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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.

How microglia regulate adult hippocampal neurogenesis and cognitive and affective behavior remains poorly understood. Here, the authors show that TGF-β-deficient microglia increase adult neurogenesis in the subgranular zone and alter anxiety-like behavior in mice.

Astrocytes can respond to diseases and injuries of the central nervous system by driving the death of neurons and mature oligodendrocytes through the delivery of long-chain saturated fatty acids contained in lipoparticles.

After spinal-cord injury, cells called astrocytes form a scar that is thought to block neuronal regeneration. The finding that the scar promotes regrowth of long nerve projections called axons challenges this long-held dogma. See Article p.195

Astrocyte activation may contribute to neurodegenerative disease. Here the authors show that the combined knockout of three factors known to promote astrogliosis, IL-1α, TNFα and C1qa, leads to improved survival in the SOD1^G93A mouse model of ALS.

Astrocytes are emerging as causal or modulating factors in diverse neurological disorders. Two papers published in Nature Neuroscience in 2007 revealed astrocytes as causally contributing to motor neuron loss in amyotrophic lateral sclerosis, thereby challenging the longstanding neuron-centric view of neurodegenerative disease.

The transcriptional program underlying the origin of glial cells is unclear. Here the authors leverage single-cell/single-nucleus transcriptional and chromatin accessibility profiling to identify candidate cell fate specification genes and optimize a rapid astrocyte differentiation protocol.

Apolipoprotein E (APOE) is the most abundant apolipoprotein in the brain, where it is primarily expressed and secreted by astrocytes and microglia. APOE seems to exert immunomodulatory effects in an isoform-dependent way, and a new study indicates that the APOE isoform dictates the glycosylation state and secretion of this apolipoprotein.

Astrocytes have important roles in disease and are difficult to modulate, owing to a paucity of known targets. Clayton et al. develop a screening platform to unbiasedly identify modulators of astrocyte reactivity. They discover that HDAC3 inhibitors regulate astrocyte transitions into their reactive phenotype in vitro and in vivo.

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.

Oxidative stress is an imbalance in the production of reactive oxygen species and the ability to remove or detoxify these molecules, which causes cellular damage. Leveraging novel sequencing methods and high-throughput screens leads to the discovery of possible new therapies.

Cells called astrocytes promote and maintain neuronal function. The discovery that astrocytes vary in their gene expression, protein levels, cellular structure and function suggests that they are specialized to support distinct circuits.

This review provides an overview of analysis and experimental design of single-cell omics in the brain, emphasizing epigenomics and spatial omics. The authors discuss how the computational and experimental designs are interlinked, with both being guided by the biological questions.

Single-cell RNA sequencing with parallel tagging of progenitor cells is used to track clonal relationships and transcriptomic signatures during development of the mouse forebrain.

Microglia and astrocytes propagate neurodegeneration by releasing fragmented and dysfunctional mitochondria into the neuronal milieu. Inhibiting pathological fragmentation of glial mitochondria blunts neuroinflammation and increases neuroprotection.

In the absence of progranulin, microglia enter a disease-specific state that causes endolysosomal dysfunction and neurodegeneration, and these microglia promote TDP-43 granule formation, nuclear pore defects and cell death specifically in excitatory neurons via the complement activation pathway.

This Review provides insights for construction of molecular cell atlases and outlines key study design considerations. The authors emphasize the power of single-cell and single-nucleus genomics in revealing cellular transitions during nervous system development and disease.

Single-cell or single-nucleus RNA-sequencing experiments form a basis for biological insights about cell types and states, but they require orthogonal experiments to confirm the functional relevance of their findings. Here the authors discuss options to support such findings and their challenges.

Astrocytes are essential for neuronal survival and function in the CNS but, under pathological conditions, they can adopt potentially harmful reactive states. This Review highlights how ‘omics’ technologies can enable the functional characterization of defined reactive astrocyte states in various pathological scenarios.

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.

ApoE4 exacerbates tau pathogenesis, neuroinflammation and tau-mediated neurodegeneration independently of brain amyloid-β pathology, and exerts a ‘toxic’ gain of function whereas its absence is protective.

This Review provides an in-depth examination of how inflammation contributes to neurodegeneration in Alzheimer disease. The authors explore the impact of extrinsic factors, such as brain trauma, diet and infections, and host-intrinsic factors, such as the activity of microglial cells and other immune, vascular and neuronal cell populations, on disease development. They also highlight emerging drugs that target this inflammatory component for therapy of Alzheimer disease.

Good–bad binary classifications fail to describe reactive astrocytes in CNS disorders. Here, 81 researchers reach consensus on widespread misconceptions and provide definitions and recommendations for future research on reactive astrocytes.