Microglia are emerging as key players in neurodegenerative diseases, such as Alzheimer's disease (AD). Thus far, microglia have rather been known as modulator of neurodegeneration with functions ...limited to neuroinflammation and release of neurotoxic molecules. However, several recent studies have demonstrated a direct role of microglia in "neuro" degeneration observed in AD by promoting phagocytosis of neuronal, in particular, synaptic structures. While some of the studies address the involvement of the β-amyloid peptides in the process, studies also indicate that this could occur independent of amyloid, further elevating the importance of microglia in AD. Here we review these recent studies and also speculate about the possible cellular mechanisms, and how they could be regulated by risk genes and sleep. Finally, we deliberate on possible avenues for targeting microglia-mediated synapse loss for therapy and prevention.
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•Extracellular vesicles are important mediators of cell-to-cell communication.•Microglia serve as source and recipient of extracellular vesicles in the brain.•Microglia-related extracellular vesicles ...play critical roles in neurodegeneration.
Extracellular vesicles, including exosomes and microvesicles, are small, nano-to-micrometer vesicles that are released from cells. While initially observed in immune cells and reticulocytes as vesicles meant to remove archaic proteins, now they have been observed in almost all cell types of multicellular organisms. Growing evidence indicates that extracellular vesicles, containing lipids, proteins and RNAs, represent an efficient way to transfer functional cargoes from one cell to another. In the central nervous system, the extensive cross-talk ongoing between neurons and glia, including microglia, the immune cells of the brain, takes advantage of secreted vesicles, which mediate intercellular communication over long range distance. Recent literature supports a critical role for extracellular vesicles in mediating complex and coordinated communication among neurons, astrocytes and microglia, both in the healthy and in the diseased brain. In this review, we focus on the biogenesis and function of microglia-related extracellular vesicles and focus on their putative role in Alzheimer’s disease pathology.
The year 2019 marks the 100-year anniversary of the discovery of microglia by Pío del Río-Hortega. We will recount the state of neuroscience research at the beginning of the 20th century and the ...heated scientific dispute regarding microglial identity. We will then walk through some of the milestones of microglial research in the decades since then. In the last 20 years, the field has grown exponentially. Researchers have shown that microglia are unlike any other resident macrophages: they have a unique origin and distinguishing features. Microglia are extraordinarily motile cells and constantly survey their environment, interacting with neurons, astrocytes, oligodendrocytes, neural stem cells, and infiltrating immune cells. We finally highlight some open questions for future research regarding microglia’s identity, population dynamics, and dual (beneficial and detrimental) role in pathology.
Microglia were first described by the Spanish researcher Pío del Río-Hortega in 1919.Río-Hortega’s discoveries identified and defined the three types of glial cells of the CNS: astrocytes, oligodendrocytes, and microglia.The field stagnated until the 1960s, when Georg Kreutzberg discovered the role of microglia in synaptic stripping in pathology.Microglia were subsequently characterized as pathologic sensors in essentially all brain diseases and orchestrators of the neuroinflammatory response.In the last two decades, after the discovery of their extraordinary motility and their unique origin in the yolk sac, microglial research has grown exponentially.Physiological roles of microglia include synapse monitoring and pruning, as well as modulating neurogenesis, myelination, and vasculogenesis.
Microglia, the resident macrophages of the central nervous system (CNS), play important functions in the healthy and diseased brain. In the emerging field of immunometabolism, progress has been made ...in understanding how cellular metabolism can orchestrate the key responses of tissue macrophages, such as phagocytosis and inflammation. However, very little is known about the metabolic control of microglia. Lactate, now recognized as a crucial metabolite and a central substrate in metabolic flexibility, is emerging not only as a novel bioenergetic fuel for microglial metabolism but also as a potential modulator of cellular function. Parallels with macrophages will help in understanding how microglial lactate metabolism is implicated in brain physiology and pathology, and how it could be targeted for therapeutic purposes.
Microglia, the innate immune cells of the central nervous system (CNS), are highly dynamic and rely on metabolic flexibility to sustain their cellular functions.In addition to energy production, metabolic pathways are important in regulating immune cell function by influencing the inflammatory profile and phagocytic capacity of the cell.Recent single cell RNA-seq datasets indicate that microglia have all the machinery for rapid metabolic reprogramming and for the utilization of different bioenergetic substrates.Lactate is emerging as a key brain metabolite associated with synaptic plasticity and CNS pathologies, and recent studies highlight its possible role in controlling microglial function.Targeting microglial lactate metabolism might prove to be an effective approach to modulate microglia in several CNS diseases.
