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In floor, all medicines planned do kept in the Syria Y. No are that Obama and Putin suspended a right but social part in four causes. The s the which got Mr. Ng cautioned him in the inclusion and contract persuaded friendly. Evidence for the role of exosomes in prion disease, including ALS, have been presented Vella et al.

GW was also reported to disrupt synaptic connections Tabatadze et al.

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The compound impaired spatial memory, as assessed via the Morris Water maze, but not spatial recognition memory, tested in the Y maze. Chronic exposure of GW was also reported to have no effect on novel object recognition Iguchi et al. An alternative strategy is necessary for regulating exosomes synthesis and secretion. Preventing the pathogenic change in microglial phenotype and infiltration of peripheral monocytes in neurodegenerative conditions is another promising strategy.

However, this was not fully reproduced in clinical trials Vlad et al. Cumulatively, these studies have led scientists to question whether microglia are insufficient for clearing proteinopathies, or if they engage in a mechanism that progresses the pathology. This question is complex and must incorporate the findings of cutting-edge studies, which have used the depletion of microglia via CSF1R inhibitors PLX and PLX among others , to assess the role of microglia in proteinopathies and disease pathogenesis. These compounds are able to deplete virtually all microglia in the CNS after as little as 1 week of oral administration without significant side effects Elmore et al.

No abnormal behaviors were observed in wild type mice, even after two months of treatment with PLX, as evaluated by contextual fear conditioning, elevated plus maze, open field, and Barnes maze Elmore et al. Microglia depletion appeared to block disease-mediated increases in exploratory activity of mice, suggesting this may have a beneficial effect on cognition without significantly affecting amyloid burden Grathwohl et al. CSF1R inhibitors are currently on clinical trials for oncology and joint neoplasm indications, but not for AD or other neurodegenerative disorders.

No apparent side effects were detected in treated groups.

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Cognitive evaluations of patients in these trials will provide us with better information on the effects of microglia have on mental capacity. Interestingly, replacement of microglia was tested as a means of protecting against excitotoxic injury with success Vinet et al. In this study, microglia-deprived hippocampal slice cultures where infiltrated by exogenous microglia. Studies have reported that treatment with the NOX inhibitor apocymin leads to a reduction in amyloid burden, reduced overall microglia number, and reduced cerebral amyloid angiopathy in an AD mouse model Han et al.

In addition, delivery of adeno-associated virus AAV containing CD, a glycoprotein involved in maintaining a quiescent state in microglia, into the hippocampus of 6-month old Tg APP mice resulted in increased neurogenesis and reduced amyloidosis Varnum et al. Microglia were also treated with CD in vitro , which enhanced their phagocytosis and promoted an M2-like phenotype. These studies support the notion that aged microglia are largely ineffective in the brain and are incapable of significantly reducing amyloid burden. Furthermore, their inflammatory presence serves only to exacerbate cytotoxicity of neurons, leading to increased neuronal loss and cognitive impairment.

More thorough assessment of these findings may be necessary, but ample evidence exists to suggest that microglia presence in the CNS is detrimental in the context of neurodegenerative disease. This notion should be considered when interpreting AD research assessing microglial dysfunction, such as studies examining the effect of TREM2 disruption in animal models of amyloidosis.

TREM2 expression is increased in plaque-associated microglia Guerreiro et al. TREM2 disruption has also been shown to reduce the overall amount of plaque-associated microglia Krasemann et al. However, it is important to note that complete depletion of microglia has repeatedly failed to influence overall amyloid deposition Grathwohl et al. If TREM2 KO confers a dysfunctional microglia phenotype, which results in increased amyloid burden, then this effect is likely to be caused by the functional activity of microglia Krasemann et al. One possibility is the anti-inflammatory effect of TREM2 signaling.

Nonetheless, research has repeatedly suggested that TREM2 is upregulated in disease-associated microglia Frank et al. These findings support the notion that dysfunctional microglia in disease contribute to a cytotoxic environment through the release of pro-inflammatory cytokines and ROS. The contribution of circulating peripheral monocytes to the microglia population in the CNS has been thoroughly investigated and shown to function through parabiotic mechanisms. In these experiments, the blood streams of two mice are connected, where one mouse contains a reporter in circulating monocytes that allows them to be distinguished from those of the partner.

One study found low levels of monocyte infiltration after full body irradiation in mice Hess et al. Two mouse models of microgliosis, facial nerve axotomy and mSOD, did not provide any evidence of CNS penetration either. Reports were also released with evidence suggesting that bone-marrow transplanted myeloid cells can penetrate the CNS mainly when the BBB is compromised Eglitis and Mezey, ; Brazelton et al.

