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Zeiser and colleagues show that CAR T cell therapy results in upregulation of the TGFβ-activated kinase-1 (TAK1)–NF-κB–p38 MAPK pathway in microglia, causing neurocognitive defects, and find that TAK1 inhibition can reduce immune effector cell-associated neurotoxicity syndrome.

Polygenic risk scores for Alzheimer’s disease derived from individuals of European ancestry can show improved performance in multiancestry settings after incorporating genome-wide association summary statistics from diverse populations.

A new study reveals that virus-associated activation of a subset of circulating monocytes results in the release of the proinflammatory cytokine tumor necrosis factor (TNF)-α, which induces increased turnover of synapses in the brain and learning deficits in mice.

Multiple state-of-the-art analyses of immune cells in 117 blood, 117 cerebrospinal fluid, 13 choroid plexus and 13 brain parenchyma samples reveal differential characteristics of immune cells in different body compartments and different diseases.

Single-cell mass cytometry was applied to comprehensively characterize postmortem and fresh human microglia. Using a hybrid workflow for multidimensional data analysis, a core signature and regional heterogeneity were identified.

Microglia and macrophages have crucial roles in nervous system development, maintenance and disease. In this Review, Prinz and Priller describe recently discovered details of the embryonic origins and functions of microglia that distinguish them from the other macrophage populations that reside in the brain.

Plasma extracellular vesicles contain quantifiable amounts of TDP-43 and full-length tau, allowing the accurate assessment of pathology in frontotemporal dementia, frontotemporal dementia spectrum disorders and amyotrophic lateral sclerosis.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Here, the authors identify a cognitive reserve-related activity pattern underlying successful memory encoding. They further derive individual reserve scores that predict the maintenance of cognitive performance in the face of Alzheimer’s disease pathology.

Resident microglia in the central nervous system are identified as the specific macrophage population that regulates myelin growth and integrity.

Single-cell profiling and fate-mapping experiments in the developing brain of mice and humans show that microglia and meningeal macrophages originate from a common prenatal precursor, but that perivascular macrophages are derived postnatally from meningeal macrophages.

Using brain organoids models, Prigione and colleagues uncovered the impact of Huntington’s disease on human brain developmental and identified early dysregulation of CHCHD2, which disrupted mitochondria and might serve as a therapeutic target.

Sankowski et al. have combined high-throughput techniques to characterize human microglia, identifying a spectrum of microglia phenotypes that are determined by localization, aging and glioblastoma.

A single-cell spatial transcriptomic and proteomic study of immune cells in the human CNS border compartments reveals differences in CNS-associated macrophages across age, perturbation and disease.

High-dimensional cytometry is a powerful technology for studying single-cell phenotypes in complex biological systems. Here, the authors develop cyCONDOR, a computational framework for high-dimensional cytometry data analysis, covering a comprehensive suite of features in an easy-to-use format.

The adipokine leptin modulates intestinal inflammation in mice. Here the authors describe a patient with inflammatory bowel disease and lipodystrophy, providing evidence that leptin aggravates intestinal inflammation with proinflammatory effects on leukocytes that are reversible by TNFα blockade.

Transcriptomic analyses of 255 primary human microglial samples from 100 individuals highlight brain region, age, sex and disease states as sources of microglial heterogeneity. Molecular quantitative trait locus analyses implicate variants involved in neurological diseases through effects on gene expression and splicing.

Platten and colleagues find that tryptophan metabolism by myeloid cells contributes to immunosuppressive microenvironment uniquely in IDH-mutant gliomas, which can be overcome by inhibiting this pathway in murine tumor models.

Leigh syndrome (LS) is a severe neurometabolic disorder which lacks effective models. Here, the authors developed human neuronal models of LS carrying mutations in SURF1 which show impaired neuronal morphogenesis due to metabolic deficiencies.

The lineage-specific receptor CSF1R controls macrophage development and homeostasis. Here the authors show that deletion of a conserved Csf1r enhancer (FIRE) selectively depletes brain microglia and resident macrophages in the epidermis, kidney, heart and peritoneum of otherwise healthy mice.

Neurotechnologies that measure and modulate brain activity have not yet reached widespread clinical relevance. To accelerate translation into patient care, we propose three strategic adjustments in neurotechnology research — to consider the scope, scalability and stakeholders.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.

Microglia progenitors seed the central nervous system from the yolk sac, but little is known about the origin of non-parenchymal macrophages. Prinz and colleagues demonstrate that these macrophages in the central nervous system are related to but distinct from microglia and are largely of embryonic origin.

Microglia can expand and divide quickly in the context of CNS pathology, but little is known about the kinetics and clonality of microgliosis. Prinz and colleagues develop a new fate mapping system to monitor microglial dynamics. Microglial self-renewal is found to be a stochastic process under steady state conditions, whereas clonal expansion is observed during disease.

Analyses at single-cell resolution show that diverse subtypes of microglia exist during development and homeostasis of the central nervous system, and identify specific subsets of microglia associated with demyelination and neurodegenerative disease in mice and humans.

Bloemeke et al. develop a method for measuring Aβ oligomers in plasma to diagnose Alzheimer’s Disease. Correlation analysis between cerebral spinal fluid and plasma oligomer concentrations indicates an impaired clearance of Aβ oligomers that is dependent on ApoE ε4 status.

Historically, the CNS has been considered immunologically privileged and separated from the peripheral immune system. In this Review, the authors highlight recent advances in our understanding of how the CNS interacts with peripheral immune cells in the context of health and disease.

Microglia have key roles in central nervous system (CNS) disease and homeostasis but their study can be challenging. Prinz and colleagues identify hexosaminidase subunit beta (Hexb) to be specifically expressed by microglia and stable even under inflammatory conditions.

Lloyd et al. find that regeneration of CNS myelin requires death of proinflammatory microglia followed by repopulation to a pro-regenerative state, revealing new therapeutic targets for neurodegenerative disease.