Role Of Microglia Research Articles

Phrenic Motor Neuron Fractalkine Signaling to Nearby Microglia Regulates Phrenic Long-Term Facilitation

Although microglia are traditionally regarded as innate CNS immune cells, recent studies demonstrate that microglia also play key roles in normal CNS functions. For example, microglia engage in bidirectional communication with other cell types ( e.g., neurons) to regulate diverse processes including neuronal excitability, architecture and synaptic plasticity. Although neuron-microglia interactions regulate hippocampal synaptic plasticity, little is known concerning the role of microglia in regulating respiratory motor plasticity. One well-studied form of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a prolonged increase in phrenic motor output following acute intermittent hypoxia (AIH). Whereas AIH consisting of moderate hypoxic episodes (mAIH) elicits pLTF by a serotonin-dominant, adenosine-constrained mechanism, severe AIH (sAIH) elicits pLTF by an adenosine-dominant, serotonin-constrained mechanism. Neurons interact with microglia via release of fractalkine (CX3CL1), activating responses from nearby microglia, the only CNS cell-type known to express fractalkine receptors (CX3CR1). Cervical spinal fractalkine protein injections elicit phrenic motor facilitation similar to pLTF and trigger glial ATP/adenosine release, consistent with the hypothesis that neuronal fractalkine release during hypoxia elicits extracellular adenosine accumulation, thereby modulating AIH-induced pLTF. Here, we tested the hypothesis that phrenic motor neuron fractalkine protein underlies the adenosine-constraint to mAIH-induced pLTF, and drives sAIH-induced pLTF. In adult male Sprague Dawley rats, siRNA knockdown of phrenic motor neuron fractalkine mRNA and protein was achieved via intrapleural injections of siRNAs targeting fractalkine mRNA for 3 successive days. Fractalkine knock-down: 1) enhanced serotonin-dependent mAIH-induced pLTF (100±7%; n=6; vs controls: 50±5%; n=7; p<0.001), but 2) attenuated adenosine-dependent, sAIH-induced pLTF (23±12%; n=5; vs controls: 88±7%; n=7; p=0.001). These findings suggest that hypoxia triggers dose-dependent phrenic motor neuron fractalkine release, activating CX3CR1 on nearby microglia. Subsequent microglial ATP release and conversion to adenosine activates phrenic motor neuron adenosine 2A receptors which: 1) undermines mAIH-induced (serotonin-dominant) pLTF; or 2) reaches levels suffcient to drive sAIH-induced (adenosine-dominant) pLTF. These findings increase our understanding of how spinal intercellular interactions regulate AIH-induced phrenic motor plasticity. NIH R01HL148030 (GSM), NIH R01HL149800 (GSM), NIH T32HL134621-5 (ABM). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Function and Mechanism of Abscisic Acid on Microglia-Induced Neuroinflammation in Parkinson's Disease.

Parkinson's disease (PD), as a neurologically implemented disease with complex etiological factors, has a complex and variable pathogenesis. Accompanying further research, neuroinflammation has been found to be one of the possible factors in its pathogenesis. Microglia, as intrinsic immune cells in the brain, play an important role in maintaining microenvironmental homeostasis in the brain. However, over-activation of neurotoxic microglia in PD promotes neuroinflammation, which further increases dopaminergic (DA) neuronal damage and exacerbates the disease process. Therefore, targeting and regulating the functional state of microglia is expected to be a potential avenue for PD treatment. In addition, plant extracts have shown great potential in the treatment of neurodegenerative disorders due to their abundant resources, mild effects, and the presence of multiple active ingredients. However, it is worth noting that some natural products have certain toxic side effects, so it is necessary to pay attention to distinguish medicinal ingredients and usage and dosage when using to avoid aggravating the progression of diseases. In this review, the roles of microglia with different functional states in PD and the related pathways inducing microglia to transform into neuroprotective states are described. At the same time, it is discussed that abscisic acid (ABA) may regulate the polarization of microglia by targeting them, promote their transformation into neuroprotective state, reduce the neuroinflammatory response in PD, and provide a new idea for the treatment of PD and the selection of drugs.

Highlight of 2023: Microglia biology.

