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Journal of Neurochemistry Dec 2019The single largest risk factor for etiology of neurodegenerative diseases like Alzheimer's disease is increased age. Therefore, understanding the changes that occur as a... (Review)
Review
The single largest risk factor for etiology of neurodegenerative diseases like Alzheimer's disease is increased age. Therefore, understanding the changes that occur as a result of aging is central to any possible prevention or cure for such conditions. Microglia, the resident brain glial population most associated with both protection of neurons in health and their destruction is disease, could be a significant player in age related changes. Microglia can adopt an aberrant phenotype sometimes referred to either as dystrophic or senescent. While aged microglia have been frequently identified in neurodegenerative diseases such as Alzheimer's disease, there is no conclusive evidence that proves a causal role. This has been hampered by a lack of models of aged microglia. We have recently generated a model of senescent microglia based on the observation that all dystrophic microglia show iron overload. Iron-overloading cultured microglia causes them to take on a senescent phenotype and can cause changes in models of neurodegeneration similar to those observed in patients. This review considers how this model could be used to determine the role of senescent microglia in neurodegenerative diseases.
Topics: Aging; Animals; Brain; Cellular Senescence; Humans; Microglia; Neurodegenerative Diseases; Neurons
PubMed: 31478208
DOI: 10.1111/jnc.14860 -
Neurotherapeutics : the Journal of the... Oct 2013Innate immune responses in the central nervous system (CNS) have key roles influencing both physiological and pathological processes. Microglia are innate immune... (Review)
Review
Innate immune responses in the central nervous system (CNS) have key roles influencing both physiological and pathological processes. Microglia are innate immune effector cells that reside within the CNS. These inflammatory cells are constantly surveying their external environment and rapidly respond to a variety of molecules that signal changes in CNS homeostasis. In response to these signals, microglia influence neuronal connections, modulate the functions of other glia, and mediate inflammatory responses to disease or injury. In parallel with the regulation of inflammatory responses outside of the CNS, investigators have observed that microglia are capable of heterogeneous responses to exogenous and endogenous signals. While much of this molecular and morphological heterogeneity is regulated by gene transcription, there is ample evidence that microglial behavior is determined, in part, by epigenetic regulation. Recent work has demonstrated that processes involving DNA methylation, histone modification, and noncoding RNAs also have important roles in modulating neuroinflammation. Here I will review the evidence supporting a role for epigenetic regulation of neuroinflammation and describe how this might influence the outcome of several CNS disorders, including addiction, infection, multiple sclerosis, and stroke.
Topics: Brain; Encephalitis; Epigenesis, Genetic; Humans; Immunity, Innate; Microglia
PubMed: 23963788
DOI: 10.1007/s13311-013-0207-4 -
Neuron Nov 2022In the central nervous system (CNS), microglia carry out multiple tasks related to brain development, maintenance of brain homeostasis, and function of the CNS. Recent... (Review)
Review
In the central nervous system (CNS), microglia carry out multiple tasks related to brain development, maintenance of brain homeostasis, and function of the CNS. Recent advanced in vitro model systems allow us to perform more detailed and specific analyses of microglial functions in the CNS. The development of human pluripotent stem cells (hPSCs)-based 2D and 3D cell culture methods, particularly advancements in brain organoid models, offers a better platform to dissect microglial function in various contexts. Despite the improvement of these methods, there are still definite restrictions. Understanding their drawbacks and benefits ensures their proper use. In this primer, we review current developments regarding in vitro microglial production and characterization and their use to address fundamental questions about microglial function in healthy and diseased states, and we discuss potential future improvements with a particular emphasis on brain organoid models.
