated microglial dysfunction accompanied by increased A␤ accumulation, collectively exacerbating neurodegeneration. Surprisingly, however, little is known about whether and how chronic stress contributes to microglia-mediated neuroinflammation that may underlie cognitive impairments in AD. This review aims to summarize the currently available clinical and preclinical data and outline potential molecular mechanisms linking stress, microglia and neurodegeneration, to foster future research in this field. © 2017 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Microglial phenotype and immune gene expression in conditions of psychosocial stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Impact of stress on microglia-mediated regulation of synaptic plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

Abbreviations: A␤, amyloid-␤; AD, Alzheimer’s Disease; AMPA, 2-amino-3-(5-methyl-3-hydroxyl-1,2-oxazol-4-yl) propanoic acid; APOE, apolipoprotein E; APP, amyloid precursor Protein; ATP, adenosine triphosphates; BBB, blood-brain barrier; BDNF, brain-derived neurotrophic factor; CaMK, calcium/calmodulin-dependent protein kinase; CD, cluster of differentiation; CNS, central nervous system; CR, complement receptor; CX3CR1, CX3C chemokine receptor 1; DISC1, disrupted in schizophrenia 1; GC, glucocorticoid; GWAS, genome-wide association study; HPA, hypothalamic-pituitary-adrenal axis; IDO, indoleamine-2,3-dioxygenase; IL, Interleukin; IL-1RA, IL-1 receptor antagonist; LOAD, late-onset Alzheimer’s Disease; LPS, lipopolysaccharide; LTP, long-term potentiation; MCI, mild cognitive impairment; NE, norepinephrine; NMDAR, N-methyl-D-aspartate receptor; NSAIDs, non-steroidal anti-inflammatory drugs; PPAR␥, peroxisome proliferator activated receptor-gamma; PTSD, posttraumatic stress disorder; TNF-␣, tumor necrosis factor-␣; TREM2, triggering receptor expressed on myeloid cells 2. ∗ Corresponding author. E-mail address: li.tian@helsinki.fi (L. Tian). http://dx.doi.org/10.1016/j.neubiorev.2017.01.046 0149-7634/© 2017 Elsevier Ltd. All rights reserved.

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4. 5. 6.

Effects of chronic stress on AD pathological progression and memory impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 Microglia and neuroinflammation in AD pathogenesis: A␤ clearance versus synaptic functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Impact of stress on microglial receptors in AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 6.1. Impact of stress on late-onset AD (LOAD) immune susceptibility genes associated with microglia-dependent A␤ clearance and cognitive deficits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 6.1.1. Triggering receptor expressed on myeloid cells (TREM)-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 6.1.2. CD33 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 6.1.3. Apolipoprotein E (APOE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 6.2. Other microglial receptors related to AD pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 6.2.1. CR1 and CR3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 6.2.2. CX3CR1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 6.2.3. CD36 and Toll-like receptors (TLRs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 7. Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 Authorship contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 Disclosure of Conflicts of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

1. Introduction Human cognition is a complex process that involves memory, attention, executive functions, perception, language and psychomotor functions. The ability to form and retrieve memories is one of the most fundamental aspects of human cognition, while attention and memory are most prominently affected by age (Glisky, 2007). Alzheimer’s disease (AD) is a severely debilitating chronic neurodegenerative disorder, accounting for 50–60% of all forms of dementia. AD is clinically characterized by progressive impairment of episodic memory and cognitive deficits, including impaired judgment, decision-making and orientation (Blennow et al., 2006). AD pathology is characterized by extracellular amyloid-beta (A␤) plaques (Mirra et al., 1991) and intracellular neurofibrillary tangles comprised of hyper-phosphorylated tau protein (Braak and Braak, 1991), along with neuronal and synaptic degeneration (Spires-Jones and Hyman, 2014). Neurodegeneration is estimated to begin 20–30 years before the onset of clinical symptoms (Davies et al., 1988), during which A␤ plaques and tau tangles accumulate with accompanied slow neurodegeneration and mild cognitive impairment (MCI) (Petersen, 2004). The role of chronic neuroinflammation in MCI and AD dementia has gained attention recently, implicating an early involvement of inflammation in the disease onset and progression (Querfurth and LaFerla, 2010). Neuroinflammation may indeed contribute to AD since genes of immune receptors, such as TREM2 (Guerreiro et al., 2013), CD33 (Bettens et al., 2013; Bradshaw et al., 2013) and CR1 (Karch and Goate, 2015; Lambert et al., 2013), are associated with AD. Microglia represent resident macrophages in the brain and are a key player in mediating neuroinflammatory response and clearance of cellular debris, thereby contributing to AD pathology and neurodegeneration (Heppner et al., 2015; Kettenmann et al., 2011). Furthermore, studies have shown that non-steroidal antiinflammatory drugs (NSAIDs) have a marked effect on preventing the onset and progression of AD (McGeer et al., 2016). Various physiological and cellular stressors, including aging and hypoxia, can “prime” microglia and exacerbate neuroinflammation in AD, as reviewed elsewhere (Head et al., 2016; Heikkinen et al., 2014; Leszek et al., 2016; Song et al., 2016). We instead focus on the psychosocial stress in AD here. As with the ever-changing and fast-paced lifestyle of modern society, it is common for many to suffer from chronic psychosocial stress during certain periods of their lives. Psychological stress, as well as its pathological comorbidities such as depression, is increasingly recognized as a risk factor for the development of AD (Alkadhi, 2012; Norton et al., 2014), as people prone to stress or depression are more likely to develop AD (Gracia-Garcia et al., 2015; Green et al., 2003; Sacuiu et al., 2016;

Wilson et al., 2005). Paralleling clinical data, in a rat model of AD, chronic stress also decreases basal levels of memory-related signaling molecules in the hippocampus and exacerbated cognitive impairment (Alkadhi and Tran, 2015; Srivareerat et al., 2009). However, our understanding of how psychosocial stress exacerbates AD-related neuroinflammation remains limited. Here, we first discuss the impacts of psychosocial stress on microglial phenotypical transformation and on cognitive impairments in AD, respectively. We also summarize findings on microglia-mediated neuroinflammation in compromising A␤ clearance and exacerbating synaptic dysfunction in AD. We further suggest potential molecular mechanisms by which psychosocial stress may exacerbate cognitive impairments in AD. We postulate that psychological stress impacts both A␤ clearance and synaptic regulation mediated by microglia, thus contributing to AD-related pathological progression. However, the exact nature of the impact of psychological stress on microglia and neuro-glia crosstalk in AD remains to be investigated further. 2. Microglial phenotype and immune gene expression in conditions of psychosocial stress Microglial cells are the first line of defense against invading pathogens in the central nervous system (CNS). They constantly surveil the brain parenchyma, sensing even slight alterations in the concentrations of extracellular ions and molecules. Microglia express a unique sensome of transcripts encoding proteins for sensing endogenous ligands and microbes, with genes for endogenous ligand-recognition downregulated whereas those involved in microbe recognition and host defense upregulated, alongside aging (Hickman et al., 2013). Although conventional microscopic images show that these cells are highly ramified in the healthy brain, live multiphoton imaging reveals microglial processes as extremely motile, constantly extending and retracting to survey the surrounding approximately 80 um3 of environment (Nimmerjahn et al., 2005). Upon activation by pathogen or injury, microglia adopt an amoeboid morphology, bearing enlarged soma along with shortened and thickened processes, and capable of migrating toward the site of the damage (Nimmerjahn et al., 2005). Meanwhile, a “dystrophic” morphology, readily distinguished from both so-called “resting” and “activated” microglia by their fragmented cytoplasmic components, has also been described for microglia in the aged brain (Kettenmann et al., 2011). Both acute and chronic stressors prime microglia, by inducing either hyper-ramification, characterized by an elongation of microglial processes along with a larger soma size (Hellwig et al., 2016; Hinwood et al., 2012; Hinwood et al., 2013), or de-