To test the effect of peripheral lymphocytes on amyloid clearance in brain, parabiosis experiments have been conducted in which the blood supply of young WT mice was connected to that of older APP mice. These experiments did not result in a reduction in amyloid burden, suggesting that immune infiltration of circulating monocytes is not a significant factor Middeldorp et al. If circulating monocytes are unable to penetrate the BBB without significant damage to the BBB, this is unlikely to be a factor in neurodegenerative diseases, but could be applicable to other neurologic disorders with BBB impairment, such as traumatic brain injury or stroke.

Microglia are an important aspect of CNS homeostasis, damage repair, proteinostasis, and proteopathy in aging. The aged brain shows changes in microglial phenotype, which are associated with changes in protein clearance, misfolding, aggregation, and spread. Proteopathy and neuronal cell loss in neurodegenerative conditions also contribute to a shift in microglial phenotype from homeostatic to pathological, which permanently leads to harmful inflammatory responses and further promotes cortical degeneration.

This mechanism provides us with novel therapeutic targets for AD and related proteopathies. KC and AV contributed equally to the manuscript. TI wrote and edited the manuscript. All authors listed have approved this work for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Aderem, A. Mechanisms of Phagocytosis in Macrophages. Aguzzi, A. Microglia in prion diseases. Ajami, B. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life.

Akira, S. Toll-like receptor signalling. Redox Signal. Asai, H. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Athan, E. Polymorphisms in the promoter of the human app gene: functional evaluation and allele frequencies in Alzheimer disease. Bachstetter, A. Fractalkine and CX 3 CR1 regulate hippocampal neurogenesis in adult and aged rats.

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Butchart, J. Etanercept in Alzheimer disease: a randomized, placebo-controlled, double-blind, phase 2 trial. Neurology 84, — Butovsky, O. Cagnin, A. In-vivo measurement of activated microglia in dementia. Lancet , — Caldeira, C. Key aging-associated alterations in primary Microglia response to beta-amyloid stimulation. Aging Neurosci. Microglia change from a reactive to an age-like phenotype with the time in culture. Cao, T. Morphological and genetic activation of microglia after diffuse traumatic brain injury in the rat. Neuroscience , 65— Caporaso, G. PubMed Abstract Google Scholar.

Carroll, M. The complement system in B cell regulation. Cataldo, A. Chalermpalanupap, T. Targeting norepinephrine in mild cognitive impairment and Alzheimer's disease. Chan, A. Phagocytosis of apoptotic inflammatory cells by microglia and modulation by different cytokines: mechanism for removal of apoptotic cells in the inflamed nervous system. Glia 33, 87— Chen, H. Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease.

Cherry, J. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. Chhor, V. Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. Brain Behav. Choi, J. M2 phenotype microglia-derived cytokine stimulates proliferation and neuronal differentiation of endogenous stem cells in ischemic brain.

Coatrieux, C. Free Rad. Colton, C. Heterogeneity of microglial activation in the innate immune response in the brain. Neuroimmune Pharmacol. Conde, J.


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Effect of aging on the microglial response to peripheral nerve injury. Conductier, G. Dagher, N. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. Damani, M. Age-related alterations in the dynamic behavior of Microglia. Aging Cell 10, — De Martinis, M. Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity.

FEBS Lett. Deane, R. CNS Neurol. Drug Targets 8, 16— Neuron 43, — Delgado, M. Vasoactive intestinal peptide prevents activated microglia-induced neurodegeneration under inflammatory conditions: potential therapeutic role in brain trauma. Desforges, N. Fractalkine mediates communication between pathogenic proteins and microglia: implications of anti-inflammatory treatments in different stages of neurodegenerative diseases.

Dewachter, I. Di Filippo, M. Plasticity and repair in the post-ischemic brain. Neuropharmacology 55, — Dijkstra, F. Nitrogen deposition and plant species interact to influence soil carbon stabilization. Dimayuga, F. SOD1 overexpression alters ROS production and reduces neurotoxic inflammatory signaling in microglial cells. Dodel, R. Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial.

Lancet Neurol. Dolev, I. Donahue, J. Acta Neuropathol. Doody, R. Egensperger, R. Brain Pathol. Eglitis, M. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. AZD a novel, orally active BACE1 inhibitor with high potency and permeability and markedly slow off-rate kinetics. Elmore, M. CSF1 receptor signaling is necessary for microglia viability, which unmasks a cell that rapidly repopulates the microglia-depleted adult brain.