The field of neuroimmunology is quickly expanding and, as the primary immune cell of the brain, microglia are truly in the spotlight. In 2023, the number of microglia related articles published on PubMed rose to 5152. This number has consistently increased year on year and has more than doubled since 2013, as we begin to appreciate the role of microglia in brain development, health and disease. The year 2023 continued to bring new important discoveries, extending our knowledge of microglia biology. This image was created in BioRender.com.

Spinal neuronal activity and neuroinflammatory component in a mouse model of CFA-induced vestibulodynia

Vestibulodynia is a complex pain disorder characterized by chronic discomfort in the vulvar region, often accompanied by tactile allodynia and spontaneous pain. In patients a depressive behaviour is also observed. In this study, we have used a model of vestibulodynia induced by complete Freund's adjuvant (CFA) focusing our investigation on the spinal cord neurons and microglia. We investigated tactile allodynia, spontaneous pain, and depressive-like behavior as key behavioral markers of vestibulodynia. In addition, we conducted in vivo electrophysiological recordings to provide, for the first time to our knowledge, the characterization of the spinal sacral neuronal activity in the L6-S1 dorsal horn of the spinal cord. Furthermore, we examined microglia activation in the L6-S1 dorsal horn using immunofluorescence, unveiling hypertrophic phenotypes indicative of neuroinflammation in the spinal cord. This represents a novel insight into the role of microglia in vestibulodynia pathology. To address the therapeutic aspect, we employed pharmacological interventions using GABApentin, amitriptyline, and PeaPol. Remarkably, all three drugs, also used in clinic, showed efficacy in alleviating tactile allodynia and depressive-like behavior. Concurrently, we also observed a normalization of the altered neuronal firing and a reduction of microglia hypertrophic phenotypes.In conclusion, our study provides a comprehensive understanding of the CFA-induced model of vestibulodynia, encompassing behavioral, neurophysiological and neuroinflammatory aspects. These data pave the way to investigate spinal cord first pain plasticity in vestibulodynia.

Ldl-stimulated microglial activation exacerbates ischemic white matter damage

The role of microglia in triggering the blood–brain barrier (BBB) impairment and white matter damage after chronic cerebral hypoperfusion is unclear. Here we demonstrated that the vessel-adjacent microglia were specifically activated by the leakage of plasma low-density lipoprotein (LDL), which led to BBB breakdown and ischemic demyelination. Interestingly, we found that LDL stimulation enhanced microglial phagocytosis, causing excessive engulfment of myelin debris and resulting in an overwhelming lipid burden in microglia. Surprisingly, these lipid-laden microglia exhibited a suppressed profile of inflammatory response and compromised pro-regenerative properties. Microglia-specific knockdown of LDLR or systematic medication lowering circulating LDL-C showed protective effects against ischemic demyelination. Overall, our findings demonstrated that LDL-stimulated vessel-adjacent microglia possess a disease-specific molecular signature, characterized by suppressed regenerative properties, which is associated with the propagation of demyelination during ischemic white matter damage.

Abstract 1432: Development of transparent transgenic zebrafish model to study CNS microglia and NF-kB activity in glioblastoma