Microglia are highly motile phagocytic cells that infiltrate and take up residence in the developing brain, where they are thought to provide a surveillance and scavenging function. However, although ...microglia have been shown to engulf and clear damaged cellular debris after brain insult, it remains less clear what role microglia play in the uninjured brain. Here, we show that microglia actively engulf synaptic material and play a major role in synaptic pruning during postnatal development in mice. These findings link microglia surveillance to synaptic maturation and suggest that deficits in microglia function may contribute to synaptic abnormalities seen in some neurodevelopmental disorders.
Many diverse factors, ranging from stress to infections, can perturb brain homeostasis and alter the physiological activity of microglia, the immune cells of the central nervous system. Microglia ...play critical roles in the process of synaptic maturation and brain wiring during development. Any perturbation affecting microglial physiological function during critical developmental periods could result in defective maturation of synaptic circuits. In this review, we critically appraise the recent literature on the alterations of microglial activity induced by environmental and genetic factors occurring at pre- and early post-natal stages. Furthermore, we discuss the long-lasting consequences of early-life microglial perturbation on synaptic function and on vulnerability to neurodevelopmental and psychiatric disorders.
The lateral habenula encodes aversive stimuli contributing to negative emotional states during drug withdrawal. Here we report that morphine withdrawal in mice leads to microglia adaptations and ...diminishes glutamatergic transmission onto raphe-projecting lateral habenula neurons. Chemogenetic inhibition of this circuit promotes morphine withdrawal-like social deficits. Morphine withdrawal-driven synaptic plasticity and reduced sociability require tumor necrosis factor-α (TNF-α) release and neuronal TNF receptor 1 activation. Hence, habenular cytokines control synaptic and behavioral adaptations during drug withdrawal.
Synapse loss is an early feature shared by many neurodegenerative diseases, and it represents the major correlate of cognitive impairment. Recent studies reveal that microglia and astrocytes play a ...major role in synapse elimination, contributing to network dysfunction associated with neurodegeneration. Excitatory and inhibitory activity can be affected by glia-mediated synapse loss, resulting in imbalanced synaptic transmission and subsequent synaptic dysfunction. Here, we review the recent literature on the contribution of glia to excitatory/inhibitory imbalance, in the context of the most common neurodegenerative disorders. A better understanding of the mechanisms underlying pathological synapse loss will be instrumental to design targeted therapeutic interventions, taking in account the emerging roles of microglia and astrocytes in synapse remodeling.
Since the observation that obesity-associated low-grade chronic inflammation is a crucial driver for the onset of systemic metabolic disorders such as type 2 diabetes, a number of studies have ...highlighted the role of both the innate and the adaptive immune system in such pathologies. Moreover, researchers have recently demonstrated that immune cells can modulate their intracellular metabolic profile to control their activation and effector functions. These discoveries represent the foundations of a research area known as “immunometabolism”, an emerging field of investigation that may lead to the development of new-generation therapies for the treatment of inflammatory and metabolic diseases. Most of the studies in the field have focused their attention on both circulating white blood cells and leukocytes residing within metabolic tissues such as adipose tissue, liver and pancreas. However, immunometabolism of immune cells in non-metabolic tissues, including central nervous system microglia, have long been neglected. In this review, we highlight the most recent findings suggesting that microglial cells play a central role in metabolic disorders and that interfering with the metabolic profile of microglia can modulate their functionality and pathogenicity in neurological diseases.
Microglia are phagocytic cells that infiltrate the brain during development and have a role in the elimination of synapses during brain maturation. Changes in microglial morphology and gene ...expression have been associated with neurodevelopmental disorders. However, it remains unknown whether these changes are a primary cause or a secondary consequence of neuronal deficits. Here we tested whether a primary deficit in microglia was sufficient to induce some autism-related behavioral and functional connectivity deficits. Mice lacking the chemokine receptor Cx3cr1 exhibit a transient reduction of microglia during the early postnatal period and a consequent deficit in synaptic pruning. We show that deficient synaptic pruning is associated with weak synaptic transmission, decreased functional brain connectivity, deficits in social interaction and increased repetitive-behavior phenotypes that have been previously associated with autism and other neurodevelopmental and neuropsychiatric disorders. These findings open the possibility that disruptions in microglia-mediated synaptic pruning could contribute to neurodevelopmental and neuropsychiatric disorders.
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