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ramification, characterized by an increased soma size but shortened processes (Kreisel et al., 2014; Wohleb et al., 2014). These extremely versatile and motile features of microglia underlie the wide spectrum of their morphology and make them the key sensor for any alterations occurring in the brain. Microglia can cross-talk with infiltrated monocyte-derived brain macrophages under psychosocial stress (McKim et al., 2016; Wohleb et al., 2012; Wohleb et al., 2014; Wohleb et al., 2013). In general, investigation of monocyte infiltration into the brain has been complicated by the difficulty to distinguish them from the brain endogenous microglia, as the commonly-used microglial markers, such as Iba-1, CD45 and CD68, stain both cell types. With the help of bone marrow chimeras to discern monocytes and microglial cells, repeated stress exposure was found to cause both microglial functional enhancement and recruitment of peripheral monocytes into the brain, contributing to development of anxietyand depression-like behaviors (Wohleb et al., 2012, 2013). Stressinduced redistribution of peripheral monocytes from the spleen into the brain led to stress-sensitized neuroimmune responses and recurrent anxiety-like behavior (McKim et al., 2016; Wohleb et al., 2014). On the molecular level, microglial phenotypical switch is evidenced by their expression of certain signature markers and secretion of pro- and anti-inflammatory cytokines. Based on this, historically two distinct phenotypes have been used and named after macrophages in the literature: M1 and M2 subtypes. These phenotypes are considered as opposing ends on a spectrum of microglial or macrophage activation (reviewed in David and Kroner, 2011; Franco and Fernandez-Suarez, 2015; Hu et al., 2015; Orihuela et al., 2016). However, the categorization of microglial activity based on these described phenotypes is not capable of recapitulating their extremely motile and versatile functions, especially in vivo. Classification of microglia into distinct functional states is thus challenging, as increasing evidence suggests that microglial functional transformation is finely tuned, and that the cells may rather adopt various intermediate phenotypes depending on the context and the stimuli (David and Kroner, 2011; Franco and Fernandez-Suarez, 2015; Hu et al., 2015; Orihuela et al., 2016). In this regard, the M1 vs M2 categorization has been abandoned by several research groups (Heppner et al., 2015; Murray et al., 2014). Nevertheless, the literature continues to use M1 and M2 as a basic classification method in understanding the functional status of microglia and macrophages in brain diseases, although it is clear that better descriptions are urgently needed. Similar to macrophages, activated microglial cells secrete a variety of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-␣), interleukin (IL)-1␤, IL-6, IL-12 and IL-18 (Alboni et al., 2010; McAfoose and Baune, 2009), which has been linked to reduced phagocytic capacity (David and Kroner, 2011; Franco and Fernandez-Suarez, 2015; Hu et al., 2015; Orihuela et al., 2016; Sutinen et al., 2012). On the other hand, secretion of antiinflammatory cytokines IL-4, IL-10, IL-13 and transforming growth factor-beta (TGF-␤) by microglia has been associated with their increased phagocytic ability, increased expressions of canonical markers FIZZ1, YM1 and ARG1, and reduced expression of NOS2 (Fu et al., 2016; Heneka et al., 2013; Lyons et al., 2007; MandrekarColucci et al., 2012; Medeiros et al., 2013; Shimizu et al., 2008). Microglia in neurodegenerative diseases are typically characterized by overt pro-inflammatory activation (Franco and Fernandez-Suarez, 2015; Orihuela et al., 2016). Similar to neurological conditions, we showed that high anxiety was associated with a higher pro-inflammatory activation of microglia in mice, especially after a peripheral lipopolysaccharide (LPS) challenge (Li et al., 2014), known to drive the pro-inflammatory polarization of macrophages and microglia (Orihuela et al., 2016). This shift in the microglial status was further characterized by increased levels of

pro-inflammatory cytokines Il1b, Il6 and Tnf, as well as diminished levels of alternative activation-marker genes, making the Nos2/Arg1 ratio elevated in the mouse strains with high anxiety (Li et al., 2014). Our follow-up studies also linked altered social behavior with differences in brain immune gene expression in two mouse strains that responded differently toward psychosocial stress (Kulesskaya et al., 2014), and identified 23 innate immune genes (Ma et al., 2015a, 2015b), some of which have been demonstrated to regulate microglial synaptic pruning as well as synaptic formation and plasticity, such as C1qb, Cx3cl1, H2-d1 and H2-k1 (McAllister, 2014; McConnell et al., 2009; Paolicelli et al., 2011; Rogers et al., 2011; Stevens et al., 2007). Further supporting that psychological stress alters immune cell activation, a chronic social defeat stress elevated serum levels of pro-inflammatory cytokine IL-7 and vascular endothelial growth factor (VEGF) in defeated mice but anti-inflammatory cytokine IL-10 in winner mice (Stewart et al., 2015). In line with our findings, acute stress (tail- or foot-shock) in rats upregulated their microglial major histocompatibility complex class II (MHCII) and downregulated Cd200r (Blandino et al., 2009; Frank et al., 2007). In a chronic stress paradigm, depressionsusceptible C57BL/6J mice showed elevated expression of TNF-␣ in the prefrontal cortex and indoleamine-2,3-dioxygenase (IDO) in the raphe, as compared to depression-resilient animals (Couch et al., 2013). Stress also primed microglia to produce more proinflammatory cytokines after animals were stimulated by LPS (de Pablos et al., 2014; Frank et al., 2007; Johnson et al., 2013; Wohleb et al., 2012). Conversely, supplementing antidepressant with recombinant IL-4 and IL-10 prevented vulnerability of prestressed mice to additional stress and restored immune factors related to alternative microglial phenotypical transformation in the hippocampus (Han et al., 2015). The major mechanism by which stress primes microglia involves the hypothalamic-pituitary-adrenal (HPA) axis, as stress induces systemic glucocorticoid (GC) secretion via the HPA axis, which regulates microglia and their expression of immune genes (Sorrells et al., 2009). Interestingly, GC exhibited not only potent anti-inflammatory property by reducing microglial IL-1␤ secretion at a high dose, but also pro-inflammatory activity by inducing inflammasome expression in the hippocampus at a low dose (Frank et al., 2014). Likewise, GC dose-dependently promoted LPS-induced activation of nuclear factor kappa B (NF-␬B) in the frontal cortex (Munhoz et al., 2010), and aggravated acute CNS injury and inflammation (Sorrells et al., 2013). Collectively, these dual effects highlight the complexity of GC in microglial priming and functional transformation (Frank et al., 2014; Sorrells et al., 2009). Stress also activates microglia via monoamine neurotransmitters (e.g., norepinephrine, NE) released by sympathetic neurons in the locus coeruleus (Delpech et al., 2015a; Goshen and Yirmiya, 2009). Sympathetic activation by repeated social defeat in mice induced microglial genes, such as Il1b and Tnf at early stage, Il6 at late stage, and Cd14 and Cx3cr1 throughout the stress procedure (McKim et al., 2016; Wohleb et al., 2011, 2014). In contrast, blocking sympathetic activity by propranolol and guanethidine counteracted (Blandino et al., 2009; McKim et al., 2016), whereas ␤-adrenergic agonism by isoproterenol amplified (Johnson et al., 2013), the stress-induced upregulation of proinflammatory cytokines, such as Il1b, in the brain. Additionally, adenosine triphosphate (ATP), but not proinflammatory cytokines, was responsible for inflammationinduced enhancement of both associative taste memory and 2-amino-3-(5-methyl-3-hydroxy-1,2-oxazol-4-yl) propanoic acid (AMPA) receptor expression in the insular cortex after intra-insular infusion of LPS in rats (Delpech et al., 2015b), unraveling the contribution of purines to cognitive function. Acute or chronic restrain stress promoted opening of astrocytic and microglial pannexin

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1 and subsequent release of ATP and glutamate, which induced neuronal death through neuronal N-methyl-D-aspartate receptor (NMDAR) and purinergic receptor P2X7R (Orellana et al., 2015). Conversely, release of hippocampal IL-1␤ and TNF␣ induced by acute restraint stress was completely blocked by P2X7R antagonist in NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-null mice (Iwata et al., 2016). Taken together, these findings suggest that psychosocial stress markedly contributes to various aspects of pro-inflammatory microglial activation, which, in turn, may negatively impact their support of synaptic functions of neighboring neurons.

