Muhammad Ali and al.

The authors performed CSF proteome analysis on a large cohort of patients with Alzheimer’s disease (AD) at different evolution stages. They identified 2,029 unique proteins from which 865 (43%) were previously reported, and 1,164 (57%) are novel. The identified proteins cluster in four different pseudo-trajectories groups spanning the AD continuum and were enriched in pathways including neuronal death, apoptosis, and tau phosphorylation (early stages), microglia dysregulation and endolysosomal dysfunction (mid stages), brain plasticity and longevity (mid stages), and microglia-neuron crosstalk (late stages). Using machine learning, the authors created and validated highly accurate and replicable (area under the curve [AUC] > 0.90) models that predict AD biomarker positivity and clinical status. These models can also identify people that will convert to AD.

Ning LIU and al.

Itaconate, a metabolite produced by the enzyme aconitate decarboxylase 1 encoded by the gene IRG1  is a pivotal metabolic regulator in immune cells, particularly in macrophages and microglia. In this study, the authors explored the role of the IRG1/itaconate pathway in regulating microglial bioenergetics and inflammatory activation post-traumatic brain injury (TBI) using a murine model of controlled cortical impact (CCI). They observed a swift but transient increase in glycolysis coupled with a prolonged disruption of mitochondrial metabolism in post-TBI microglia. Despite an up-regulation of Irg1 expression, itaconate in microglia declined after TBI. Microglia-specific Irg1 gene knockout (Irg1-Mi-KO) exacerbated metabolic changes, intensified proinflammatory activation and neurodegeneration, and worsened certain long-term neurological deficits. Supplementation with 4-octyl itaconate (OI) reinstated the use and oxidative metabolism of glucose, glutamine, and fatty acid, thereby enhancing microglial bioenergetics post-TBI. OI supplementation also attenuated proinflammatory activation and neurodegeneration and improved long-term neurological outcomes. These results suggest that therapeutically targeting the itaconate pathway could improve microglial energy metabolism and neurological outcomes after TBI.

Shirin Schneeberger and al.

The authors show that IL-12 receptors are predominantly expressed in neurons and oligodendrocytes in AD-like APPPS1 mice and in patients with Alzheimer’s disease (AD), whereas IL-23 receptor transcripts are barely detectable. Consistently, deletion of the IL-12 receptor in neuroectodermal cells ameliorate AD pathology in APPPS1 mice, whereas removal of IL-23 receptors has no effect. Genetic ablation of IL-12 signaling alone reverts the loss of mature oligodendrocytes, restores myelin homeostasis, rescues the amyloid-β-dependent reduction of interneurons and restores phagocytic functions in microglia of APPPS1 mice. Data obtained in patients with AD confirm these results.

Rocio Vicario and al.

Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders associated with mitogen-activated protein (MAP)-kinase-activating mutations and an increased risk of neurodegeneration. The authors found microglial mutant clones in LCH and ECD patients, whether or not they presented with clinical symptoms of neurodegeneration, associated with microgliosis, astrocytosis, and neuronal loss, predominantly in the rhombencephalon gray nuclei. Neurological symptoms were associated with PU.1+ clone size (p = 0.0003) in patients with the longest evolution of the disease, indicating a phase of subclinical neurodegeneration. Genetic barcoding analysis suggests that clones may originate from definitive or yolk sac hematopoiesis, depending on the patients. In a mouse model, disease topography was attributable to a local clonal proliferative advantage, and microglia depletion by a CSF1R-inhibitor limited neuronal loss and improved survival. These results characterize a neurodegenerative disease associated with clonal proliferation of inflammatory microglia. The long preclinical stage represents a therapeutic window before irreversible neuronal depletion.

Francisco Javier Rodriguez-Baena and al.

Using preclinical models and single-cell transcriptomics, the authors identified a mechanism that enhances antitumor immunity in melanoma brain metastasis. They show that activation of the Rela/NF-κB pathway in microglia promotes melanoma brain metastasis. Targeting this pathway elicits microglia reprogramming toward a proinflammatory phenotype, which enhances antitumor immunity and reduces brain metastatic burden. Furthermore, the authors found that proinflammatory microglial markers in melanoma brain metastasis are associated with improved responses to immune checkpoint inhibitors in patients and that targeting Rela/NF-κB pathway in mice improves responses to these therapies in the brain.