Topics: Humans; Microglia; Brain; Central Nervous System; Homeostasis; Pluripotent Stem Cells
PubMed: 36327894
DOI: 10.1016/j.neuron.2022.10.004 -
Neurobiology of Disease Jan 2021In injury and disease, microglia and astrocytes - two major non-neuronal cell types in the central nervous system (CNS) - undergo morphological, transcriptional, and... (Review)
Review
In injury and disease, microglia and astrocytes - two major non-neuronal cell types in the central nervous system (CNS) - undergo morphological, transcriptional, and functional changes, which can underlie pathogenesis and dysfunction of the CNS. Microglia, the brain's tissue resident parenchymal macrophages, are described as becoming "activated" as they deftly change their production of different inflammatory mediators, alter the surveillance behavior of their cellular protrusions, and differentially influence the function of astrocytes. For their part, astrocytes - the most abundant glial cell type - are said to become "reactive", which implies (perhaps inappropriately) causality for the changes astrocytes undergo. Reactive astrocytes variably undergo process hypertrophy, decrease their normal homeostatic functions such as facilitating synapse formation, and in some cases act to form a tissue scar in response to insult. But what do these terms "activation" and "reactivity" mean, anyway? And how do these changed microglia and astrocytes contribute to neurodegenerative disease (ND)? Here, we describe our current understanding of the role of activated and reactive microglia and astrocytes in ND, as well as our current understanding about what these states are and might mean. We survey the earliest description of these cells by histopathologists, their transcriptomic identities, and finally our mechanistic understanding of their functions in ND.
Topics: Astrocytes; Humans; Microglia; Neurodegenerative Diseases; Neuroglia
PubMed: 33171230
DOI: 10.1016/j.nbd.2020.105172 -
CNS Neuroscience & Therapeutics Dec 2019
Topics: Animals; Central Nervous System; Humans; Macrophages; Microglia; Nervous System Physiological Phenomena
PubMed: 31793210
DOI: 10.1111/cns.13257 -
Cells Oct 2019Microglia originate from yolk sac-primitive macrophages and auto-proliferate into adulthood without replacement by bone marrow-derived circulating cells. In... (Review)
Review
Microglia originate from yolk sac-primitive macrophages and auto-proliferate into adulthood without replacement by bone marrow-derived circulating cells. In inflammation, stroke, aging, or infection, microglia have been shown to contribute to brain pathology in both deleterious and beneficial ways, which have been studied extensively. However, less is known about their role in the healthy adult brain. Astrocytes and oligodendrocytes are widely accepted to strongly contribute to the maintenance of brain homeostasis and to modulate neuronal function. On the other hand, contribution of microglia to cognition and behavior is only beginning to be understood. The ability to probe their function has become possible using microglial depletion assays and conditional mutants. Studies have shown that the absence of microglia results in cognitive and learning deficits in rodents during development, but this effect is less pronounced in adults. However, evidence suggests that microglia play a role in cognition and learning in adulthood and, at a cellular level, may modulate adult neurogenesis. This review presents the case for repositioning microglia as key contributors to the maintenance of homeostasis and cognitive processes in the healthy adult brain, in addition to their classical role as sentinels coordinating the neuroinflammatory response to tissue damage and disease.
Topics: Adult; Animals; Astrocytes; Brain; Cognition; Humans; Learning; Microglia; Oligodendroglia
PubMed: 31652490
DOI: 10.3390/cells8101293 -
Neural Plasticity 2013A series of discoveries spanning for the last few years has challenged our view of microglial function, the main form of immune defense in the brain. The surveillance of... (Review)
Review
A series of discoveries spanning for the last few years has challenged our view of microglial function, the main form of immune defense in the brain. The surveillance of neuronal circuits executed by each microglial cell overseeing its territory occurs in the form of regular, dynamic interactions. Microglial contacts with individual neuronal compartments, such as dendritic spines and axonal terminals, ensure that redundant or dysfunctional elements are recognized and eliminated from the brain. Microglia take on a new shape that is large and amoeboid when a threat to brain integrity is detected. In this defensive form, they migrate to the endangered sites, where they help to minimize the extent of the brain insult. However, in neurodegenerative diseases that are associated with misfolding and aggregation of synaptic proteins, these vital defensive functions appear to be compromised. Many microglial functions, such as phagocytosis, might be overwhelmed during exposure to the abnormal levels of misfolded proteins in their proximity. This might prevent them from attending to their normal duties, such as the stripping of degenerating synaptic terminals, before neuronal function is irreparably impaired. In these conditions microglia become chronically activated and appear to take on new, destructive roles by direct or indirect inflammatory attack.