Abstract Microglia are resident macrophages of the central nervous system (CNS) and have crucial roles in normal brain homeostasis, function, and immune response. Microglia play key roles in the healthy brain, ranging from phagocytosis of dying neurons and CNS debris to modulating adaptability. The role of microglia has been well documented but their specific contributions to the development and progression of cancers, such as glioblastoma, have recently garnered wide attention. The zebrafish have proven novel tool for modeling innate immune responses. A macrophage-specific marker mpeg1 and its promoter are used in mpeg1-driven transgenes. mpeg1-driven transgenes mpeg1:mCherryFP are expressed in macrophage-lineage cells that do not express neutrophil-marking transgenes. These zebrafish transgenes contribute to the fields of inflammation, infection, and leukocyte biology. We have recently developed a novel transparent transgenic homozygous strain Tg(6xNF-kB:EGFP); Casper(roy−/−, nacre−/−) of zebrafish to the in-vivo study of NF-kB activity under normal and inflammation stage at the cellular, organ-specific and whole organism level. To perform an in-vivo study of microglial function, we are developing Casper;mpeg1:mCherryFP microglia specific strain and integrating with newly developed Tg(6xNF-kB:EGFP); Casper(roy−/−, nacre−/−) strain through crossbreeding of Casper and transgenic zebrafish. We have generated F1 generation of newly developed strains of Casper;mpeg1:mCherryFP and Tg(6xNF-kB:EGFP);Casper. The presence of fluorescence mCherry and GFP, in crossbred progeny was identified through the screening of larvae at 72 HPF stage. The expression of these fluorescent proteins determines the presence of the reporter genes. F1 generation confirmed heterozygous and allowed them to grow into adults to breed transparent transgenic strain to get F2 generation. This process will be continued to F2, F3, F4, and F5 generation until achieving homozygous progeny. This model allows for in-vivo examination of microglia functional morphology by using fluorescent and confocal microscopy. This novel transgenic model will be applied to identify novel anti-inflammatory drug inhibitors in NF-kB pathophysiology for glioblastoma and cardio-oncology experimental therapeutics. Citation Format: Surendra K. Rajpurohit, Sai Nasanally, Simran Hotwani, Taitum Gossman, Keshu Bhatt, Aiden Van Derhei, Rohan Pasi, Devan-Anmol Manhiani, Kirk Kimmerling, Balakrishna L. Lokeshwar. Development of transparent transgenic zebrafish model to study CNS microglia and NF-kB activity in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1432.

Abstract 1509: Microglial dominance in glioma dissemination: Unraveling TAMs' impact and therapeutic implications through modulating cathepsin activity

Abstract Introduction: It is well known that tumor-associated macrophages/microglia (TAMs) play a vital role in brain tumor progression. Our previous studies suggested that the activated microglia could reduce the cytotoxic effect of chemotherapeutic drugs on glioma cells in a 2D/3D model. This study delves into TAMs within diverse brain TME regions, emphasizing the distinction of resident microglia from infiltrating macrophages in invasion areas and their role in glioma migration and invasion. Material and Method: We employed the murine orthotopic astrocytoma model (ALTS1C1), dissecting brain tumor tissues into normal, invasion, edge, and core regions. Immunofluorescence staining, utilizing TMEM119 and CD68 markers to identify resident microglia and infiltrating macrophages, respectively. The IHC results were analyzed with QuPath software and validated via flow cytometry. Microglia (BV2) and macrophage (RAW264.7) cell lines were directly co-cultured with ALTS1C1 in 2D and 3D migration/invasion models. Bulk RNA sequencing analysis unraveled the differences between BV2 and RAW264.7. Bone marrow-derived macrophages (BMDM) were used for the TAMs activation test, and the cathepsin inhibitor, E64, was applied to elucidate cathepsin's role in microglia within co-culture models. Results: The IHC results reveal more TMEM119+ microglia than CD68+ infiltrating macrophages in the tumor invasion area. On the other hand, there are more CD68+ infiltrating macrophages than TMEM119+ microglia in the tumor core regions, signifying a specific role of microglia in tumor invasion. Flow cytometry further supported that more CD11b+CD45low microglia prevalence in tumor surrounding tissues than in tumor core. ALTS1C1 astrocytoma cells, in the presence of microglia, exhibited more increased invasion and migration ability than the presence of macrophages in 2D/3D models. RNA sequencing highlighted M2 activation and cathepsin gene upregulation in microglia over macrophages. M2-polarized TAMs enhanced 2D migration, while cathepsin inhibition significantly decreased glioma's 3D invasion potential. Conclusion: This study identifies microglia as primary TAMs in brain tumor invasion areas and their roles in glioma cell survival and dissemination. Notable differences in activation states and the critical impact of cathepsin in microglia for their roles on brain tumor invasion and survival offer promising therapeutic avenues. Targeting cathepsin in microglia emerges as a novel glioma prevention and treatment strategy. These findings contribute valuable insights to enhance clinical interventions for glioma patients. Citation Format: Sheng-Yan Wu, Chi-Shiun Chiang. Microglial dominance in glioma dissemination: Unraveling TAMs' impact and therapeutic implications through modulating cathepsin activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1509.

