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International Journal of Molecular... Dec 2023Neurodevelopmental disorders (NDDs) include various neurological disorders with high genetic heterogeneity, characterized by delayed or impaired cognition,... (Review)
Review
Neurodevelopmental disorders (NDDs) include various neurological disorders with high genetic heterogeneity, characterized by delayed or impaired cognition, communication, adaptive behavior, and psychomotor skills. These disorders result in significant morbidity for children, thus burdening families and healthcare/educational systems. However, there is a lack of early diagnosis and effective therapies. Therefore, a more connected approach is required to explore these disorders. Microglia, the primary phagocytic cells within the central nervous system, are crucial in regulating neuronal viability, influencing synaptic dynamics, and determining neurodevelopmental outcomes. Although the neurobiological basis of autism spectrum disorder (ASD) and schizophrenia (SZ) has attracted attention in recent decades, the role of microglia in ASD and SZ remains unclear and requires further discussion. In this review, the important and frequently multifaceted roles that microglia play during neurodevelopment are meticulously emphasized and potential microglial mechanisms that might be involved in conditions such as ASD and SZ are postulated. It is of utmost importance to acquire a comprehensive understanding of the complexities of the interplay between microglia and neurons to design effective, targeted therapeutic strategies to mitigate the effects of NDDs.
Topics: Child; Humans; Autism Spectrum Disorder; Microglia; Schizophrenia; Brain; Neurons
PubMed: 38139124
DOI: 10.3390/ijms242417297 -
Cells Jun 2021Microglia are the resident immune cells of the central nervous system (CNS), including the retina. Similar to brain microglia, retinal microglia are responsible for... (Review)
Review
Microglia are the resident immune cells of the central nervous system (CNS), including the retina. Similar to brain microglia, retinal microglia are responsible for retinal surveillance, rapidly responding to changes in the environment by altering morphotype and function. Microglia become activated in inflammatory responses in neurodegenerative diseases, including multiple sclerosis (MS). When activated by stress stimuli, retinal microglia change their morphology and activity, with either beneficial or harmful consequences. In this review, we describe characteristics of CNS microglia, including those in the retina, with a focus on their morphology, activation states and function in health, ageing, MS and other neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, glaucoma and retinitis pigmentosa, to highlight their activity in disease. We also discuss contradictory findings in the literature and the potential ways of reducing inconsistencies in future by using standardised methodology, e.g., automated algorithms, to enable a more comprehensive understanding of this exciting area of research.
Topics: Aging; Alzheimer Disease; Animals; Brain; Central Nervous System; Humans; Microglia; Multiple Sclerosis; Neurodegenerative Diseases; Parkinson Disease; Retina
PubMed: 34203793
DOI: 10.3390/cells10061507 -
Folia Neuropathologica 2020Lipopolysaccharide (LPS) is a potent immunogen when administered locally and/or systemically. The peripheral immunization with LPS could contribute to the progression... (Review)
Review
Lipopolysaccharide (LPS) is a potent immunogen when administered locally and/or systemically. The peripheral immunization with LPS could contribute to the progression of neurological diseases because a strong link between neuroinflammation and dopaminergic degeneration has been found. The switch between the survival and neuronal death in substantia nigra could be related to M1 (neurotoxic) and M2 (neuroprotective) microglia phenotypes. In this review, we present the current findings about microglia roles, biomarkers, and natural or synthetic immune modulators determined in the LPS-based murine model.
Topics: Animals; Cell Differentiation; Disease Models, Animal; Humans; Inflammation; Lipopolysaccharides; Microglia
PubMed: 32729290
DOI: 10.5114/fn.2020.96755 -
International Journal of Molecular... Mar 2021Microglia are resident immune cells of the central nervous system and play critical roles during the development, homeostasis, and pathologies of the brain. Originated... (Review)
Review
Microglia are resident immune cells of the central nervous system and play critical roles during the development, homeostasis, and pathologies of the brain. Originated from yolk sac erythromyeloid progenitors, microglia immigrate into the embryonic brain parenchyma to undergo final postnatal differentiation and maturation driven by distinct chemokines, cytokines, and growth factors. Among them, TGFβ1 is an important regulator of microglial functions, mediating homeostasis, anti-inflammation, and triggering the expression of microglial homeostatic signature genes. Since microglia studies are mainly based on rodent cells and the isolation of homeostatic microglia from human tissue is challenging, human-induced pluripotent stem cells have been successfully differentiated into microglia-like cells recently. However, employed differentiation protocols strongly vary regarding used cytokines and growth factors, culture conditions, time span, and cell yield. Moreover, the incomplete differentiation of human microglia can hamper the similarity to primary human microglia and dramatically influence the outcome of follow-up studies with these differentiated cells. This review summarizes the current knowledge of the molecular mechanisms driving rodent microglia differentiation in vivo, further compares published differentiation protocols, and highlights the potential of TGFβ as an essential maturation factor.