3. Impact of stress on microglia-mediated regulation of synaptic plasticity Microglia have recently been implicated in the development and maintenance of neurons, as they actively monitor and modulate synaptic numbers and strength in the rodent brain (Wu et al., 2015). Abnormally high or low synaptic density is associated with many mental disorders, including AD (Penzes et al., 2011). Because synaptic strength is a fundamental physiological property of a synapse that contributes directly to brain plasticity, this aspect is critical for experience-related adaptation and learning functions (Penzes et al., 2011). Extensive studies have shown that microglia participate in synaptic network remodeling through phagocytosis of synapses (synaptic pruning) in the developing brain and, in an experiencedependent manner, in the adult brain (Schafer and Stevens, 2015). Microglia dynamically interacted with neuronal synapses in response to visual light stimuli (Tremblay et al., 2010). Furthermore, they increased synchronized firing of cortical neurons by displacing inhibitory presynaptic terminals, leading to activated calcium/calmodulin-dependent protein kinase (CaMK) IV and cAMP response element binding protein (CREB) in adult mice (Chen et al., 2014). On the molecular level, microglia utilize multiple receptors for synaptic pruning (Fig. 1). They scan and respond to environmental stimuli rapidly in a coordinated manner to facilitate phagocytosis, in which purinergic receptors, such as P2X7 and P2Y12, help microglia to sense and elongate their protrusions to the target site following ATP/adenosine gradients (Arnoux et al., 2013; Davalos et al., 2005; Haynes et al., 2006; Sipe et al., 2016). Microglia further use the complement system for sculpting synaptic networks, as microglia lacking the complement receptor 3 (CR3) cannot prune synapses, leading to persistent synaptic hyper-multiplicity (Schafer et al., 2012). In rodents subjected to hypoxia and treated with LPS, microglia induced the synaptic long-term-depression in the hippocampus, dependant on CR3-signaling that in turn promoted NADPH oxidase-mediated activation of protein phosphatase 2A and internalization of AMPA receptors (Zhang et al., 2014a). Microglia also refine synaptic connections and plasticity through secretion of neurotrophic factors, such as brain derived neurotrophic factor (BDNF), as depletion of microglia and microglia-derived BDNF led to severe deficits in motor learning-dependent synaptic formation and working memory (Parkhurst et al., 2013). Furthermore, deletion of microglial chemokine receptor CX3C chemokine receptor 1 (CX3CR1) transiently compromised synaptic pruning (Paolicelli et al., 2011), contributing to altered connectivity of brain regions and social deficits (Zhan et al., 2014). CX3CR1-knockout (KO) mice also showed altered performance in hippocampus-dependent spatial learning and memory functions in Morris water maze (Maggi et al., 2011; Rogers et al., 2011). Besides pruning, microglia-derived cytokines and chemokines, particularly IL-1␤ and TNF-␣, can both modulate molecular and cellular mechanisms sub-serving learning, memory and cognition

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under physiological conditions, and hence contribute to dementia (de Haas et al., 2007; McAfoose and Baune, 2009). For example, induction of long-term potentiation (LTP), a form of persistent synaptic strengthening and cellular correlate of learning and memory, promoted IL-1␤ gene expression both in vitro and in vivo, whereas blocking IL-1␤ by IL-1 receptor antagonist (IL-1RA) impaired the maintenance of LTP (Schneider et al., 1998). IL1␤ plays an important role in learning and memory formation (Balschun et al., 2003; Schneider et al., 1998). Importantly, a recent genetic study of progressive cognitive decline in individuals with asymptomatic cerebral amyloidosis identified IL1RAP as the key factor associated with conversion from asymptomatic amyloidosis to cognitive impairment (Ramanan et al., 2015). Besides IL-1, IL-6 and IL-18 are also overexpressed during LTP maintenance in a brain region-specific manner. Different cytokines may have opposing effects in LTP maintenance, where, for example, IL-1␤ is a stabilizer and IL-6 acts as an inhibitor (del Rey et al., 2013). In addition, TNF-␣ is essential for the excitatory synaptic efficacy via upregulation of the glutamatergic cell surface AMPA receptor expression (Beattie et al., 2002) and regulates synaptic scaling − a type of homeostatic adjustment of activity-dependent synaptic connectivity that is important for a stable neural network (Stellwagen and Malenka, 2006). Cytokines may also promote synaptic formation. For instance, microglia-derived IL-10 was recently shown to induce dendritic spine formation in developing hippocampal neurons (Lim et al., 2013). Stress affects synaptic functions of microglia. Chronic stress promoted microglial secretion of IL-1␤, IL-18 and TNF-␣ (Goshen et al., 2008; Munhoz et al., 2004; Rossetti et al., 2016; Sugama et al., 2007), which dose-dependently affected neuronal plasticity (Bobula et al., 2015; Goshen et al., 2008). Psychological stress-induced recruitment of bone marrow-derived CX3 CR1low CCR2+ CXCR4high myeloid cells to the paraventricular nucleus – a hypothalamic structure that regulates food intake among other functions in mice. These cells displayed highly expressed IL-1␤ and were attached to neurons expressing IL-1R and phosphorylated NMDAR (Ataka et al., 2013). In corroboration, chronic mild stress-induced anhedonia, as characterized by a deficit in sucrose-intake, was accompanied by increased expressions of IL-1␤ and IL-6 as well as microglial CD11b (CR3), CX3CL1 and CX3CR1 in stress-susceptible mice in comparison with stress-resilient mice (Rossetti et al., 2016). By contrast, anti-inflammatory cytokine IL-10 was reduced in wild-type but not BDNF+/− mice subject to repeated unpredictable mild stress (Dugan et al., 2015). A recent study demonstrated that CX3CR1-deficiency prevented microglial cytokine response and synaptic phagocytosis in the hippocampus to chronic unpredictable stress, accompanied by a lack of weakening in LTP measured from acute brain slices (Milior et al., 2016). In a highly stress-sensitive Balb/cByj mouse strain, stress induced by brief daily maternal separation decreased the expression of an innate immune molecule, lipopolysaccharide-binding protein (LBP), in the developing hippocampus. LBP-KO animals displayed impaired microglia-mediated hippocampal synaptic pruning, and thus more dendritic spines, during development, accompanied by behavioral and cognitive impairments resembling stressed animals in adulthood (Wei et al., 2012). Likewise, chronic unpredictable stress induced pro-inflammatory microglial activation, attenuated phosphorylation of glutamate receptor 1 (GluR1), and impaired LTP and spatial learning in Morris water maze in rats, which can be rescued by a broad-spectrum antibiotic minocycline that inhibits microglia (Liu et al., 2015b). Furthermore, anti-IL-1␤ antibody prevented the occurrence of repeated restraint stressinduced alterations in synaptic transmission and LTP in the rat frontal cortex (Bobula et al., 2015). Stress can also activate microglial IDO-kynurenine pathway, leading to formation of neurotoxic kynurenine metabolites

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Fig. 1. Psychosocial stress impairs synaptic functions. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, eliciting secretion of corticotropin-releasing hormone (CRH) from the hypothalamus and subsequent release of adrenocortocotropic hormone (ACTH) from the anterior pituitary gland. This, in turn, triggers the secretion of glucocorticoids (GC) from the adrenal cortex. GC inside the brain at low, physiological concentration has direct impact on microglial function by increasing pro-inflammatory cytokines, such as IL-1␤. This leads to altered neuronal glutamate NMDAR (GluN1) or AMPAR (GluR1) phosphorylation and subsequently impaired long term potentiation (LTP). GC-modulation of microglia may also alter their phagocytic and synaptic pruning functions, thereby disturbing A␤ clearance and/or A␤-dependent synaptic remodeling in AD, meriting further studies.