Abstract 5287: Ex vivo pharmacologic inhibition of STAT3 effectively targets tumor and tumor associated suppressor cells in high-grade glioma 3D spheroids

Abstract Gliomas, a type of brain tumor originating from glial cells, comprise a heterogenous group of neoplasms. High-grade gliomas, in particular, present significant therapeutic challenges in the clinic. Unlike other solid tumors, the heterogenous glioma microenvironment is heavily enriched with tumor associated suppressor cells including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), which can account for 30-40% of the cellular composition1. These pro-tumorigenic myeloid cells are thought to contribute to the resistance of glioma to immunotherapy. Efforts to target the suppressive nature of these dominating cell types are in development to yield more therapeutic options for patients with these devastating diseases. Constitutive activation of STAT3 in gliomas has been associated with increased tumor progression and reduced immune response. We have observed in other cancer models that a phenotypic switch occurs from STAT3 pathway activation in 3D spheroid culture to STAT3 inactivation when cultured in 2D. Therefore, we sought to determine the role of STAT3 activation and its role in the interplay between glioma and their immune suppressive environment using a 3D spheroid model. We modified our commercially available test platform, 3D-Predict™ Glioma, such that it is conducive to monitoring immune cell function. Newly diagnosed treatment naive primary samples from HGG patients were dissociated and cryogenically preserved and banked. Samples were profiled for the abundance of tumor associated suppressive myeloid cells using flow cytometry. We determined that relative proportions of tumor suppressor cells were detectable and varied across HGG primary patient samples with TAMs being the predominate immune cell type identified. Pro-tumorigenic TAM markers including CD163 and CD206 were correlated with temozolomide response and were associated with poor patient prognosis. When we evaluated the role of p-STAT in HGG primary samples, p-STAT was detected at baseline and abundance was related back to the presence of tumor associated immune suppressor cells. The impact of STAT3 signaling blockade by the inhibitor WP1066 was determined ex vivo, and efficacy was related back to MGMT promotor methylation status and patient clinical outcome. We detected shifts in cytokine signatures following treatment of HGG 3D spheroid models with WP1066 which are known to target tumor associated suppressor cell functions. This work demonstrates the critical role suppressive immune cells play in HGG clinical response. Given p-STAT can be altered in 2D culture compared to 3D culture, ex vivo therapeutic response profiling of HGG samples is necessary using the more physiologically relevant spheroid culture model. 1.Hambardzumyan et al. The role of microglia and macrophages in glioma maintenance and progression. Nat. Neurosci. 19, 20-27 (2016). Citation Format: Katy A. Lassahn, Ashley K. Elrod, Teresa M. DesRochers, Kathryn M. Appleton. Ex vivo pharmacologic inhibition of STAT3 effectively targets tumor and tumor associated suppressor cells in high-grade glioma 3D spheroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5287.

Genetic contribution to microglial activation in schizophrenia

Several lines of evidence indicate the involvement of neuroinflammatory processes in the pathophysiology of schizophrenia (SCZ). Microglia are brain resident immune cells responding toward invading pathogens and injury-related products, and additionally, have a critical role in improving neurogenesis and synaptic functions. Aberrant activation of microglia in SCZ is one of the leading hypotheses for disease pathogenesis, but due to the lack of proper human cell models, the role of microglia in SCZ is not well studied. We used monozygotic twins discordant for SCZ and healthy individuals to generate human induced pluripotent stem cell-derived microglia to assess the transcriptional and functional differences in microglia between healthy controls, affected twins and unaffected twins. The microglia from affected twins had increased expression of several common inflammation-related genes compared to healthy individuals. Microglia from affected twins had also reduced response to interleukin 1 beta (IL1β) treatment, but no significant differences in migration or phagocytotic activity. Ingenuity Pathway Analysis (IPA) showed abnormalities related to extracellular matrix signaling. RNA sequencing predicted downregulation of extracellular matrix structure constituent Gene Ontology (GO) terms and hepatic fibrosis pathway activation that were shared by microglia of both affected and unaffected twins, but the upregulation of major histocompatibility complex (MHC) class II receptors was observed only in affected twin microglia. Also, the microglia of affected twins had heterogeneous response to clozapine, minocycline, and sulforaphane treatments. Overall, despite the increased expression of inflammatory genes, we observed no clear functional signs of hyperactivation in microglia from patients with SCZ. We conclude that microglia of the patients with SCZ have gene expression aberrations related to inflammation response and extracellular matrix without contributing to increased microglial activation.