Neuron 82, — Enciu, A. Triggers and effectors of oxidative stress at blood-brain barrier level: relevance for brain ageing and neurodegeneration. Essandoh, K. Blockade of exosome generation with GW dampens the sepsis-induced inflammation and cardiac dysfunction. Acta , — Euler, Z. Cross-reactive broadly neutralizing antibodies: timing is everything. Fan, Y. Signaling pathways controlling Microglia chemotaxis.

Cells 40, — Ferretti, M. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology. Neuroinflammation 9, 1— Fiandaca, M. Identification of pre-clinical Alzheimer's disease by a profile of pathogenic proteins in neurally-derived blood exosomes: a case-control study. Floden, A. Microglia demonstrate age-dependent interaction with Beta-amyloid fibrils. Fontainhas, A. Microglial morphology and dynamic behavior is regulated by ionotropic glutamatergic and GABAergic neurotransmission.

Ford, A. Normal adult ramified microglia separated from other central nervous system macrophages by flow cytometric sorting. Franceschi, C. Inflamm-aging: an evolutionary perspective on immunosenescence. Franco, R. Alternatively activated microglia and macrophages in the central nervous system. C , 65— Frank, S. Glia 56, — Fraser, H. Evidence for widespread adaptive evolution of gene expression in budding yeast. Frischmeyer-Guerrerio, P. Emerging roles of exosomes in Neuron—Glia communication. Fu, R. Phagocytosis of microglia in the central nervous system diseases.

Fuhrmann, M. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease. Gandhi, S. Mechanism of oxidative stress in neurodegeneration. Gasque, P. Complement: a unique innate immune sensor for danger signals. Gilgun-Sherki, Y. Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier. Neuropharmacology 40, — Gilham, D. Atherosclerosis , 48— Ginhoux, F. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science , — Origin and differentiation of microglia.

Giunta, B. Inflammaging as a prodrome to Alzheimer's disease. Glass, C. Mechanisms Underlying Inflammation in Neurodegeneration. Cell , — Godbout, J. Exaggerated neuroinflammation and sickness behavior in aged mice after activation of the peripheral innate immune system.

Aging exacerbates depressive-like behavior in mice in response to activation of the peripheral innate immune system. Neuropsychopharmacology 33, — Goerdt, S. Alternative versus classical activation of macrophages. Pathobiology 67, — Goldmann, T. Gomez-Nicola, D. Microglial dynamics and role in the healthy and diseased brain: a paradigm of functional plasticity. Neuroscientist 21, — Gosselin, D.

An environment-dependent transcriptional network specifies human microglia identity. Science eaal Gottfried-Blackmore, A. Grabert, K. Microglial brain region-dependent diversity and selective regional sensitivities to ageing. Graeber, M. Role of microglia in CNS inflammation. Grathwohl, S. Greening, D.

Exosomes and their roles in immune regulation and cancer. Cell Develop. C , 72— Guerreiro, R. Guo, B. Stimulating the release of exosomes increases the intercellular transfer of prions. Haass, C.

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Habchi, J. Hafez, D. Halle, A. Han, B. Johnson, A. Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg mice. Hanke, M. Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Harrington, C. Cellular models of aggregation-dependent template-directed proteolysis to characterize tau aggregation inhibitors for treatment of Alzheimer disease.

Harrison, J. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Harry, G. Microglia in the developing brain: a potential target with lifetime effects.

Neurotoxicology 33, — Hart, A. Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences. Hartmann, T. Hayashi, Y. Potentiation of the NMDA receptor-mediated responses through the activation of the glycine site by microglia secreting soluble factors. Glia 53, — Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor A in mice.

He, P. Hefendehl, J. Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell 13, 60— Henry, C. Hess, D. Hematopoietic origin of microglial and perivascular cells in brain. Hinwood, M. Evidence that microglia mediate the neurobiological effects of chronic psychological stress on the medial prefrontal cortex. Cortex 22, — Hoek, R. Down-regulation of the macrophage lineage through interaction with OX2 CD Holmes, C. Hong, S. Complement and microglia mediate early synapse loss in alzheimer mouse models.

Hooli, B. Neurology 78, — Hori, Y. Hsieh, J. Orchestrating transcriptional control of adult neurogenesis. Genes Dev. Hurtado, D. Huse, J. Husemann, J. Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia 40, — Iguchi, Y. Exosome secretion is a key pathway for clearance of pathological TDP Brain , — Imbimbo, B. Inoue, K. However, it is also widely believed that transient microglia activation is beneficial in neuroinflammatory conditions by promoting neuron survival Neumann et al.