3-hydroxykynurenine and quinolinic acid, both of which are extensively studied in depression (O’Farrell and Harkin, 2017). Acute restraint stress induced region-specific changes in enzymes associated with the kynurenine metabolic pathway in the corticolimbic circuit, particularly those producing the quinolinic acid (Vecchiarelli et al., 2016). Chronic social stress also increased kynurenine pathway activities in the blood and the brain, and caused fear-like behavior in mice, which both were reversed by inhibition of IDO (Fuertig et al., 2016). In humans, inflammatory response to psychosocial stress was enhanced in major depression patients with early-life stress (Pace et al., 2006). Moreover, perivascular macrophages and the proportion of primed versus resting microglia in the white matter of dorsal anterior cingulate cortex (dACC) − a brain area regulating emotion and mood − were increased in depressed suicidal patients (Torres-Platas et al., 2014). A recent meta-analysis on post-mortem human brains demonstrated associations of suicidal behavior with inflammatory cytokines, kynurenine pathway and microgliosis in the orbitofrontal cortex, a brain region involved in suicidal vulnerability (Courtet et al., 2016). Such findings identify the kynurenine pathway as a potential therapeutic target for both neurodegenerative and stress-related neuropsychiatric disorders (O’Farrell and Harkin, 2017). This was further highlighted by a recent evidence that both blocking the skeletal kynurenine pathway and reducing plasma kynurenine protected mice from stress-induced depression, thereby opening therapeutic avenues for the treatment of depression by targeting this pathway without the need to cross the blood-brain barrier (BBB) (Agudelo et al., 2014). 4. Effects of chronic stress on AD pathological progression and memory impairment The involvement of psychosocial stress in AD has been suggested by multiple epidemiological studies, as people with posttraumatic

stress disorder (PTSD) or depression often develop dementia and even clinical AD (Gracia-Garcia et al., 2015; Green et al., 2003; Qureshi et al., 2010; Sacuiu et al., 2016; Wilson et al., 2005; Yaffe et al., 2010). This association has been attributed to elevated levels of cortisol found in AD patients (Elgh et al., 2006; Hartmann et al., 1997). However, the mechanism underpinning the impact of psychosocial stress on AD pathology and cognitive dysfunction has rarely been systemically analyzed so far, with only limited evidence from a few preclinical studies (Alkadhi, 2012). Nevertheless, animal studies have demonstrated the association of the HPA axis with AD pathogenesis in the frontal cortex and/or hippocampus (Green et al., 2006; Joshi et al., 2012; Justice et al., 2015; Sotiropoulos et al., 2008). Chronic stress or administration of stress hormones increased A␤ accumulation and tau phosphorylation in mice (Joshi et al., 2012). When triple transgenic AD mice were given GC for over 7 days, they developed both A␤ and tau pathologies in an age-dependent manner (Green et al., 2006). Furthermore, rats subjected to 4-week chronic unpredictable stress had a significant increase in amyloid precursor protein (APP) fragments, and A␤ infusion triggered APP misprocessing in the hippocampus and prefrontal cortex, and this effect was further exacerbated by stress (Catania et al., 2009). Being among the first affected brain regions in AD, the frontal cortex and hippocampus are particularly vulnerable to harmful effects of stress, suggesting the converging effects of stress and aging on localized synaptic structures and brain circuits involving these areas, as well as the common molecular pathways between neurological and neuropsychiatric diseases. Indeed, shared mechanisms of inflammation and oxidative stress have been suggested between stress and aging (Prenderville et al., 2015), as well as between depression and AD (Rodrigues et al., 2014). AD pathogenesis is also likely to be associated with PTSD accompanied by neuroendocrine deficits (Justice et al., 2015). Besides GC, sympathetically released neurotransmitter NE is also involved in pro-inflammatory responses of microglia to stress

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in AD. Intriguingly, depletion of NE in the locus coeruleus of APP transgenic mice exacerbated neuroinflammation and reduced microglial A␤ phagocytosis, while supplement of NE precursor L-threo-3,4-dihydroxyphenylserine increased microglial A␤ phagocytosis, dampened microglia-mediated neuroinflammation and restored microglial motility toward A␤ plagues (Heneka et al., 2010). This suggests the potential anti-inflammatory effects promoted by the locus coeruleus in the CNS compared to the pro-inflammatory effects provoked by the peripheral sympathetic nervous system, as well as the heterogeneity in adrenergic receptor-mediated neuroinflammation in stress-involved A␤ pathology. Similar to aggravated A␤ pathology, impaired LTP and memory deficits can also be exacerbated by chronic stress or administration of stress hormones in AD models (Alkadhi, 2012). In a prodromal AD rat model, chronic stress exacerbated deficits in spatial learning and short-term memory associated with reduced earlyphase LTP (Srivareerat et al., 2009). These effects were correlated with decreased high frequency stimulation-induced CaMKII phosphorylation during LTP (Alkadhi, 2012; Srivareerat et al., 2009). Corroboratively, social instability-stress during adolescence also impaired hippocampal development and spatial memory of rats in adulthood, and attenuated phosphorylated CamKII, despite the kinase itself was upregulated (McCormick et al., 2012). Although the impact of stress on microglia-associated synaptopathy in AD currently remains unclear, data extrapolated from work on mental disorders may shed some light on the potential mechanisms. Interestingly, a novel regulation of proteolytic processing of APP was recently reported for the disrupted in schizophrenia-1 (DISC1) gene, which regulates GluR activities and brain network connectivity in both depression and schizophrenia (Dawson et al., 2015; Wei et al., 2014). Disc1-knockdown significantly reduced the level of A␤ (Shahani et al., 2015). The A␤-clearing complement system (as discussed in section 6) may provide another pathway linking stress to AD synaptopathy. Allelic variants of complement C4A and C4B genes were positively associated with schizophrenia susceptibility and C4-deficieny compromised synaptic elimination in mice (Sekar et al., 2016). Given the detrimental effects of stress on microglial functions, these findings suggest potential mechanisms of how stress may exacerbate microglia-mediated neuropathologies and synaptic dysfunction, which underlie cognitive impairments in AD.

5. Microglia and neuroinflammation in AD pathogenesis: A␤ clearance versus synaptic functions The role of microglia in AD pathogenesis has long been debated. While microglia play a pivotal role in A␤ phagocytosis and clearance (Gandy and Heppner, 2013; Hickman et al., 2008), persistent microglial pro-inflammatory activation exacerbates amyloidosis, neuronal damage and neuroinflammation (Heppner et al., 2015; Perry and Holmes, 2014) (Fig. 2). Under normal conditions, microglial phenotype is regulated by neurons and astrocytes, necessary for keeping microglia in check while maintaining their phagocytic activity (Hu et al., 2014; Tian et al., 2009; Varnum et al., 2015). With the chronic neurodegenerative aspect of AD along with abnormal A␤ accumulation, this negative regulation is lost, and microglia then demonstrate enhanced sensitivity to inflammatory stimuli (Perry and Holmes, 2014). Neuroinflammation caused by microglial priming is characterized by increased production of cytokines (such as IL-1, IL-18 and TNF-␣) and release of nitric oxide (Combrinck et al., 2002; Cunningham et al., 2005, 2009; Heneka et al., 2013; Ojala et al., 2009). These, in turn, may exacerbate A␤ accumulation and neuronal loss, resulting in a cycle of microglial priming and

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Fig. 2. Psychosocial stress may influence microglial A␤-clearing functions through multiple receptors. Activity of various receptors expressed on microglial cell surface may change following chronic stress, and many of these receptors can recognize and bind A␤. Increased immunopositivity of these receptors has been reported in conditions of chronic stress, and as a net outcome, an increased production of pro-inflammatory cytokines has been observed. However, the effects of psychological stress on microglial A␤ phagocytosis are yet to be examined.