Prolonged exposure to lung-derived cytokines is associated with activation of microglia in patients with COVID-19.

BACKGROUNDSurvivors of pneumonia, including SARS-CoV-2 pneumonia, are at increased risk for cognitive dysfunction and dementia. In rodent models, cognitive dysfunction following pneumonia has been linked to the systemic release of lung-derived pro-inflammatory cytokines. Microglia are poised to respond to inflammatory signals from the circulation, and their dysfunction has been linked to cognitive impairment in murine models of dementia and in humans.METHODSWe measured levels of 55 cytokines and chemokines in bronchoalveolar lavage fluid and plasma from 341 patients with respiratory failure and 13 healthy controls, including 93 unvaccinated patients with COVID-19 and 203 patients with other causes of pneumonia. We used flow cytometry to sort neuroimmune cells from postmortem brain tissue from 5 patients who died from COVID-19 and 3 patients who died from other causes for single-cell RNA-sequencing.RESULTSMicroglia from patients with COVID-19 exhibited a transcriptomic signature suggestive of their activation by circulating pro-inflammatory cytokines. Peak levels of pro-inflammatory cytokines were similar in patients with pneumonia irrespective of etiology, but cumulative cytokine exposure was higher in patients with COVID-19. Treatment with corticosteroids reduced expression of COVID-19-specific cytokines.CONCLUSIONProlonged lung inflammation results in sustained elevations in circulating cytokines in patients with SARS-CoV-2 pneumonia compared with those with pneumonia secondary to other pathogens. Microglia from patients with COVID-19 exhibit transcriptional responses to inflammatory cytokines. These findings support data from rodent models causally linking systemic inflammation with cognitive dysfunction in pneumonia and support further investigation into the role of microglia in pneumonia-related cognitive dysfunction.FUNDINGSCRIPT U19AI135964, UL1TR001422, P01AG049665, P01HL154998, R01HL149883, R01LM013337, R01HL153122, R01HL147290, R01HL147575, R01HL158139, R01ES034350, R01ES027574, I01CX001777, U01TR003528, R21AG075423, T32AG020506, F31AG071225, T32HL076139.

The Cl- transporter ClC-7 is essential for phagocytic clearance by microglia.

Microglia, professional phagocytic cells of the brain, rely upon the appropriate activation of lysosomes to execute their immune and clearance functions. Lysosomal activity is, in turn, modulated by a complex network of over 200 membrane and accessory proteins that relay extracellular cues to these key degradation centers. The ClC-7 chloride (Cl-)-proton (H+) antiporter (also known as CLCN7) is localized to the endolysosomal compartments and mutations in CLCN7 lead to osteopetrosis and neurodegeneration. Although the functions of ClC-7 have been extensively investigated in osteoclasts and neurons, its role in microglia in vivo remains largely unexamined. Here, we show that microglia and embryonic macrophages in zebrafish clcn7 mutants cannot effectively process extracellular debris in the form of apoptotic cells and β-amyloid. Despite these functional defects, microglia develop normally in clcn7 mutants and display normal expression of endosomal and lysosomal markers. We also find that mutants for ostm1, which encodes the β-subunit of ClC-7, have a phenotype that is strikingly similar to that of clcn7 mutants. Together, our observations uncover a previously unappreciated role of ClC-7 in microglia and contribute to the understanding of the neurodegenerative phenotypes that accompany mutations in this channel.

Microglia maintain structural integrity during fetal brain morphogenesis

Microglia (MG), the brain-resident macrophages, play major roles in health and disease via a diversity of cellular states. While embryonic MG display a large heterogeneity of cellular distribution and transcriptomic states, their functions remain poorly characterized. Here, we uncovered a role for MG in the maintenance of structural integrity at two fetal cortical boundaries. At these boundaries between structures that grow in distinct directions, embryonic MG accumulate, display a state resembling post-natal axon-tract-associated microglia (ATM) and prevent the progression of microcavities into large cavitary lesions, in part via a mechanism involving the ATM-factor Spp1. MG and Spp1 furthermore contribute to the rapid repair of lesions, collectively highlighting protective functions that preserve the fetal brain from physiological morphogenetic stress and injury. Our study thus highlights key major roles for embryonic MG and Spp1 in maintaining structural integrity during morphogenesis, with major implications for our understanding of MG functions and brain development.

