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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Brain injury is associated with neuroinflammation, and microglia are key players in this process. Microglia can acquire pro-inflammatory or anti-inflammatory properties, but how this affects neural stem cells (NSCs) remains controversial. Here, NSCs were grown in conditioned media collected from either non-stimulated microglia, or microglia stimulated with pro- or anti-inflammatory agents. ⋯ We found that NSCs kept in conditioned medium from the anti-inflammatory microglial subtype had better survival, increased migration, and lower astrocytic differentiation compared to NSCs grown in conditioned medium collected from the pro-inflammatory subtype. Finally, we found that NSCs differentiated in microglial conditioned media generated cells expressing the pro-inflammatory chemokine CCL2, most pronounced when differentiated in medium from the pro-inflammatory microglia subtype. Our results show that microglial subtypes regulate NSCs differently and induce generation of cells with inflammatory properties.