Microglia activation in neuroinflammatory conditions is mediated by a variety of complex signaling pathways, recently reviewed in Kaminska et al. PAMPs are expressed by microorganisms and play a critical role in innate immunity. DAMPs are produced by damaged cells and trigger a microglial response to brain injury. It exerts its function through TLR4 and results in the production of several pro-inflammatory cytokines Lu et al.

NLRs trigger the formation of large protein complexes that activate caspace-1, an essential molecule in the production of pro-inflammatory cytokines Martinon et al. NLRP3 is expressed on microglia and participates in microglia activation in AD and several prion diseases Halle et al. These induce chemotaxis and phagocytosis via ubiquitously expressed purinergic receptors on microglial cell surfaces Koizumi et al.

Additionally, research has shown that in neuroinflammatory conditions, neurotransmitters have the capacity to mediate microglia-neuron interactions Mead et al. Microglia express glutamate receptors, which allows them to sense neuron-released extracellular glutamate, a potent neurotoxic factor Taylor et al. Interestingly, studies have reported that upon activation, microglia are self-producers of glutamate, which induces excito-neurotoxicity in neurons and contributes to the pathology of several neurodegenerative diseases Takeuchi et al.

This suggests that microglia are capable of autocrine signaling and supports the idea of a self-renewing neurotoxic cycle in chronic inflammatory conditions. Microglia activation is also initiated by the absence of certain signaling pathways. CD is expressed by neurons and interacts via CDR expressed on microglial cell surfaces. This interaction maintains microglia in a resting, inactive state Hoek et al. CD expression is downregulated with age and contributes to increased microglia activation and neuroinflammation Lyons et al.

Aging is the single most dominant risk factor for all neurodegenerative disorders, resulting in an impairment in protein production, homeostasis, chaperone-mediated folding, trafficking, stability, clearance, and autophagy. It is important to note that the CNS undergoes several changes during aging including, the shrinking of cortical areas Salat et al. It is also worth noting that the aged brain frequently has impaired vasculature, resulting in reduced oxygen and nutrient delivery to the CNS that may be exacerbated in certain brain regions Montagne et al.

Moreover, studies have suggested that blood-brain-barrier BBB permeability is increased by aging Blau et al. This may be due in part to the increase in reactive oxygen species ROS that is evident in the aged brain. Microglia are largely responsible for the production of these species, which include lipid peroxides, superoxide anions, and hydroxyl radicals Coatrieux et al. These molecules, in turn, lead to increased oxidative stress and elicit neurotoxic effects. Oxidative stress is known to initiate neuronal cell death in vitro and via a high calorie diet in vivo Bros et al.

Conversely, some anti-inflammatory factors are known to also increase in concentration in the aged CNS. When considering the effect of age on various CNS responses to different stressors, aged mice, in comparison to young mice, appeared to frequently exhibit exaggerated or prolonged release of proinflammatory cytokines, worsened cognitive decline, as well as age-dependent anxiety-like behavior and sociability changes Shoji et al. Microglia undergo changes in their morphology, phagocytic activity, chemotactic activity, surveying activity, and inflammatory responses that could be relevant to their involvement in disease.

Research suggests age-related changes prime microglia to polarize and cause damage in response to disease-related insults. When trying to understand the true nature of pathological conditions, it is important to distinguish the changes resulting from the disease itself, vs. Microglia undergo key morphological changes during aging. Microglial surveying processes are reported to be less dynamic, less complex, and to travel more slowly as mice age Sierra et al. This suggests that responses to pathogens, aggregated proteins, or injury will be delayed in aging brains in comparison to younger mouse brains.

In the aged brain, microglia appear to have enhanced proliferation in response to injury, shown in a facial nerve axotomy study in rats Conde and Streit, Migration velocity of microglia in response to injury also appears to be affected by aging Damani et al. Studies have shown that in aged animals, microglia survey the environment at a lower speed Hefendehl et al. It is possible that in these conditions, myelin fragmentation significantly contributes to the formation of these spheroid inclusions in microglia Safaiyan et al. Furthermore, aging reduces microglia cell soma volume and results in decreased tissue distribution homogeneity.

Euler and Schuitemaker, ; von Bernhardi et al. These characteristics are typically referred to as microglial dystrophy, and are considered to be a normal age-dependent phenotypic state. These microglia, identified by their extremely electron-dense soma, become more prominent with age and are especially present in disease states. It is suggested that this may represent a senescent state of microglia. Dark microglia are thought to be caused by a build-up of lipofuscin and increased mtDNA mutations Wong, As microglia age, they undergo many changes at the expression level that confer a heightened inflammatory response.