release of pro-inflammatory cytokines, with a subsequent escalation of neurodegeneration (Heneka et al., 2013; Perry and Holmes, 2014; Sutinen et al., 2012; Tweedie et al., 2012). We have previously shown that the mechanism of memory impairment induced by chronic A␤ administration in vivo involves an imbalance between cytokines and neurotrophins in the hippocampus, including increased cytokines levels and decreased expression of neurotrophins (Ji et al., 2011). This ‘vicious cycle’ of neuroinflammation and neurodegeneration may enhance microglial pro-inflammatory activation and impair their ability to clear A␤. The importance of neuroinflammation for AD is further corroborated by a recent large genome-wide association study (GWAS) on more than 74,000 AD participants, showing over-representation of immune–inflammatory genes and supporting the notion that microgliopathy contributes to LOAD (Lambert et al., 2013). This suggests that some forms of sporadic AD may benefit from anti-inflammatory treatment with or without amyloid clearance, especially since ∼14% of autopsied subjects clinically diagnosed with mild-to-moderate AD had no or sparse neuritic plaques (Serrano-Pozo et al., 2014). Several of the identified LOAD risk genes are cell surface receptors able to recognize and bind A␤. These receptors have various functions in microglia and, depending on the context, are associated with microglia-dependent neuroinflammation (Fig. 2, see section 6 for details). Besides affecting A␤ clearance, neuroinflammation may interfere with synaptic remodeling functions of microglia through confounding the currently known molecular mechanisms (as shown in Fig. 1). In fact, A␤ administration caused cognitive impairment in animals in the absence of neurodegeneration (Shankar et al., 2008). This is substantiated by studies showing that both insoluble A␤ and tau fibrils mediate synaptic loss and trans-synaptic spread of pathology through the brain, which jointly contributes to neurodegeneration (Dorostkar et al., 2015; Spires-Jones and Hyman, 2014). A␤ increased hippocampal IL-1␤ expression, and LTP impairment induced by A␤ was inhibited by the caspase-1 inhibitor (Ac-YVAD-CMK), suggesting a significant role of IL-1␤ in mediating the effects of A␤ (Minogue et al., 2003). Increases in IL-1␤ and IL-1␤-induced signaling were also more profound in aged rats that failed to sustain LTP, whereas downregulation of IL4-induced signaling in the hippocampus contributed to deficits in the LTP in the aged rats (Maher et al., 2005).

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While appropriate synaptic pruning by microglia is important for neurons under normal conditions, harmful effects of microglia on propagation of synaptic loss in AD has been indicated by several studies. For example, microglial pro-inflammatory activation and synaptic loss preceded the appearance of tau pathology and neuronal loss (Yoshiyama et al., 2007). Also, soluble A␤ oligomers impaired LTP and purportedly promoted microgliamediated synaptic phagocytosis through interaction with the complement system in a mouse AD model, suggesting that cognitive impairment due to microglia-mediated synaptic loss may well precede the A␤ pathology in AD (Hong et al., 2016a). However, relevance of A␤-induced microglial pro-inflammatory activation to AD pathogenesis has been questioned from microglial depletion studies. Depletion of microglia in APP transgenic mice once failed to alter AD-like pathology, thereby challenging the importance of microglia in AD progression (Grathwohl et al., 2009). In contrast, partial depletion of microglia in adult triple transgenic AD mice improved cognition without affecting the brain A␤ levels, suggesting that prevention of microglial reactivity to A␤ deposits was beneficial (Dagher et al., 2015). Likewise, depletion of microglia suppressed the propagation of tau pathology, most likely due to microglia-secreted exosomes that mediated the spreading of tau pathology in a mouse model (Asai et al., 2015). Thus, the impact of microglia on AD pathology is multi-faceted, and conflicting results may arise depending on the AD-model used, the animal age, as well as the time point and the extent of microglial depletion. Similar to stress, monocytic infiltration may impact neuroinflammation also in AD. Previously, the involvement of peripheral infiltrating monocytes in AD pathogenesis was suspected due to the challenge of discerning them from resident microglia. In this regard, studies by us and others using bone marrow chimeras showed increased infiltration of bone marrow-derived monocytes in the AD transgenic mouse brain (Malm et al., 2005; Simard et al., 2006), suggesting the role of peripheral monocytes in the progression of AD-like pathology and related neuroinflammation. Whilst these studies were influenced by irradiation and partial compromise of the BBB, subsequent studies have provided evidence that without compromising BBB, peripheral monocytes are capable of infiltrating into the AD brain and can clear A␤ even better than endogenous microglia (Jay et al., 2015; Michaud et al., 2013; Mildner et al., 2011; Naert and Rivest, 2012; Simard et al., 2006), suggesting that they can be used to therapeutically enhance the brain A␤ clearance (Malm et al., 2010). However, two recent papers suggested that although monocytes can infiltrate into the brain, they had no impact on A␤ clearance and the development of AD-like pathology (Prokop et al., 2015; Varvel et al., 2015). Collectively, our understanding on the exact contribution of monocytes in the AD pathology is still incomplete, and at present, the contribution of monocytes to AD under psychosocial stress remains unclear. Considering their robust A␤-phagocytic capacity and the impact of chronic stress on their infiltration into the brain, this endows an interesting research area. Over the past two decades, various AD immunotherapies have been developed to remove A␤ plaques, inhibit A␤ aggregation and deposition, or reduce the production of A␤ in the brain via inhibition of ␥-secretase and ␤-secretase, trialed both pre-clinically and clinically. Although antibodies directed against A␤ can successfully clear plaques and reverse cognitive deficits in mouse models, all these strategies, however, failed in clinical trials (Liu et al., 2015a; Siemers et al., 2016) (also see (Gandy and Sano, 2015; Wang, 2014)). The failure of these immunotherapy trials suggests that targeting A␤ alone may not be enough to prevent or slow down AD progression, as multiple mechanisms are involved in AD pathogenesis, and their relative contributions may vary at different stages of the disease, among which neuroinflammation is a key component (Krstic and Knuesel, 2013). The importance of neu-

roinflammation is indeed reflected in anti-A␤ trials, as their key problem is inflammatory side effects in the brain, because antibodies clear plaques but simultaneously induce inflammation. A recent study found that a murine analog of bapineuzumab (a monoclonal antibody 3D6, targeting the N-terminal region of A␤) significantly increased pro-inflammatory cytokines IL-1␤ and TNF-␣, and upregulated microglial expression of CD11b and CD68 in the mouse hippocampus (Fuller et al., 2015). Studies using NSAIDs suggest beneficial effects of dampening microglial pro-inflammatory activation in AD (McGeer and McGeer, 2013). A recent in vitro research showed that activated human microglia promoted the expression of A␤ and tau in human neuroblastoma cells (Lee et al., 2015). Preconditioning of the cells with NSAIDs − Aspirin and Ibuprofen, as well as with anti-inflammatory cytokine IL-10, lowered the phospho-tau protein (Lee et al., 2015). Other studies have also supported the importance of antiinflammatory treatments in AD. For instance, minocycline reduced insoluble A␤ and soluble fibrils, and decreased immune-related molecules glial fibrillary acid protein (GFAP), TNF-␣ and IL-6 while increasing chemokines CXCL1 and macrophage-inflammatory protein 1 alpha (MIP-1␣), along with rescued cognitive impairments in triple transgenic AD mice (Parachikova et al., 2010). A small, open-label pilot study showed that inhibition of the inflammatory cytokine TNF-␣ by etanercept for 6 months improved cognitive functions in AD patients (Tobinick et al., 2006). However, recent studies suggested harmful effects of antiinflammation, as IL-10 was detrimental for AD-related disease progression by inhibiting A␤-phagocytosis in an APP/PS1 AD mouse model (Chakrabarty et al., 2015; Guillot-Sestier et al., 2015; Michaud and Rivest, 2015), while knocking-down IL-10 increased A␤-removal, restored synaptic integrity and ameliorated cognitive deficits (Guillot-Sestier et al., 2015). IL-10 was overexpressed in the post-mortem AD brains (Guillot-Sestier et al., 2015). Another anti-inflammatory cytokine, IL-4, exacerbated amyloid deposition (Chakrabarty et al., 2012). By contrast, massive gliosis induced by IL-6 suppressed A␤ deposition in vivo, arguing against inflammation as a driving force for amyloid deposition (Chakrabarty et al., 2010). Of note, inflammatory processes seem to be active in the relatively early stage of AD patients (< 80 years) and then wane during aging (Hoozemans et al., 2011), potentially explaining the above-mentioned discrepancies and suggesting the likely critical time window for effective beneficial anti-inflammatory treatments before the disease formation. For instance, an early-stage antiinflammatory drug (MW-151) treatment selectively attenuated pro-inflammatory cytokine production and rescued synaptic dysfunction in an AD mouse model (Bachstetter et al., 2012). This is further corroborated by recent evidence that treatment by an anti-inflammatory drug − pioglitazone, or by IL-1RA, rescued impairments in dendritic spine plasticity by increasing spine density and remodeling of neural networks in an AD mouse model at pre-symptomatic stage (Zou et al., 2016). Using a transgenic McGillThy1-APP mouse model at early pre-morbid stage yet without AD pathological hallmarks, a study demonstrated that minocycline corrected pre-plaque neuroinflammation, accompanied with reduced APP levels and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) expression (Ferretti et al., 2012). Despite these preclinical and clinical data, successful antiinflammatory regimes have not been established for AD patients so far (McGeer and McGeer, 2013), owing to the main focus on the amyloidogenic hypothesis of AD. These studies, nevertheless, provide a proof-of-concept for the anti-inflammatory approach to AD therapy. Given the contribution of chronic stress to synaptic dysfunction and microglia-associated inflammation, a deeper understanding of the relationship between stress and sporadic AD pathogenesis may help clarify its relevancy to the temporal and spa-