Topics: Alzheimer Disease; Animals; Health; Humans; Microglia; Neurodegenerative Diseases; Prion Diseases; Synapses
PubMed: 24392228
DOI: 10.1155/2013/425845 -
Mechanisms of Ageing and Development Jul 2021Among all major organs, the brain is one of the most susceptible to the inexorable effects of aging. Throughout the last decades, several studies in human cohorts and... (Review)
Review
Among all major organs, the brain is one of the most susceptible to the inexorable effects of aging. Throughout the last decades, several studies in human cohorts and animal models have revealed a plethora of age-related changes in the brain, including reduced neurogenesis, oxidative damage, mitochondrial dysfunction and cell senescence. As the main immune effectors and first responders of the nervous tissue, microglia are at the center of these events. These cells experience irrevocable changes as a result from cumulative exposure to environmental triggers, such as stress, infection and metabolic dysregulation. The age-related immunosenescent phenotype acquired by microglia is characterized by profound modifications in their transcriptomic profile, secretome, morphology and phagocytic activity, which compromise both their housekeeping and defensive functions. As a result, aged microglia are no longer capable of establishing effective immune responses and sustaining normal synaptic activity, directly contributing to age-associated cognitive decline and neurodegeneration. This review discusses how lifestyle and environmental factors drive microglia dysfunction at the molecular and functional level, also highlighting possible interventions to reverse aging-associated damage to the nervous and immune systems.
Topics: Aging; Animals; Brain; Cellular Senescence; Cognitive Dysfunction; Humans; Microglia; Neurogenesis; Neuronal Plasticity; Oxidative Stress
PubMed: 34022277
DOI: 10.1016/j.mad.2021.111512 -
Translational Research : the Journal of... Apr 2023Traumatic brain injury (TBI) and Alzheimer's disease (AD) represent 2 of the largest sources of death and disability in the United States. Recent studies have identified... (Review)
Review
Traumatic brain injury (TBI) and Alzheimer's disease (AD) represent 2 of the largest sources of death and disability in the United States. Recent studies have identified TBI as a potential risk factor for AD development, and numerous reports have shown that TBI is linked with AD associated protein expression during the acute phase of injury, suggesting an interplay between the 2 pathologies. The inflammasome is a multi-protein complex that plays a role in both TBI and AD pathologies, and is characterized by inflammatory cytokine release and pyroptotic cell death. Products of inflammasome signaling pathways activate microglia and astrocytes, which attempt to resolve pathological inflammation caused by inflammatory cytokine release and phagocytosis of cellular debris. Although the initial phase of the inflammatory response in the nervous system is beneficial, recent evidence has emerged that the heightened inflammatory response after trauma is self-perpetuating and results in additional damage in the central nervous system. Inflammasome-induced cytokines and inflammasome signaling proteins released from activated microglia interact with AD associated proteins and exacerbate AD pathological progression and cellular damage. Additionally, multiple genetic mutations associated with AD development alter microglia inflammatory activity, increasing and perpetuating inflammatory cell damage. In this review, we discuss the pathologies of TBI and AD and how they are impacted by and potentially interact through inflammasome activity and signaling proteins. We discuss current clinical trials that target the inflammasome to reduce heightened inflammation associated with these disorders.
Topics: Humans; Inflammasomes; Alzheimer Disease; Brain Injuries, Traumatic; Cytokines; Inflammation; Microglia
PubMed: 36070840
DOI: 10.1016/j.trsl.2022.08.014 -
International Journal of Molecular... Jan 2024The temporal and spatial pattern of microglia colonization and vascular infiltration of the nervous system implies critical associated roles in early stages of nervous... (Review)
Review
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.
Topics: Microglia; Macrophages; Yolk Sac; Brain
PubMed: 38279280
DOI: 10.3390/ijms25021281