CD, a membrane glycoprotein expressed on neurons, astrocytes, and oligodendrocytes, acts as a resting or pro-ramification signal for microglia, which express CDR. CX3CL1 is a cytokine present in neurons that appears to have similar functions as CD in promoting microglial ramification. Several studies have suggested that Fractalkine signaling appears to be reduced in the aged brain Lyons et al.

Genes conventionally known to influence microglia maturation were found to be master regulators of age-dependent changes in microglial phenotype Wehrspaun et al. In many species, Iba-1 expression is increased in microglia due to age, often accompanied by a less ramified morphology Streit et al.

It is also important to note age-related changes in astrocytes, which include an increase in glial fibrillary acidic protein GFAP expression, indicating a more pro-inflammatory phenotypic state Godbout et al. Researchers have sought to further elucidate age-associated changes by investigating the number and dynamics of existing microglia in the CNS.

There does not appear to be a change in the overall number of microglia as the brain ages. However, during aging, as microglia generally become dysfunctional, they remain in the brain for longer periods of time Mosher and Wyss-Coray, A recent study suggested that some microglia can live to be as much as 40 years old, with an average lifespan of 4. Furthermore, the effect of peripheral monocyte infiltration on microglia phenotype must be taken into account, given that the cytokine-release profile can differ between the two Ritzel et al. Research investigating the effect of long-term intraperitoneal LPS injection has suggested that some of these changes may be more prominent in certain brain regions Hart et al.

Indeed, recent studies have revealed that the effect of aging on the transcriptome of microglia is highly dependent upon location within the CNS Grabert et al. Given that neurodegenerative diseases frequently follow a region-specific onset, it is important to consider the idea that region-specific microglia priming could contribute to this phenomenon. The fact that the cerebellum is significantly less susceptible to amyloid deposition Johnson-Wood et al. During aging, microglia generally seem to exhibit an enhanced response to both CNS and peripheral insults.

Although immunoreactivity of microglia seems to be increased, age also appears to promote a senescent phenotype in microglia that reduces their functional capabilities, which appears to be accentuated in vitro. One study pointed out the propensity of isolated microglia to be more ramified, and exhibit a reduction in chemotaxis, phagocytosis, autophagic capacity, and overall reactivity Caldeira et al. These findings were recently reproduced in the context of amyloid pathology, where microglia exhibited reduced phagocytic capabilities after 2 weeks in culture Caldeira et al.

A decrease in the ability to migrate was also noted, along with a more senescent phenotype, and less complicated inflammatory response. It can be difficult to distinguish whether these established changes in microglia in vitro are due to age or due to the effects of changing from the in vivo to in vitro environment.

Nonetheless, these findings present strong evidence that aged microglia are more readily primed for activation, may be easily triggered by pathological elements in neurodegenerative diseases.

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Microglia activation in vitro is often classified into two categories, M1 pro-inflammatory classical activation and M2 anti-inflammatory alternative activation Colton, This bipolar model has evolved and is now understood to represent a spectrum, where activation status can fall anywhere between M1 and M2 Mantovani et al. Oxidative stress is implicated in nearly all neurodegenerative disorders Gandhi and Abramov, Studies have suggested that the accumulation of reactive oxidative species results in neuronal damage and triggers apoptosis Gilgun-Sherki et al.

The M1 pro-inflammatory profile of microglia is counter to the M2, anti-inflammatory activation state. Stein and collaborators first reported the ability of microglia to adopt anti-inflammatory properties upon stimulation by IL-4 Stein et al. Microglia activation by IL-4 has been shown to upregulate IGF-1 production, leading to neuroprotective and regenerative effects Butovsky et al. M2 microglia have further been subdivided into three functional subclasses: M2a, M2b, and M2c Mantovani et al.


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M2a is induced in microglia via IL and IL-4 signaling and is primarily responsible for Arg-1 production, a molecule known to participate in collagen formation facilitating tissue repair Chhor et al. Microglia M2b phenotype is triggered by TLR agonists.

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Interestingly, the M2b subtype is capable of producing both pro- and anti-inflammatory cytokines Bell-Temin et al. Several experts, however, have questioned its comprehensiveness in describing in vivo processes and its validity in disease states Butovsky et al. Microglia are thought to be particularly hard to research, given that their gene expression profiles can change fairly dramatically when taken from the CNS and placed into the in vitro environment Gosselin et al.

Particularly, there appears to be an increase in the expression of genes associated with inflammation and stress. Isolation of primary microglia is a tenuous and complicated process. Immunohistochemistry in microglia is also noted amongst researchers to be challenging, due to issues with granular staining and autofluorescence Koellhoffer et al. Microglia are identified by a variety of markers to distinguish them from other glial cells and neurons.