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tial features of neuroinflammation in AD, thereby clarifying specific formulation of anti-inflammatory therapeutics at different stages of the disease progression. 6. Impact of stress on microglial receptors in AD Since chronic stress markedly impacts the expression of A␤recognizing receptors and influences microglial functions, it likely has an impact on the AD pathology through microglia-mediated effects. Here, we discuss key microglial receptors, the expression and function of which have been implicated in chronic psychosocial stress (Table 1, Fig. 2). A recent review on microglial transcriptomics in both health and neurodegenerative diseases also highlights prominent effects of epigenetic factors on the risk of developing AD (Wes et al., 2016). 6.1. Impact of stress on late-onset AD (LOAD) immune susceptibility genes associated with microglia-dependent Aˇ clearance and cognitive deficits Mutations in the APP, presenilin 1 and 2 genes have been associated with the early-onset familial AD. However, over 95% of AD patients are diagnosed after the age of 65 as LOAD with estimated heritability of 60–80%. Comparing allele frequencies in patients vs non-disease controls, recent GWASs have unveiled multiple risk gene loci for LOAD (Karch et al., 2014), including the APOE, ABCA7, BIN1, CASS4, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5-DBR1, INPP5D, MS4A, MEF2 C, NME8, PICALM, PTK2B, SLC24H4-RIN3, SORL1 and ZCWPW1, as well as the coding variants of PLD3 and TREM2 (Karch and Goate, 2015). Among them, immune genes include TREM2, CR1, CD33, CLU, ABCA7, EPHA1, HLA-DRB5-DBR1, INPP5D, MEF2 C and MS4A (Karch and Goate, 2015). Several of these immune genes are expressed by microglia and regulate microglial phagocytic functions, but are also associated with cognitive deficits in AD and may be involved in stress-induced inflammation, such as TREM2, CR1, CD33 and APOE. Immune genes that currently do not relate to this context will not be addressed here (but see recent reviews on microglial immune genes in AD in Karch and Goate, 2015; Villegas-Llerena et al., 2016). 6.1.1. Triggering receptor expressed on myeloid cells (TREM)-2 TREM2 is a receptor involved in pathogen phagocytosis, and triggers an immunoreceptor tyrosine-based activation motif (ITAM) signaling pathway via its trans-membrane binding partner TYROBP (also called DAP-12) (Bouchon et al., 2001; Klesney-Tait et al., 2006; Takahashi et al., 2005). TREM2 is so far the best characterized risk immune gene for LOAD, mutations of which increase LOAD risk by 1.7 ∼ 3.4-fold (Guerreiro et al., 2013; Lill et al., 2015). TREM2 mutation-carriers with AD had more extensive brain atrophy and cognitive deficit than AD non-carriers (Jonsson et al., 2013), and variants in TREM2 were also associated with tau levels in the cerebrospinal fluid (Cruchaga et al., 2013). Studies using various AD animal models have yielded conflicting results on the role of TREM2 in A␤ plaque clearance (Table 1), tau-pathology and microglial recruitment, but generally suggest a beneficial role of TREM2 in microglia-mediated A␤ plaque clearance (Jay et al., 2015; Jiang et al., 2015; Savage et al., 2015). How chronic psychosocial stress may affect TREM2 expression and function in microglia in AD models is not clear, and warrants future investigation. Interestingly, a recent study linked TREM2 expression with chronic stress, showing that TREM2+ “dark” microglia, rarely present in the normal brain, became abundant in chronic stress and associated with AD pathology in mice (Bisht et al., 2016). The function of these dark microglia in A␤ phagocytosis remains to be investigated.

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6.1.2. CD33 CD33 is a member of the sialic acid-binding immunoglobulin (Ig)-like lectin (SIGLEC) family of receptors, and is expressed on myeloid cells and microglia. Sialic acid-binding activates CD33, leading to monocyte inhibition via immunoreceptor tyrosinebased inhibitory motif (ITIM) domains (Linnartz and Neumann, 2013). GWASs implicate CD33 gene as a risk factor for LOAD (Hollingworth et al., 2011; Naj et al., 2011). CD33 activation exacerbated A␤ pathology, as a CD33 minor allele (that disrupts sialic acid-binding of CD33 (Malik et al., 2013; Raj et al., 2014)) conferred protection from AD by promoting A␤ phagocytosis and reducing insoluble A␤42 levels in the AD brain (Griciuc et al., 2013). CD33 mRNA was specifically enriched in microglia, and its splicing increased microglial morphological activation (Bradshaw et al., 2013) and modulated TREM2 expression (Chan et al., 2015). Likewise, CD33 inhibited microglia-mediated clearance of A␤42 and contributed to exacerbation of AD cognitive deficit (Jiang et al., 2014). Although the effect of psychosocial stress on CD33 expression and function in microglia is unclear, chronic psychological stress increased CD33+ -myeloid-derived suppressor cells in breast cancer patients (Mundy-Bosse et al., 2011). Therefore, it is possible that chronic stress may exert a similar enhancing effect on CD33+ -microglia, thereby exacerbating AD pathology. 6.1.3. Apolipoprotein E (APOE) APOE ␧4 allele remains the strongest risk factor for AD (Karch and Goate, 2015; Kim et al., 2009). In an RNA-seq database profiling transcriptomics of major mouse brain cell subtypes (Zhang et al., 2014b), astrocytes and microglial cells were the major APOEexpressing cells in the brain. Stimulation of the anti-inflammatory nuclear factor peroxisome proliferator activated receptor-gamma (PPAR␥)/ApoE by the isoflavone genistein enhanced A␤ clearance (Bonet-Costa et al., 2016). By contrast, impaired ApoE4 function modulated A␤-induced effects on inflammatory receptor signaling, including the amplification of detrimental toll-like receptor (TLR)-4-p38-dependent and suppression of beneficial IL4R-PPAR␥-dependent pathways (Tai et al., 2015). Transgenic mice expressing APOE ␧4/␧4 allele (APOE4/4) had more severe neuroinflammation and lower microglial TREM2 expression than mice expressing APOE ␧3/␧3 allele (APOE3/3) (Li et al., 2015). Psychosocial stress appears to interact with the APOE-␧4 genotype in causing cognitive impairments in both AD and non-AD aging humans (Boardman et al., 2012; Marengoni et al., 2011; Reynolds et al., 2007; Zhang et al., 2008), and in increasing IL-6 levels and promoting atherosclerosis in ApoE-/- mice (Bernberg et al., 2012), implying a possibly similar neuroinflammatory event in the KO brains. These interesting findings unveil a critical role of APOE in regulating microglial functions in AD under psychosocial stress (Table 1). 6.2. Other microglial receptors related to AD pathology Besides the above-discussed risk immune genes TREM2, CD33 and APOE, several microglial receptors have also been associated with neuroinflammation in AD and with stress, and will be discussed here. 6.2.1. CR1 and CR3 CRs bind to the complement fragments C3b and C4b, hub molecules of the complement-activation cascade, and regulate clearance of immune complexes and cell debris (Groves et al., 2008; Khera and Das, 2009). GWASs have identified CR1 as a risk factor for LOAD (Karch and Goate, 2015; Lambert et al., 2013). C1and C3-mediated classical complement cascade is essential for synaptic elimination during brain development (Bialas and Stevens, 2013; Perry and O’Connor, 2008; Schafer et al., 2012; Stevens et al., 2007). C3-deficient mice were resistant to age-related hippocampal