Perinatal Stroke as It is: Updates, Insights and Challenges

Perinatal stroke comprises a heterogeneous group of focal cerebrovascular injuries that occur between 20 weeks of gestation and 28 days of postnatal life. Perinatal stroke is a leading cause of life-long disability, causing most cases of hemiparetic cerebral palsy. The intent of this article was to provide a comprehensive review of the 6 different types of perinatal stroke based on neuroimaging and clinical presentation, highlighting their similarities and distinctions in etiology and outcome, and further discuss a neuroimaging pathway for suspected perinatal stroke and follow-up imaging.Learning Objective: To provide an update on the current knowledge of the role of neuroimaging in diagnosis and long-term prognosis of perinatal stroke diseases and to understand the microglial role in perinatal arterial stroke

Proteomic analysis identifies HSP90AA1, PTK2B, and ANXA2 in the human entorhinal cortex in Alzheimer's disease: Potential role in synaptic homeostasis and Aβ pathology through microglial and astroglial cells.

Alzheimer's disease (AD), the most prevalent neurodegenerative disorder worldwide, is clinically characterized by cognitive deficits. Neuropathologically, AD brains accumulate deposits of amyloid-β (Aβ) and tau proteins. Furthermore, these misfolded proteins can propagate from cell to cell in a prion-like manner and induce native proteins to become pathological. The entorhinal cortex (EC) is among the earliest areas affected by tau accumulation along with volume reduction and neurodegeneration. Neuron-glia interactions have recently come into focus; however, the role of microglia and astroglia in the pathogenesis of AD remains unclear. Proteomic approaches allow the determination of changes in the proteome to better understand the pathology underlying AD. Bioinformatic analysis of proteomic data was performed to compare ECs from AD and non-AD human brain tissue. To validate the proteomic results, western blot, immunofluorescence, and confocal studies were carried out. The findings revealed that the most disturbed signaling pathway was synaptogenesis. Because of their involvement in synapse function, relationship with Aβ and tau proteins and interactions in the pathway analysis, three proteins were selected for in-depth study: HSP90AA1, PTK2B, and ANXA2. All these proteins showed colocalization with neurons and/or astroglia and microglia and with pathological Aβ and tau proteins. In particular, ANXA2, which is overexpressed in AD, colocalized with amoeboid microglial cells and Aβ plaques surrounded by astrocytes. Taken together, the evidence suggests that unbalanced expression of HSP90AA1, PTK2B, and ANXA2 may play a significant role in synaptic homeostasis and Aβ pathology through microglial and astroglial cells in the human EC in AD.

Developmental Associations between Neurovascularization and Microglia Colonization.

The temporal and spatial pattern of microglia colonization and vascular infiltration of the nervous system implies critical associated roles in early stages of nervous system development. Adding to existing reviews that cover a broad spectrum of the various roles of microglia during brain development, the current review will focus on the developmental ontogeny and interdependency between the colonization of the nervous system with yolk sac derived macrophages and vascularization. Gaining a better understanding of the timing and the interdependency of these two processes will significantly contribute to the interpretation of data generated regarding alterations in either process during early development. Additionally, such knowledge should provide a framework for understanding the influence of the early gestational environmental and the impact of genetics, disease, disorders, or exposures on the early developing nervous system and the potential for long-term and life-time effects.

Role of microglia in brain development after viral infection.

Microglia are immune cells in the brain that originate from the yolk sac and enter the developing brain before birth. They play critical roles in brain development by supporting neural precursor proliferation, synaptic pruning, and circuit formation. However, microglia are also vulnerable to environmental factors, such as infection and stress that may alter their phenotype and function. Viral infection activates microglia to produce inflammatory cytokines and anti-viral responses that protect the brain from damage. However, excessive or prolonged microglial activation impairs brain development and leads to long-term consequences such as autism spectrum disorder and schizophrenia spectrum disorder. Moreover, certain viruses may attack microglia and deploy them as "Trojan horses" to infiltrate the brain. In this brief review, we describe the function of microglia during brain development and examine their roles after infection through microglia-neural crosstalk. We also identify limitations for current studies and highlight future investigated questions.

Aducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations.

Aducanumab, an anti-amyloid immunotherapy for Alzheimer's disease, efficiently reduces Aβ, though its plaque clearance mechanisms, long-term effects, and effects of discontinuation are not fully understood. We assessed the effect of aducanumab treatment and withdrawal on Aβ, neuritic dystrophy, astrocytes, and microglia in the APP/PS1 amyloid mouse model. We found that reductions in amyloid and neuritic dystrophy during acute treatment were accompanied by microglial and astrocytic activation, and microglial recruitment to plaques and adoption of an aducanumab-specific pro-phagocytic and pro-degradation transcriptomic signature, indicating a role for microglia in aducanumab-mediated Aβ clearance. Reductions in Aβ and dystrophy were sustained 15 but not 30 wk after discontinuation, and reaccumulation of plaques coincided with loss of the microglial aducanumab signature and failure of microglia to reactivate. This suggests that despite the initial benefit from treatment, microglia are unable to respond later to restrain plaque reaccumulation, making further studies on the effect of amyloid-directed immunotherapy withdrawal crucial for assessing long-term safety and efficacy.

The role of microglia in the pathogenesis of diabetic-associated cognitive dysfunction.

The role of microglia in the pathogenesis of diabetic-associated cognitive dysfunction.

Role of microglia in stroke.

Microglia play key roles in the post-ischemic inflammatory response and damaged tissue removal reacting rapidly to the disturbances caused by ischemia and working to restore the lost homeostasis. However, the modified environment, encompassing ionic imbalances, disruption of crucial neuron-microglia interactions, spreading depolarization, and generation of danger signals from necrotic neurons, induce morphological and phenotypic shifts in microglia. This leads them to adopt a proinflammatory profile and heighten their phagocytic activity. From day three post-ischemia, macrophages infiltrate the necrotic core while microglia amass at the periphery. Further, inflammation prompts a metabolic shift favoring glycolysis, the pentose-phosphate shunt, and lipid synthesis. These shifts, combined with phagocytic lipid intake, drive lipid droplet biogenesis, fuel anabolism, and enable microglia proliferation. Proliferating microglia release trophic factors contributing to protection and repair. However, some microglia accumulate lipids persistently and transform into dysfunctional and potentially harmful foam cells. Studies also showed microglia that either display impaired apoptotic cell clearance, or eliminate synapses, viable neurons, or endothelial cells. Yet, it will be essential to elucidate the viability of engulfed cells, the features of the local environment, the extent of tissue damage, and the temporal sequence. Ischemia provides a rich variety of region- and injury-dependent stimuli for microglia, evolving with time and generating distinct microglia phenotypes including those exhibiting proinflammatory or dysfunctional traits and others showing pro-repair features. Accurate profiling of microglia phenotypes, alongside with a more precise understanding of the associated post-ischemic tissue conditions, is a necessary step to serve as the potential foundation for focused interventions in human stroke.

Synapse Regulation.

Microglia are the resident immune cells of the brain. As such, they rapidly detect changes in normal brain homeostasis and accurately respond by fine-tuning in a tightly regulated manner their morphology, gene expression, and functional behavior. Depending on the nature of these changes, microglia can thicken and retract their processes, proliferate and migrate, release numerous signaling factors and compounds influencing neuronal physiology (e.g., cytokines and trophic factors), in addition to secreting proteases able to transform the extracellular matrix, and phagocytosing various types of cellular debris, etc. Because microglia also transform rapidly (on a time scale of minutes) during experimental procedures, studying these very special cells requires methods that are specifically non-invasive. The development of such methods has provided unprecedented insights into the roles of microglia during normal physiological conditions. In particular, transcranial two-photon in vivo imaging revealed that presumably "resting" microglia continuously survey the brain parenchyma with their highly motile processes, in addition to modulating their structural and functional interactions with neuronal circuits along the changes in neuronal activity and behavioral experience occurring throughout the lifespan. In this chapter, we will describe how surveillant microglia interact with synaptic elements and modulate the number, maturation, function, and plasticity of synapses in the healthy developing, mature, and aging brain, with consequences on neuronal activity, learning and memory, and the behavioral outcome.