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Astrocytes undergo an inflammatory transition after infections, acute injuries and chronic neurodegenerative diseases. How this transition is affected by time and sex, its heterogeneity at the single-cell level and how sub-states are spatially distributed in the brain remains unclear. In this study, we investigated transcriptome changes of mouse cortical astrocytes after an acute inflammatory stimulus using the bacterial cell wall endotoxin lipopolysaccharide. We identified fast transcriptomic changes in astrocytes occurring within hours that drastically change over time. By sequencing ~80,000 astrocytes at single-cell resolution, we show that inflammation causes a widespread response with subtypes of astrocytes undergoing distinct inflammatory transitions with defined transcriptomic profiles. We also attribute key sub-states of inflammation-induced reactive astrocytes to specific brain regions using spatial transcriptomics and in situ hybridization. Together, our datasets provide a powerful resource for profiling astrocyte heterogeneity and will be useful for understanding the biological importance of regionally constrained reactive astrocyte sub-states. Using single-cell RNA sequencing and spatial transcriptomics, Hasel et al. uncover complex reactive astrocyte subtypes that occupy distinct areas of the brain. They find two super-responders expressing unique genes in strategic locations in the brain.

Activation of microglia by classical inflammatory mediators can convert astrocytes into a neurotoxic A1 phenotype in a variety of neurological diseases 1 , 2 . Development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat these diseases for which there are no disease-modifying therapies. Glucagon-like peptide-1 receptor (GLP1R) agonists have been indicated as potential neuroprotective agents for neurologic disorders such as Alzheimer’s disease and Parkinson’s disease 3 – 13 . The mechanisms by which GLP1R agonists are neuroprotective are not known. Here we show that a potent, brain-penetrant long-acting GLP1R agonist, NLY01, protects against the loss of dopaminergic neurons and behavioral deficits in the α-synuclein preformed fibril (α-syn PFF) mouse model of sporadic Parkinson’s disease 14 , 15 . NLY01 also prolongs the life and reduces the behavioral deficits and neuropathological abnormalities in the human A53T α-synuclein (hA53T) transgenic mouse model of α-synucleinopathy-induced neurodegeneration 16 . We found that NLY01 is a potent GLP1R agonist with favorable properties that is neuroprotective through the direct prevention of microglial-mediated conversion of astrocytes to an A1 neurotoxic phenotype. In light of its favorable properties, NLY01 should be evaluated in the treatment of Parkinson’s disease and related neurologic disorders characterized by microglial activation. Agonism of microglial glucagon-like peptide-1 receptor (GLP1R) using a brain-penetrant peptide prevents the generation of neurotoxic astrocytes and ameliorates disease progression in two rodent models of Parkinson’s disease.

Key Points Alzheimer disease (AD), like other proteinopathic neurodegenerative disorders, is characterized by the accumulation of amyloidogenic proteins A neuroinflammatory component in AD has been known for more than a decade; however, the importance of the contribution of inflammation in the pathogenesis of AD has been appreciated only recently. Genetic and bioinformatic data from individuals with AD and insights from preclinical models now substantiate the present view that inflammation participates in and exacerbates AD pathology. Neuroinflammation in AD is primarily driven by the brain's intrinsic myeloid cells (known as microglia) and escalates with disease progression; thus AD-associated neuroinflammation contrasts with traditionally defined neuroinflammatory diseases such as multiple sclerosis and encephalitides, which are mainly driven by blood-derived leukocytes and B and T lymphocytes, invading the CNS. Manipulation of some of the molecules of the innate immune system or their respective pathways in animal models of AD has resulted in substantial alteration of disease pathology, indicating the potential to ameliorate the disease course through targeting components of the immune system. The immune system thus appears to provide exciting novel and accessible targets for the diagnosis, control and treatment of AD; however, precise knowledge about specific and defined immune events, which may change during the disease course or differ among individuals with AD, is required. Diagnostics research needs to develop sensitive methods to detect immune alterations prior to the onset of AD to identify those patients at risk who may benefit most from specific, tailored anti-inflammatory interventions. It is now emerging that the neuroinflammation that is associated with Alzheimer disease may have a key role in driving this disease. In this Review, Heppner, Ransohoff and Becher examine the contribution of the immune system to the pathogenesis of this disorder. The past two decades of research into the pathogenesis of Alzheimer disease (AD) have been driven largely by the amyloid hypothesis; the neuroinflammation that is associated with AD has been assumed to be merely a response to pathophysiological events. However, new data from preclinical and clinical studies have established that immune system-mediated actions in fact contribute to and drive AD pathogenesis. These insights have suggested both novel and well-defined potential therapeutic targets for AD, including microglia and several cytokines. In addition, as inflammation in AD primarily concerns the innate immune system — unlike in 'typical' neuroinflammatory diseases such as multiple sclerosis and encephalitides — the concept of neuroinflammation in AD may need refinement.