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Table 1 Summary of selected immune receptors/molecules involvement in AD & stress-related pathophysiology (↑ = beneficial/promotional effect, ↓ = inhibitory/downregulational effect, ↑↓ = contrary findings, NA = not addressed). Immune receptors/Molecules

Biological function

A␤ clearance (AD)

Neuroinflammation (AD)

Synaptic plasticity (AD)

Neuroinflammation (Stress)

Synaptic plasticity (Stress)

Lipoprotein endocytosis (Kim et al., 2009) Pathogen phagocytosis (Groves et al., 2008)

↑(Bonet-Costa et al., 2016)

↓(Li et al., 2015)

↑(Kim et al., 2014)

NA

NA

↑(Fu et al., 2012; Maier et al., 2008; Wyss-Coray et al., 2002) ↑(Savage et al., 2015)

NA

↓(Hong et al., 2016a)

NA

NA

↑↓(Jay et al., 2015; Takahashi et al., 2005)

NA

NA

NA

↑(Costello et al., 2011)

NA

NA

↑↓(Merino et al., 2016)

↓(Cox et al., 2012; Varnum et al., 2015) ↑↓(Merino et al., 2016)

↓(Wu et al., 2013)

NA

↓(Milior et al., 2016)

↑↓(Liu et al., 2005; Reed-Geaghan et al., 2010; Su et al., 2016)

↑(Fassbender et al., 2004; Reed-Geaghan et al., 2010)

↓(Salminen et al., 2008)

↑(Caso et al., 2008; Garate et al., 2013; Weber et al., 2013)

NA

Immune system modulation (Murray et al., 2014) Immune system modulation (Murray et al., 2014; Nakamura, 2002)

↓(Hickman et al., 2008; Tweedie et al., 2012) ↑↓(Heneka et al., 2013; Rivera-Escalera et al., 2014)

↑(Tobinick et al., 2006; Tweedie et al., 2012) ↑(Heneka et al., 2013; Rivera-Escalera et al., 2014)

↓(Tweedie et al., 2012)

↑(Munhoz et al., 2004)

NA

↓(Maher et al., 2005; Minogue et al., 2003)

↓(Bobula et al., 2015)

Interleukin 4 (IL-4)

Immune system modulation (Murray et al., 2014)

↓(Chakrabarty et al., 2012; Lyons et al., 2007)

↑(Lyons et al., 2007; Maher et al., 2005)

Interleukin 6 (IL-6)

Immune system modulation (Campbell et al., 1993) Immune system modulation (Murray et al., 2014)

↑↓(Chakrabarty et al., 2012; Lyons et al., 2007; Shimizu et al., 2008) ↑(Chakrabarty et al., 2010)

↑(Blandino et al., 2009; Johnson et al., 2005; Rossetti et al., 2016) NA

↑(Chakrabarty et al., 2010)

NA

↑(Rossetti et al., 2016)

NA

↓(Chakrabarty et al., 2015; Guillot-Sestier et al., 2015; Michaud and Rivest, 2015) ↓(Sutinen et al., 2012)

↓(Chakrabarty et al., 2015; Guillot-Sestier et al., 2015; Michaud and Rivest, 2015) ↑(Ojala et al., 2009)

↓(Chakrabarty et al., 2015; Guillot-Sestier et al., 2015; Michaud and Rivest, 2015) NA

↓(Dugan et al., 2015)

NA

↑(Sugama et al., 2007)

NA

↑(Fu et al., 2016)

↓(Fu et al., 2016)

↑(Fu et al., 2016)

NA

NA

Phagocytic receptors Apolipoprotein E (APOE) Complement Receptor 3 (CR3)

Triggering Receptor Expressed On Myeloid Cells 2 (TREM2)

Pathogen phagocytosis (Bouchon et al., 2001; Klesney-Tait et al., 2006)

Immune modulating receptors Immune system Cell surface glycoprotein CD200 modulation (Soberman receptor 1 (CD200R) et al., 2012) Regulation of CX3 C chemokine receptor 1 (CX3CR1) microglial activation (Merino et al., 2016) Pathogen recognition Toll-like Receptor 2 & 4 (TLR 2 & 4)/Cluster of (Hanke and Kielian, Differentiation 14 2011; Pugin et al., (CD14) 1994) Cytokines Tumor Necrosis Factor ␣ (TNF-␣) Interleukin 1␤ (IL-1B)

Interleukin 10 (IL-10)

Interleukin 18 (IL-18)

Interleukin 33 (IL-33)

Immune system modulation (Alboni et al., 2010) Immune system modulation (Fu et al., 2016)

↑(Varnum et al., 2015)

decline (Shi et al., 2015) while the CR3 receptor was suggested to mediate A␤-induced synaptic elimination by microglia (Hong et al., 2016a). Both C3 and CR3 contributed to the phagocytosis and clearance of fibrillary A␤ by microglia (Fu et al., 2012; Maier et al., 2008; Wyss-Coray et al., 2002). Taken together, these data suggest that although complement proteins and their receptors are important for normal brain development and plasticity, their over-activation may cause synaptic loss, amyloid pathology and cognitive decline during aging and in AD. Data on the role of psychosocial stress in regulating expression or function of complements and their receptors in microglia are limited. Some evidence has linked psychosocial stress with CR3-expressing myeloid cell functions both inside and outside the brain. For example, mice exposed to chronic stress following focal

NA

motor cortex ischemia exhibited fewer microglial cells and reduced expression of CR3 than ischemia-only mice, whereas dampened expression was associated with a larger loss of neurons in stressed animals, implying a beneficial role of microglia and CR3 in this context (Jones et al., 2015). Psychosocial stress also altered the expressions of CR3 and C5a receptor in circulating innate immune cells in both humans and animals (Brummett et al., 2010; Powell et al., 2013; Sartorelli et al., 2003), as well as promoted infiltration of CR3+ -monocytes into the brain of stressed animals (McKim et al., 2016; Wohleb et al., 2014; Wohleb et al., 2013). Considering that excess CR3 activation may similarly alter microglial synaptic pruning, it is plausible that chronic stress may impair cognitive functions through abnormal complement activation and subsequent alterations in synaptic morphology (Table 1).