Topics: Animals; Cell Differentiation; Cell-Matrix Junctions; Humans; Induced Pluripotent Stem Cells; Microglia; Models, Biological; Transforming Growth Factor beta
PubMed: 33803024
DOI: 10.3390/ijms22063088 -
Current Opinion in Genetics &... Dec 2020Microglia are instrumental to the development, function, homeostasis and pathologies of the central nervous system. These brain-resident macrophages arise early in... (Review)
Review
Microglia are instrumental to the development, function, homeostasis and pathologies of the central nervous system. These brain-resident macrophages arise early in embryogenesis and seed the developing brain, where they differentiate in response to cues provided by their neural niche. Throughout life, microglia regulate the neural tissue through a variety of cellular functions influenced by intrinsic and extrinsic factors. Despite their importance, we are only starting to uncover how microglia colonize the brain, adopt distinct functional states during development and the long-term impact of early alteration of their functions. This review highlights the latest knowledge on the ontogeny of microglia, their developmental trajectory and emerging roles. Characterizing these processes will be critical for our understanding of both brain physiology and pathologies.
Topics: Animals; Brain; Homeostasis; Humans; Macrophages; Microglia; Neurodevelopmental Disorders; Neurogenesis
PubMed: 32823206
DOI: 10.1016/j.gde.2020.06.013 -
Aging Cell Feb 2021Metformin, a drug widely used for treating diabetes, can prolong the lifespan in several species. Metformin also has the promise to slow down age-related cognitive...
Metformin, a drug widely used for treating diabetes, can prolong the lifespan in several species. Metformin also has the promise to slow down age-related cognitive impairment. However, metformin's therapeutic use as an anti-aging drug is yet to be accepted because of conflicting animal and human studies results. We examined the effects of metformin treatment in late middle age on cognitive function in old age. Eighteen-month-old male C57BL6/J mice received metformin or no treatment for 10 weeks. A series of behavioral tests revealed improved cognitive function in animals that received metformin. Such findings were evident from a better ability for pattern separation, object location, and recognition memory function. Quantification of microglia revealed that metformin treatment reduced the incidence of pathological microglial clusters with alternative activation of microglia into an M2 phenotype, displaying highly ramified processes in the hippocampus. Metformin treatment also seemed to reduce astrocyte hypertrophy. Additional analysis demonstrated that metformin treatment in late middle age increased adenosine monophosphate-activated protein kinase activation, reduced proinflammatory cytokine levels, and the mammalian target of rapamycin signaling, and enhanced autophagy in the hippocampus. However, metformin treatment did not alter neurogenesis or synapses in the hippocampus, implying that improved cognitive function with metformin did not involve enhanced neurogenesis or neosynaptogenesis. The results provide new evidence that metformin treatment commencing in late middle age has promise for improving cognitive function in old age. Modulation of microglia, proinflammatory cytokines, and autophagy appear to be the mechanisms by which metformin facilitated functional benefits in the aged brain.
Topics: Aging; Animals; Autophagy; Cognition; Hippocampus; Male; Metformin; Mice; Mice, Inbred C57BL; Microglia
PubMed: 33443781
DOI: 10.1111/acel.13277 -
Neuroscience Bulletin Mar 2023As prominent immune cells in the central nervous system, microglia constantly monitor the environment and provide neuronal protection, which are important functions for... (Review)
Review
As prominent immune cells in the central nervous system, microglia constantly monitor the environment and provide neuronal protection, which are important functions for maintaining brain homeostasis. In the diseased brain, microglia are crucial mediators of neuroinflammation that regulates a broad spectrum of cellular responses. In this review, we summarize current knowledge on the multifunctional contributions of microglia to homeostasis and their involvement in neurodegeneration. We further provide a comprehensive overview of therapeutic interventions targeting microglia in neurodegenerative diseases. Notably, we propose microglial depletion and subsequent repopulation as promising replacement therapy. Although microglial replacement therapy is still in its infancy, it will likely be a trend in the development of treatments for neurodegenerative diseases due to its versatility and selectivity.