A hallmark of nervous system aging is a decline of white matter volume and function, but the underlying mechanisms leading to white matter pathology are unknown. In the present study, we found age-related alterations of oligodendrocyte cell state with a reduction in total oligodendrocyte density in aging murine white matter. Using single-cell RNA-sequencing, we identified interferon (IFN)-responsive oligodendrocytes, which localize in proximity to CD8+ T cells in aging white matter. Absence of functional lymphocytes decreased the number of IFN-responsive oligodendrocytes and rescued oligodendrocyte loss, whereas T-cell checkpoint inhibition worsened the aging response. In addition, we identified a subpopulation of lymphocyte-dependent, IFN-responsive microglia in the vicinity of the CD8+ T cells in aging white matter. In summary, we provide evidence that CD8+ T-cell-induced, IFN-responsive oligodendrocytes and microglia are important modifiers of white matter aging.Aging is associated with the formation of focal white matter lesions and atrophy. The authors discovered a role for CD8+ T cells in driving white matter-specific interferon responses in microglia and oligodendrocytes, leading to oligodendrocyte loss.

Glial cells are abundant in the CNS and are essential for brain development and homeostasis. These cells also regulate tissue recovery after injury and their dysfunction is a possible contributing factor to neurodegenerative and psychiatric disease. Recent evidence suggests that microglia, which are also the brain’s major resident immune cells, provide disease-modifying regulation of the other major glial populations, namely astrocytes and oligodendrocytes. In addition, peripheral immune cells entering the CNS after injury and in disease may directly affect microglial, astrocyte and oligodendrocyte function, suggesting an integrated network of immune cell–glial cell communication.Interactions between immune cells and neurons are now widely believed to be important for the regulation of brain function. In their Review, Greenhalgh, David and Bennett highlight the importance of interactions between resident and infiltrating immune cells and the brain’s other major cellular population — glial cells — for brain function.

Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer’s, Huntington’s and Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases. A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes. The production and roles of reactive astrocytes Different types of reactive astrocyte are generated after various injuries and insults to the brain, but less is known about what these astrocyte subtypes do. Here, Shane Liddelow et al . describe how these reactive astrocytes are induced by neuroinflammatory microglia. The authors also explore the functional roles of reactive astrocytes in the progression of disease or damaged states, and show that A1 astrocytes contribute to the death of neurons in the central nervous system under certain conditions.

The precise timing of impulse transmission along axons is crucial for synaptic plasticity and brain oscillations, and is partly determined by myelin thickness. In this Opinion article, R. Douglas Fields discusses how electrical activity influences myelin thickness and thus conduction velocity and circuit properties. The synapse is the focus of experimental research and theory on the cellular mechanisms of nervous system plasticity and learning, but recent research is expanding the consideration of plasticity into new mechanisms beyond the synapse, notably including the possibility that conduction velocity could be modifiable through changes in myelin to optimize the timing of information transmission through neural circuits. This concept emerges from a confluence of brain imaging that reveals changes in white matter in the human brain during learning, together with cellular studies showing that the process of myelination can be influenced by action potential firing in axons. This Opinion article summarizes the new research on activity-dependent myelination, explores the possible implications of these studies and outlines the potential for new research.

Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health 1 , it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1–TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease 2 , 3 . Resident microglia in the central nervous system are identified as the specific macrophage population that regulates myelin growth and integrity.

In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glial cells. The propagation of the inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration—one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.

Safaiyan et al . demonstrate that myelin fragments progressively pinch off from aged myelin sheaths and are taken up and cleared by microglia. Age-associated myelin breakdown is substantial and saturates the degradative capacities of microglia, leading to lysosomal storage and an immune activation in microglia with time. Myelin is synthesized as a multilamellar membrane, but the mechanisms of membrane turnover are unknown. We found that myelin pieces were gradually released from aging myelin sheaths and were subsequently cleared by microglia. Myelin fragmentation increased with age and led to the formation of insoluble, lipofuscin-like lysosomal inclusions in microglia. Thus, age-related myelin fragmentation is substantial, leading to lysosomal storage and contributing to microglial senescence and immune dysfunction in aging.