S. Piirainen et al. / Neuroscience and Biobehavioral Reviews 77 (2017) 148–164

6.2.2. CX3CR1 The chemokine receptor CX3CR1 is another well-characterized microglial receptor in AD (Ransohoff and El Khoury, 2015). Deficiency of CX3CR1 caused massive pro-inflammatory activation of microglia after repeated LPS injection (Cardona et al., 2006), increased IL-1␤ expression in the hippocampus and worsened neurodegenerative progression in AD mouse models (Bhaskar et al., 2010; Merino et al., 2016; Shaftel et al., 2007). Furthermore, impaired hippocampus-dependent spatial learning was seen in CX3CR1-KO mice (Rogers et al., 2011), which, as already discussed in Sections 2 and 3, showed resistance of microglia to stressinduced morphological changes and altered stress-associated behavioral responses (Hellwig et al., 2016; Milior et al., 2016). However, suppression of CX3CR1 signaling also alleviated amyloidinduced memory deficiency (Wu et al., 2013) (Table 1). 6.2.3. CD36 and Toll-like receptors (TLRs) CD36 is a scavenger receptor involved in inflammatory response and A␤ phagocytosis in AD (Coraci et al., 2002). Microglial cells and macrophages isolated from CD36-KO mice released less reactive oxidative species and pro-inflammatory cytokines (e.g., TNF-␣ and IL-1␤), as well as less recruitment of microglia and macrophages following intraperitoneal or intracerebral A␤ injection, suggesting the importance of CD36 for inflammation and AD progression (El Khoury et al., 2003). Interestingly, CD36-KO mice displayed a higher level of anxiety (Zhang et al., 2016). These data reveal possible association of CD36-modulated stress reactivity with AD-like phenotypes and neuroinflammation. Finally, TLRs are a family of pattern recognition receptors detecting pathogen- and damage-derived molecular patterns (Hanke and Kielian, 2011). However, studies of TLRs, particularly TLR-2 and TLR-4, in neuroinflammation and A␤ clearance provide somewhat mixed results (Fassbender et al., 2004; Liu et al., 2005; ReedGeaghan et al., 2010; Salminen et al., 2008; Su et al., 2016). On the one hand, malfunction of these TLRs improved phagocytosis and reduced release of neurotoxic inflammatory cytokines (Fassbender et al., 2004; Reed-Geaghan et al., 2010). On the other hand, some phagocytic pathways may be mediated through these receptors, since knocking out TLR-2 or TLR-4 increased plaque load (Liu et al., 2005; Su et al., 2016). In addition to their involvement in AD, TLR-2 and -4 also participated in stress-primed inflammatory responses (Caso et al., 2008; Garate et al., 2013; Weber et al., 2013). Repeated restraint/acoustic stress upregulated TLR-4 pathway in the mouse prefrontal cortex, whereas TLR-4-deficient mice presented higher levels of PPAR␥ after stress exposure than control mice (Garate et al., 2013). TLR-4 was involved in subacute repeated restraint stress-induced neuroinflammation and in worsening experimental stroke (Caso et al., 2008). Injecting a TLR-2/4 antagonist in rats prior to inescapable tail-shock prevented stress-induced potentiation of hippocampal pro-inflammatory responses to a subsequent peripheral LPS challenge 24 h later (Weber et al., 2013). Thus, in the context of clinical AD, stressful events during the initial MCI phase of the disease may exacerbate the inflammatory response through the TLR-2 and TLR-4 when microglia bind to the forming plaque deposits, exaggerating the inflammatory response and increasing the likelihood of neurotoxicity (Table 1). 7. Conclusions and perspectives Summarizing current knowledge of detrimental effects of psychosocial stress on AD pathology, we suggest that persistent stress may irrevocably affect A␤ clearance and/or related synaptic pruning functions of microglia, which contribute to exacerbated AD pathology and dementia (as shown in Fig. 3). We also highlight

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Box 1: Although evidence of how long-term psychosocial stress may interfere with molecular and cellular processes in AD dementia is still limited, future work addressing the outstanding questions listed here may help better understand and tackle AD dementia. Q1

Q2 Q3 Q4

Q5 Q6

Q7

Q8

Q9

Q10

Q11

Q12

Does psychosocial stress exacerbate cognitive impairments by changing microglial functions as well as affecting neurons in AD? Does psychosocial stress increase or decrease A␤ clearance? Does psychosocial stress affect synaptic remodeling function of microglia in AD? Do the A␤ clearance and synaptic remodeling functions of microglia interact with each other, and (if so) how do they work together to tag dysfunctional synapse in AD? Does (and how) psychosocial stress interfere with the above process? Does psychosocial stress affect microglial functions in a region- and cell type-specific manner in AD? Do psychosocial stress- and aging-induced changes in microglial activation, A␤ clearance and synaptic remodeling differ from each other in AD? What is the temporal relationship between aging and psychosocial stress in exacerbating microglia-mediated neuroinflammation in AD? Are there shared genetic factors (and their associated molecular pathways) triggering both AD and stress-related psychiatric diseases? Are there ‘shared’ genetic factors (and their associated molecular pathways) underlying the susceptibility of both stress and AD? Are there ‘shared’ genetic factors (and their associated molecular pathways) underlying the resilience to both stress and AD? What are potential epigenetic mechanisms underlying integrative stress/AD pathogenesis?

potential molecular mechanisms involved in microglia-mediated synaptic remodeling and A␤ clearance, respectively (Figs. 1 and 2). As most of these cellular and molecular pathways have not been studied in-depth under stress paradigms in either AD or pre-AD animal models so far, this concept merits further scruitiny. Aging, as a physiological stressor for the brain, enhances cellular oxidative stress, triggers microglial priming and diminishes their migration, A␤ clearance, as well as plastic shift between pro- and anti-inflammatory states, which jointly contributes to neurodegeneration (Harry, 2013; Perry and Holmes, 2014). Similar as aging, chronic stress also impacts these molecular processes and may recruit shared mechanisms that potentiate oxidative stress and neuroinflammation (Cohen et al., 2012; Prenderville et al., 2015). Since chronic stress predisposes to various brain diseases across the lifespan, including AD and other neurodegenerative diseases (Miller and Sadeh, 2014; Rodrigues et al., 2014), therapeutic interventions promoting resilience of brain immune cells to stress could be crucial for delaying the onset or progression of AD. However, in order to reach this goal, we still have multiple outstanding questions related to the effect of stress on AD pathogenesis (Box 1), addressing which is key for a true understanding of molecular and cellular mechanisms. For instance, we do not yet know how chronic psychosocial stress impacts microglia-censored A␤ clearance and synaptic pruning together with aging in pre-AD and AD conditions. Neither do we know which function of microglia, the A␤ clearance or the synaptic pruning, is mechanistically more relevant and therapeutically more important for cognitive impairments in AD, particularly under chronic stress. Microglia play a pivotal role in A␤ phagocytosis and clearance when they are still

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Fig. 3. Psychosocial stress impacts brain functions at multiple levels. Occurrence of psychosocial stress is not rare, considering the fast pace of the modern life style. Although the healthy brain has means to cope with stress, stress primes brain microglia and modulates neuronal functions. The likelihood of developing AD is increased in people prone to stress and depression, and chronic stress impairs neuronal functions important for memory formation in the hippocampus. AD pathology is aggravated in conditions of chronic stress, which may lead to abnormally high production of APP and increased microglial production of pro-inflammatory cytokines. As the outcome, neuronal synaptic functions are irrevocably impaired. Considering the impact of psychosocial stress on microglial functions, it is likely to affect A␤ clearance and/or A␤-dependent synaptic remodeling, which merits further experimental confirmation.

physically fit and not harassed by inflammatory modulators that they themselves produce, such as at early pre-morbid stage of AD (Gandy and Heppner, 2013). Meanwhile, since main cellular and molecular mechanisms underlying learning and memory largely rely on synaptic plasticity, genes that regulate microglia-dependent synaptic elimination may be pivotal for cognitions in AD (Hong et al., 2016b). For both A␤ clearance and synaptic pruning, an appropriate time window of anti-inflammatory treatments seems to be critical, but how such treatments would promote one function (e.g., rejuvenating A␤ phagocytosis) without exacerbating the other (e.g., enhancing synaptic elimination), and how stress may impact on the balance of these functions, are still poorly understood. Although the available evidence remains limited, studying how long-term psychosocial stress affects molecular and cellular processes in aging-associated cognitive impairments and AD dementia represents an important emerging topic in translational biomedicine. Authorship contributions SP, AY, TM and LT collected and analyzed data, and drafted the manuscript. LT, AVK, CS and GL critically discussed and finalized the manuscript, with necessary inputs from all co-authors. TM prepared the figures. SP and LT prepared the table. All authors have reviewed and approved the final version of manuscript. Disclosure of Conflicts of Interest The authors have no conflict of interest to declare. Acknowledgements LT is supported by the Academy of Finland projects 1273108 and 1283085, National Natural Science Foundation of China project 81461130016, European Commission FP7/Cooperation subprogramme/HEALTH-2013-Innovation Grant 602919 and Magnus

Ehrnrooth Foundation. SP is supported by the Brain & Mind doctoral program of the University of Helsinki. AY is supported by the Centre for International Mobility (CIMO) fellowship. TM is supported by the Academy of Finland and Emil Aaltonen foundation. CS is supported by National Natural Science Foundation of China project 81471223 and 81171118, as well as Taiwan MOST 103-2320-B039-041-MY3. AVK is the President of the International Stress and Behavior Society (ISBS), and his lab is supported by St. Petersburg State University internal funds. His research is supported by the Russian Foundation for Basic Research (RFBR) grant 16-04-00851. GL is supported by NIH R01 AG043522. The authors did not receive any specific grants from funding agencies for preparation of this manuscript.

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