Neuroscience
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The understanding of the contribution of microglial cells to the onset and/or progression chronic neurodegenerative diseases is key to identify disease-modifying therapies, given the strong neuroimmune component of these disorders. In this review, we dissect the different pathways by which microglia can affect, directly or indirectly, neuronal function and dysfunction associated with diseases like Alzheimer's. We here present the rationale for proposing a model to explain the contribution of microglia to the pathophysiology of Alzheimer's disease, defining microglial cells as necessary transducers of pathology and ideal targets for intervention.
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Microglia are the main resident immune-competent cell type of the central nervous system (CNS); these cells are highly sensitive to subtle changes in the chemical environment of the brain. Microglia are activated during diverse conditions, such as apoptosis, trauma, inflammation, and infection. The specific activities of microglia result from the confluence of environmental stimuli and the cellular state. ⋯ Adenosine tri-phosphate (ATP) belongs to the purinergic signaling system, which includes P2X, P2Y, and P1 receptors, as well as other proteins participating in ATP secretion and extracellular ATP degradation, and molecules that recognize purines as a ligand. In this review, we focus on the latest pre-clinical and basic purinergic system and microglial research, with particular attention to data collected in vivo and ex vivo. This chapter is divided into sections related to microglial ATP release, ATP degradation, and ATP-related actions mediated by P2X and P2Y receptor activation.
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Microglia have long been recognized as the endogenous innate immune elements in the central nervous system (CNS) parenchyma. Besides fulfilling local immune-related functions, they provide cross-talk between the CNS and the immune system at large. ⋯ The full scale of their potential abilities has been highlighted by improvements in microglia isolation methods, the development of genetically tagged mouse models, advanced imaging technologies and the application of next-generation sequencing in recent years. Genome-wide expression analysis of relatively pure microglia populations from both mouse and human CNS tissues has thereby greatly contributed to our knowledge of their biology; what defines them under homeostatic conditions and how microglia respond to processes like aging and CNS disease? How and to what degree beneficial functions of microglia can be restored in the aged or diseased brain will be the key issue to be addressed in future research.
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Microglia are instrumental for recognition and elimination of amyloid β1-42 oligomers (AβOs), but the long-term consequences of AβO-induced inflammatory changes in the brain are unclear. Here, we explored microglial responses and transciptome-level inflammatory signatures in the rat hippocampus after chronic AβO challenge. Middle-aged Long Evans rats received intracerebroventricular infusion of AβO or vehicle for 4 weeks, followed by treatment with artificial CSF or MCC950 for the subsequent 4 weeks. ⋯ Furthermore, MCC950 abrogated AβO-invoked reduction of serum IL-10. These findings provide evidence that in response to AβO infusion microglia change their phenotype, but the resulting inflammatory changes are sustained for at least one month after the end of AβO challenge. Lasting NLRP3-driven inflammatory alterations and altered hippocampal gene expression contribute to spatial memory decline.
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Microglia are the primary immune cells of the central nervous system. However, recent data indicate that microglia also contribute to diverse physiological and pathophysiological processes that extend beyond immune-related functions and there is a growing interest to understand the mechanisms through which microglia interact with other cells in the brain. In particular, the molecular processes that contribute to microglia-neuron communication in the healthy brain and their role in common brain diseases have been intensively studied during the last decade. ⋯ Despite the exponentially increasing knowledge about microglia, the role of these cells in health and disease is still extremely controversial and the precise molecular targets for intervention are not well defined. This is in part due to the lack of microglia-specific manipulation approaches until very recently and to the high level of complexity of the interactions between microglia and other cells in the brain that occur at different temporal and spatial scales. In this review, we briefly summarize the known physiological roles of microglia-neuron interactions in brain homeostasis and attempt to outline some major directions and challenges of future microglia research.