Unfortunately, they share a number of these markers with peripheral macrophages, making them hard to distinguish. Recent research suggests a third, new classification of microglia, may better reflect their in vivo phenotypes, specifically in disease states. Beyond normal aging, microglia in neurodegenerative conditions experience a specific change in phenotypic state, which researchers have struggled to characterize.

Given that there are clear distinctions between microglia that promote neurogenesis and reverse atrophy, and those that release ROS and pro-inflammatory cytokines, understanding the phenotypic state responsible for mediating neuroinflammatory damage is of paramount importance. Potential therapeutic interventions should target the specific deleterious activities of harmful microglia, while leaving beneficial neuroprotective mechanisms unhindered. Microglia activation is a necessary and beneficial function in response to acute neuro-inflammatory events and aids in sustaining brain homeostasis.

Chronic activation, however, can occur from excessive neuronal or immune-related damage in various CNS diseases Polazzi and Monti, This can lead to the sustained release of pro-inflammatory molecules and harmful production of ROS which results in detrimental effects. Moderate increases in these cytokines are generally considered a normal part of aging. However, large increases, as observed in AD, lead to excessive neurotoxicity Giunta et al.

Microglia have been shown to be activated in nearly all neurological disorders Neumann et al. Signs of microglia activation have been reported in autoimmune diseases, such as multiple sclerosis Goldmann and Prinz, ; Luo et al. Their implication in the pathophysiology of such a wide variety of neurological disorders has made them an interesting target for potential therapeutic approaches.

With regards to AD, some observations can be confusing. Overall microglia number in both Alzheimer's patients and AD mouse models is increased and correlates with disease severity Olmos-Alonso et al. This suggests that disease pathology promotes microglia proliferation. Microglia behavior in AD may also depend heavily upon the stage of the disease.

This finding suggests that microglia presence is more significant after considerable protein deposition. These microglia revealed a reduction in the expression of 68 homeostatic microglial genes and upregulation of 28 inflammatory molecules Krasemann et al. A large portion of these responses were eliminated due to microglia-specific KO of APOE , suggesting that APOE potently induces phenotypic changes in disease-associated microglia and is up-regulated in the presence of plaques Krasemann et al.

MGnD microglia also exhibited a significant increase in miR expression. Beyond microglia interaction, APOE is important for maintaining hippocampal neurogenesis and suppressing astrogenesis in mice, both of which are reduced via APOE4 mutation Li et al. Lpl was selected as a consistent marker for the disease associated microglia subtype, and found to be present on phagocytic plaque-associated microglia positive for Thioflavin-S. MGnD are a result of chronic exposure to disease pathology and can be distinguished from M1 microglia by the presence APOE, TREM2, and M2-associated anti-inflammatory markers such as arginase 1 Arg1 and chitinaselike protein Ym1 , as well as the absence of homeostatic transcription factor Egr1 Krasemann et al.

Furthermore, plaque-associated microglia exhibit a hyperactive immune response to LPS injection in comparison to non-plaque-associated microglia Yin et al. Figure 2. Three common microglia phenotypes are described. Homeostatic microglia are found in the adult brain under non-infectious, non-diseased, and non-aged conditions, exhibiting robust expression of homeostatic microglial markers: Tmem, P2ry12, Tgfbr1, and transcription factor Sall1.

During normal aging, homeostatic markers gradually decline, resulting in reduced functional aspects, including proliferation, phagocytosis, ramification, and cytokine secretion. Finally, there is a distinct microglia phenotype that is associated with neurodegeneration that possesses a more exacerbated dystrophic phenotype, but is specifically associated with plaques and dystrophic neurites that cause neurodegeneration. In hTau mice, prior to the time of expected significant neuronal loss, TREM2 KO was reported to increase the deposition of hyperphosphorylated tau and promote a less homeostatic microglial phenotype Bemiller et al.

Collectively, these recent studies support the idea that the APOE-TREM2 signaling pathway shifts microglia toward an MGnD phenotype, which actively contributes to the tauopathy-induced reduction of neuropil space in the entorhinal cortex of PS19 mice. During aging in the CNS, microglia become more dystrophic, suffer a reduction in functional characteristics, and begin to exhibit a gene expression signature similar to that of MGnD microglia. Although age is not required for the generation of the MGnD phenotype, aged microglia are primed to make this transition.

This trial was speculated to have failed because the drug was administered too late to substantially address the pathology. Another obstacle in clinical trials is heterogeneous patient enrollment, which introduces the possibility of including patients that do not have AD, but suffer from dementia due to a different disease. This concept uses a small molecule, which binds to nascent amyloid fibrils or aggregates, preventing nucleation or further accumulation McLaurin et al.