Topics: Humans; Microglia; Central Nervous System; Neurodegenerative Diseases; Brain; Homeostasis
PubMed: 36593381
DOI: 10.1007/s12264-022-01013-6 -
International Journal of Molecular... Mar 2017Autophagy is emerging as a core regulator of Central Nervous System (CNS) aging and neurodegeneration. In the brain, it has mostly been studied in neurons, where the... (Review)
Review
Autophagy is emerging as a core regulator of Central Nervous System (CNS) aging and neurodegeneration. In the brain, it has mostly been studied in neurons, where the delivery of toxic molecules and organelles to the lysosome by autophagy is crucial for neuronal health and survival. However, we propose that the (dys)regulation of autophagy in microglia also affects innate immune functions such as phagocytosis and inflammation, which in turn contribute to the pathophysiology of aging and neurodegenerative diseases. Herein, we first describe the basic concepts of autophagy and its regulation, discuss key aspects for its accurate monitoring at the experimental level, and summarize the evidence linking autophagy impairment to CNS senescence and disease. We focus on acute, chronic, and autoimmunity-mediated neurodegeneration, including ischemia/stroke, Alzheimer's, Parkinson's, and Huntington's diseases, and multiple sclerosis. Next, we describe the actual and potential impact of autophagy on microglial phagocytic and inflammatory function. Thus, we provide evidence of how autophagy may affect microglial phagocytosis of apoptotic cells, amyloid-β, synaptic material, and myelin debris, and regulate the progression of age-associated neurodegenerative diseases. We also discuss data linking autophagy to the regulation of the microglial inflammatory phenotype, which is known to contribute to age-related brain dysfunction. Overall, we update the current knowledge of autophagy and microglia, and highlight as yet unexplored mechanisms whereby autophagy in microglia may contribute to CNS disease and senescence.
Topics: Aging; Animals; Autophagy; Central Nervous System; Humans; Microglia; Neurodegenerative Diseases
PubMed: 28282924
DOI: 10.3390/ijms18030598 -
International Journal of Molecular... Apr 2022Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, leaving the inflammation process without a proper resolution, leading... (Review)
Review
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, leaving the inflammation process without a proper resolution, leading to tissue damage and possibly sequelae. The central nervous system (CNS) is one of the first regions affected by the peripheral inflammation caused by sepsis, exposing the neurons to an environment of oxidative stress, triggering neuronal dysfunction and apoptosis. Sepsis-associated encephalopathy (SAE) is the most frequent sepsis-associated organ dysfunction, with symptoms such as deliriums, seizures, and coma, linked to increased mortality, morbidity, and cognitive disability. However, the current therapy does not avoid those patients' symptoms, evidencing the search for a more optimal approach. Herein we focus on microglia as a prominent therapeutic target due to its multiple functions maintaining CNS homeostasis and its polarizing capabilities, stimulating and resolving neuroinflammation depending on the stimuli. Microglia polarization is a target of multiple studies involving nerve cell preservation in diseases caused or aggravated by neuroinflammation, but in sepsis, its therapeutic potential is overlooked. We highlight the peroxisome proliferator-activated receptor gamma (PPARγ) neuroprotective properties, its role in microglia polarization and inflammation resolution, and the interaction with nuclear factor-κB (NF-κB) and mitogen-activated kinases (MAPK), making PPARγ a molecular target for sepsis-related studies to come.
Topics: Humans; Inflammation; Microglia; Multiple Organ Failure; PPAR gamma; Sepsis
PubMed: 35563317
DOI: 10.3390/ijms23094925 -
Frontiers in Immunology 2020Microglia are specialized resident macrophages of the central nervous system (CNS) that have important functions during neurodevelopment, homeostasis and disease. This... (Review)
Review
Microglia are specialized resident macrophages of the central nervous system (CNS) that have important functions during neurodevelopment, homeostasis and disease. This mini-review provides an overview of the current tools and approaches for studying microglia . We focus on tools for labeling microglia, highlighting the advantages and limitations of microglia markers/antibodies and reporter mice. We also discuss techniques for imaging microglia , including live imaging of brain and retinal microglia. Finally, we review microglia depletion approaches and their use to investigate microglial function in CNS homeostasis and disease.
Topics: Animals; Antibodies; Biomarkers; Central Nervous System; Homeostasis; Humans; Microglia
PubMed: 33117395
DOI: 10.3389/fimmu.2020.583647