Despite the development of highly effective treatments for relapsing-remitting multiple sclerosis (MS), limited progress has been made in addressing primary progressive or secondary progressive MS, both of which lead to loss of oligodendrocytes and neurons and axons, and to irreversible accumulation of disability. Neuroinflammation is central to all forms of MS. The current effective therapies for relapsing-remitting MS target the peripheral immune system; these treatments, however, have repeatedly failed in progressive MS. Greater understanding of inflammation driven by CNS-resident cells - including astrocytes and microglia - is, therefore, required to identify novel potential therapeutic opportunities. Advances in imaging, biomarker analysis and genomics suggest that microglia and astrocytes have central roles in the progressive disease process. In this Review, we provide an overview of the involvement of astrocytes and microglia at major sites of pathology in progressive MS. We discuss current and future therapeutic approaches to directly target glial cells, either to inhibit pathogenic functions or to restore homeostatic functions lost during the course of the disease. We also discuss how bidirectional communication between astrocytes and microglia needs to be considered, as therapeutic targeting of one is likely to alter the functions of the other.

Genome-wide association studies and functional genomics studies have linked specific cell types, genes, and pathways to Alzheimer's disease (AD) risk. In particular, AD risk alleles primarily affect the abundance or structure, and thus the activity, of genes expressed in macrophages, strongly implicating microglia (the brain-resident macrophages) in the etiology of AD. These genes converge on pathways (endocytosis/phagocytosis, cholesterol metabolism, and immune response) with critical roles in core macrophage functions such as efferocytosis. Here, we review these pathways, highlighting relevant genes identified in the latest AD genetics and genomics studies, and describe how they may contribute to AD pathogenesis. Investigating the functional impact of AD-associated variants and genes in microglia is essential for elucidating disease risk mechanisms and developing effective therapeutic approaches.

Immune cells react to their environment by flexibly reprogramming intracellular metabolic pathways that subsequently alter immune function, in a process called immunometabolism. However, in the CNS, the impact of metabolic reprogramming on microglia, neuroinflammation, and subsequently on brain function is poorly understood. As brain-resident macrophages, microglia are the CNS immune effectors and share similarities with peripheral immune cells. New tools for studying immunometabolism now allow the analysis of bioenergetic regulation with cellular resolution and, as a result, have uncovered previously unappreciated roles for microglial immunometabolism in shaping neuroinflammation. This review highlights evidence that microglia metabolism adapts to changes in brain energy homeostasis and that metabolic reprogramming regulates microglial polarization, thereby impacting pathological inflammatory responses in the brain.

Alzheimer's disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to lack of a clear underlying mechanism. Studies within the last few decades provide growing evidence for a central role of amyloid β (Aβ) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis. Herein, we review recent progress with respect to Aβ- and tau-associated mechanisms, and discuss glial dysfunction in AD with emphasis on neuronal and glial receptors that mediate Aβ-induced toxicity. We also discuss other critical factors that may affect AD pathogenesis, including genetics, aging, variables related to environment, lifestyle habits, and describe the potential role of apolipoprotein E (APOE), viral and bacterial infection, sleep, and microbiota. Although we have gained much towards understanding various aspects underlying this devastating neurodegenerative disorder, greater commitment towards research in molecular mechanism, diagnostics and treatment will be needed in future AD research.

In the adult mammalian hippocampus, new neurons arise from stem and progenitor cell division, in a process known as adult neurogenesis. Adult-generated neurons are sensitive to experience and may participate in hippocampal functions, including learning and memory, anxiety and stress regulation, and social behavior. Increasing evidence emphasizes the importance of new neuron connectivity within hippocampal circuitry for understanding the impact of adult neurogenesis on brain function. In this Review, we discuss how the functional consequences of new neurons arise from the collective interactions of presynaptic and postsynaptic neurons, glial cells, and the extracellular matrix, which together form the "tetrapartite synapse."

Microglia were first recognized as a distinct cell population in the CNS one century ago. For a long time, they were primarily considered to be phagocytes responsible for removing debris during CNS development and disease. More recently, advances in imaging and genetics and the advent of single-cell technologies provided new insights into the much more complex and fascinating biology of microglia. The ontogeny of microglia was identified, and their functions in health and disease were better defined. Although many questions about microglia and their roles in human diseases remain unanswered, the prospect of targeting microglia for the treatment of neurological and psychiatric disorders is tantalizing.

As resident macrophages of the central nervous system (CNS), microglia are associated with diverse functions essential to the developing and adult brain during homeostasis and disease. They are aided in their tasks by intricate bidirectional communication with other brain cells under steady-state conditions as well as with infiltrating peripheral immune cells during perturbations. Harmonious cell-cell communication involving microglia are considered crucial to maintain the healthy state of the tissue environment and to overcome pathology such as neuroinflammation. Analyses of such intercellular pathways have contributed to our understanding of the heterogeneous but context-associated microglial responses to environmental cues across neuropathology, including inflammatory conditions such as infections and autoimmunity, as well as immunosuppressive states as seen in brain tumors. Here, we summarize the latest evidence demonstrating how these interactions drive microglia immune and non-immune functions, which coordinate the transition from homeostatic to disease-related cellular states.