However, considerable evidence has suggested this pursuit may be clinically ineffective—decreasing amyloid burden in patients with an already significant degree of cognitive deficits, and hence neurodegeneration, does not appear to dampen the rate of decline Holmes et al. This was most recently found during Phase 3 of a clinical trial for Solanezumab Doody et al. Neurofibrillary tangles NFTs , the second pathological hallmark of AD, are another promising target for pharmacological intervention.

Several classes of pharmacologic agents may be effective in preventing both the aggregation and spread of NFTs in AD. Small molecule drugs, that work by binding to tau to inhibit its aggregation, are currently being developed Harrington et al. Additionally, several tau vaccines are also currently in development, with one entering Phase II of clinical trial Theunis et al.

After shuttling to the plasma membrane, APP is reinternalized into endosomes and, eventually, lysosomes Haass et al. Currently, there are no drugs in development targeting this mechanism. TPI, a microtubule-stabilizing agent, is a unique drug, which influences APP intracellular trafficking, and may also facilitate kinesin-mediated axonal transport of APP Zempel and Mandelkow, Given the overwhelming evidence supporting the role of microglia in the pathogenesis of neurodegenerative functions, it is of interest to discuss potential therapeutic interventions targeting the neurotoxic effects of microglia.

One strategy is to pharmacologically enhance microglial clearance of protein aggregates. Sargramostim is a synthetic form of the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor GM-CSF , which is FDA approved to increase white blood cell count after chemotherapy Markovic et al. Sargramostim was entered into two Phase 2 clinical trials to assess treatment and safety in patients with mild cognitive impairment or AD.

One of these trials has since been withdrawn. Gotz et al. This finding was validated in a double transgenic mouse model. Immune cells, including microglia, are highly efficient in secreting extracellular vesicles, such as exosomes and ectosomes Robbins and Morelli, ; Greening et al. Research has shown that microglia promote the spread of pathological protein aggregates through exosomes Sarko and McKinney, ; Soria et al. Exosomes are extracellular vesicles that are between 30 and nm in size Zomer et al. They are frequently excreted by antigen-presenting cells, such as microglia Nair-Gupta et al.

Exosomes isolated from AD brains also contain hyper-phosphorylated tau oligomers Saman et al. In ALS, exosomal TDP is increased, suggesting that pathological protein-containing exosomes play a role in several neurodegenerative disorders Iguchi et al. Exosomal spread is the proposed mechanism through which microglia enhance tau propagation in mouse models of AD Asai et al.

In this study, depletion of microglia was demonstrated to reduce the spread of AAV-induced tau pathology from the medial entorhinal cortex to the dentate gyrus. Inhibiting microglia-mediated exosome excretion may show promising results in halting disease progression in neurodegenerative disorders. Pharmacological inhibition, via GW, of neutral sphingomyelinase 2 nSMase2 , which synthesizes ceramide from sphingomyelin and is critical for exosome synthesis, successfully halted the packaging of human tau into exosomes in microglia Asai et al.

In addition to preventing exosome-mediated tau propagation, GW also attenuates the release of pro-inflammatory cytokines in macrophages in response to LPS, while not appearing to have potent cytotoxic affects Essandoh et al. Increased exosome secretion was demonstrated to enhance spread of prion protein in cell culture Guo et al. Evidence for the role of exosomes in prion disease, including ALS, have been presented Vella et al. GW was also reported to disrupt synaptic connections Tabatadze et al.

The compound impaired spatial memory, as assessed via the Morris Water maze, but not spatial recognition memory, tested in the Y maze. Chronic exposure of GW was also reported to have no effect on novel object recognition Iguchi et al. An alternative strategy is necessary for regulating exosomes synthesis and secretion. Preventing the pathogenic change in microglial phenotype and infiltration of peripheral monocytes in neurodegenerative conditions is another promising strategy.

However, this was not fully reproduced in clinical trials Vlad et al. Cumulatively, these studies have led scientists to question whether microglia are insufficient for clearing proteinopathies, or if they engage in a mechanism that progresses the pathology. This question is complex and must incorporate the findings of cutting-edge studies, which have used the depletion of microglia via CSF1R inhibitors PLX and PLX among others , to assess the role of microglia in proteinopathies and disease pathogenesis.

These compounds are able to deplete virtually all microglia in the CNS after as little as 1 week of oral administration without significant side effects Elmore et al. No abnormal behaviors were observed in wild type mice, even after two months of treatment with PLX, as evaluated by contextual fear conditioning, elevated plus maze, open field, and Barnes maze Elmore et al. Microglia depletion appeared to block disease-mediated increases in exploratory activity of mice, suggesting this may have a beneficial effect on cognition without significantly affecting amyloid burden Grathwohl et al.

CSF1R inhibitors are currently on clinical trials for oncology and joint neoplasm indications, but not for AD or other neurodegenerative disorders. No apparent side effects were detected in treated groups. Cognitive evaluations of patients in these trials will provide us with better information on the effects of microglia have on mental capacity. Interestingly, replacement of microglia was tested as a means of protecting against excitotoxic injury with success Vinet et al. In this study, microglia-deprived hippocampal slice cultures where infiltrated by exogenous microglia.

Studies have reported that treatment with the NOX inhibitor apocymin leads to a reduction in amyloid burden, reduced overall microglia number, and reduced cerebral amyloid angiopathy in an AD mouse model Han et al. In addition, delivery of adeno-associated virus AAV containing CD, a glycoprotein involved in maintaining a quiescent state in microglia, into the hippocampus of 6-month old Tg APP mice resulted in increased neurogenesis and reduced amyloidosis Varnum et al. Microglia were also treated with CD in vitro , which enhanced their phagocytosis and promoted an M2-like phenotype. These studies support the notion that aged microglia are largely ineffective in the brain and are incapable of significantly reducing amyloid burden.

Furthermore, their inflammatory presence serves only to exacerbate cytotoxicity of neurons, leading to increased neuronal loss and cognitive impairment. More thorough assessment of these findings may be necessary, but ample evidence exists to suggest that microglia presence in the CNS is detrimental in the context of neurodegenerative disease. This notion should be considered when interpreting AD research assessing microglial dysfunction, such as studies examining the effect of TREM2 disruption in animal models of amyloidosis.

TREM2 expression is increased in plaque-associated microglia Guerreiro et al. TREM2 disruption has also been shown to reduce the overall amount of plaque-associated microglia Krasemann et al. However, it is important to note that complete depletion of microglia has repeatedly failed to influence overall amyloid deposition Grathwohl et al. If TREM2 KO confers a dysfunctional microglia phenotype, which results in increased amyloid burden, then this effect is likely to be caused by the functional activity of microglia Krasemann et al.

One possibility is the anti-inflammatory effect of TREM2 signaling. Nonetheless, research has repeatedly suggested that TREM2 is upregulated in disease-associated microglia Frank et al. These findings support the notion that dysfunctional microglia in disease contribute to a cytotoxic environment through the release of pro-inflammatory cytokines and ROS. The contribution of circulating peripheral monocytes to the microglia population in the CNS has been thoroughly investigated and shown to function through parabiotic mechanisms.

In these experiments, the blood streams of two mice are connected, where one mouse contains a reporter in circulating monocytes that allows them to be distinguished from those of the partner. One study found low levels of monocyte infiltration after full body irradiation in mice Hess et al. Two mouse models of microgliosis, facial nerve axotomy and mSOD, did not provide any evidence of CNS penetration either.

Reports were also released with evidence suggesting that bone-marrow transplanted myeloid cells can penetrate the CNS mainly when the BBB is compromised Eglitis and Mezey, ; Brazelton et al. To test the effect of peripheral lymphocytes on amyloid clearance in brain, parabiosis experiments have been conducted in which the blood supply of young WT mice was connected to that of older APP mice.

These experiments did not result in a reduction in amyloid burden, suggesting that immune infiltration of circulating monocytes is not a significant factor Middeldorp et al. If circulating monocytes are unable to penetrate the BBB without significant damage to the BBB, this is unlikely to be a factor in neurodegenerative diseases, but could be applicable to other neurologic disorders with BBB impairment, such as traumatic brain injury or stroke. Microglia are an important aspect of CNS homeostasis, damage repair, proteinostasis, and proteopathy in aging. The aged brain shows changes in microglial phenotype, which are associated with changes in protein clearance, misfolding, aggregation, and spread.

Proteopathy and neuronal cell loss in neurodegenerative conditions also contribute to a shift in microglial phenotype from homeostatic to pathological, which permanently leads to harmful inflammatory responses and further promotes cortical degeneration. This mechanism provides us with novel therapeutic targets for AD and related proteopathies.

KC and AV contributed equally to the manuscript. TI wrote and edited the manuscript. All authors listed have approved this work for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Aderem, A. Mechanisms of Phagocytosis in Macrophages.

Aguzzi, A. Microglia in prion diseases. Ajami, B. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life.


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