bims-micgli 2026-06-07 papers

bims-micgli

Biomed News

on Microglia

Issue of 2026–06–07
33 papers selected by
Matheus Garcia Fragas, Universidade de São Paulo

Microglia modulate concussion biomarkers and cognitive recovery in male mice.
Enhancing the specificity of microglia genetic targeting using a CSF1R inhibitor.
Somatic mutations reveal the ontogeny of human microglia.
ApoE expression across the CNS: Who, What, Where, When, and How (much)?
Activity-dependent protein synthesis in neurons requires microglial-metabolic coupling.
Human microglial transitions at the Aβ-tau inflection point associate with divergent pathways to dementia and resilience.
FcγR- and CD9-dependent synapse engulfing microglia in the thalamus drives cognitive impairment following cortical brain injury.
Elevated phagocytic capacity directs innate spinal cord repair.
APOE4 and INPP5D converge on membrane mechanics to regulate endocytosis in human astrocytes.
Neuronal UBE3A loss engages a TNF-driven neuron-to-microglia axis that promotes synapse remodeling.
Astrocyte-microglia crosstalk via CSF1 and IFN-β promotes central nervous system repair.
Microglia and neuroinflammation: function, heterogeneity, and crosstalk.
Microglial state transitions are constrained by developmental and metabolic checkpoints.
Defining functional states and roles of microglia in neuropsychiatric disorders.
Placental and juvenile immune responses to maternal immune activation are differentially regulated by sex chromosomes and gonads across gestation.
GPNMB modulates neutrophil extracellular trap formation: therapeutic implications for ischemic stroke.
Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction.
Astrocytic ACSBG1 depletion improves lipid-cytokine signaling and attenuates α-Synuclein pathology in a Parkinson's disease mouse model.
Early-onset neuroinflammation drives neurodegeneration caused by lysosomal PI(3,5)P2 insufficiency.
Disturbed lipid metabolism in microglia after cerebral ischemia-reperfusion.
Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer's knock-in mouse phenotypes.
Soluble TREM1 Contributes to Aging-Related Neurodegeneration via ROBO2/ERK Pathway.
Microglial CD31 suppresses Aβ clearance and promotes Alzheimer pathology in 5×FAD mice.
Distinct and combined interferon-ɑ/β-receptor-1 loss in neurons and astrocytes disrupt brain energy metabolism and drive Parkinsonian dementia.
Microglia in diffuse midline glioma contribute to extracellular matrix remodelling and cancer cell invasion.
Pre-treatment bacterial cell states shape antibiotic-induced transcriptional reprogramming and survival.
Microglial galectin-3 disrupts parvalbumin interneurons and hippocampal synchrony, driving cognitive deficits.
Integrated Lipidomics and Nitro-Fatty Acid Profiling Link Adipose Redox Imbalance to Alzheimer's Disease-Related Neurovascular Injury.
Emerging roles of ferroptosis in modulating the immune landscape of glial tumours.
Stress, stress systems, and Alzheimer's disease.
Reticulophagy limits Alzheimer's disease pathology through FAM134B-dependent APP clearance.
Brain Bioenergetics in Aging: Neurovascular and Neurometabolic Coupling and Fuels: 15th International Conference on Brain Energy Metabolism.
Bang! Exploding immune cells splatter potent toxins everywhere.

bioRxiv. 2026 May 19. pii: 2025.05.01.651070. [Epub ahead of print]

Microglia modulate concussion biomarkers and cognitive recovery in male mice.

Erin D Anderson, Daunel V Augustin, Anastasia P Georges, Taehwan Kim, David A Issadore, David F Meaney.

Microglial state at the time of concussion dictates cognitive outcomes, yet the underlying mechanisms remain unclear, and non-invasive tools to predict recovery trajectories remain elusive. Here, we tested whether microglia are causally required for concussion-induced deficits and the neuroprotection conferred by subconcussive preconditioning. Using PLX5622 to deplete microglia in a preclinical model, we observed opposing cognitive effects: depletion rescues deficits from concussion alone but eliminates preconditioning-induced protection. To characterize the molecular mechanisms underlying these divergent trajectories, we performed single-nuclei transcriptomics and isolated brain-derived (GluR1/2+) extracellular vesicles (EVs) from plasma. We found that microglial presence and subconcussive preconditioning fundamentally alter injury biomarkers and signaling pathways across multiple cell types. Furthermore, we identified a plasma EV miRNA panel that predicts cognitive recovery across varied injury conditions. Together, these results demonstrate a dual, context-dependent role for microglia in concussion outcomes and establish brain-derived EVs as a powerful tool for surveilling neuroinflammatory processes governing recovery.
Teaser: Microglial state during concussion affects cognitive recovery and neuron-enriched extracellular vesicle biomarkers.

DOI: https://doi.org/10.1101/2025.05.01.651070
Cell Rep. 2026 May 29. pii: S2211-1247(26)00489-4. [Epub ahead of print]45(6): 117411

Enhancing the specificity of microglia genetic targeting using a CSF1R inhibitor.

Isaac W Babcock, Sydney A Labuzan, Abigail G Kelly, Anne E Schuster, Seblework Alemu, Lydia A Sibley, Anne E Marchildon, Tajie H Harris.

  Microglia are the resident macrophages of the brain and are central to neuroimmunology research. The roles of microglia are often probed by pharmacological depletion with CSF1R inhibitors or by genetic manipulation using Cre-lox systems, but microglia-specific genetic targeting remains challenging due to limited specificity or efficiency of Cre lines. We confirm that Cx3cr1CreERT2 mice, widely used for microglial studies, also target multiple peripheral tissue macrophage populations that fail to turn over within the standard 4-week period intended to improve specificity. To overcome this limitation, we combined tamoxifen induction in Cx3cr1CreERT2 mice with PLX5622 treatment to accelerate peripheral macrophage turnover. In a brain infection model, this strategy increased the specificity of gene deletion in microglia in Cx3cr1CreERT2 mice and eliminated confounding contributions from peripheral macrophages. In sum, the use of a CSF1R inhibitor provides a solution to enhance the precision of microglial genetic manipulation using a common Cre line.

Keywords:  CP: immunology; CP: neuroscience; genetics; microglia; neuroimmunology; tissue-resident macrophages

DOI:  https://doi.org/10.1016/j.celrep.2026.117411
bioRxiv. 2026 May 20. pii: 2026.05.19.726366. [Epub ahead of print]

Somatic mutations reveal the ontogeny of human microglia.

Julia A Belk, Yaowen Zhang, Quanming Shi, Lisa Ma, Raja Kalluru, Alejandro Medina Enciso, Emily E Reilly, Jacob Weiss, Rui Li, Anna E Eastman, Nicole Womack-Gambrel, Debasmita Paul, Arnav Chakravarthy, Syed Bukhari, Dipabarna Bhattacharya, Suyash Raj, Daniel Richard, Simone Brioschi, Matthew R Chrostek, Daniel C Nachun, Christopher M Arends, Jayakrishnan Gopakumar, Isak W Tengesdal, Ademar Bynum, Shaneice Mitchell, Katalin Sandor, Badri N Vardarajan, Inma Cobos, Donald E Born, Anne Brunet, Marco Colonna, Hannes Vogel, Thomas J Montine, Jody E Hooper, Irving L Weissman, C Dirk Keene, Howard Y Chang, Siddhartha Jaiswal.

Microglia are the resident hematopoietic cells of the central nervous system 1 . In mice, microglia seed the brain during embryogenesis and can be maintained throughout life with minimal input from adult hematopoiesis 2-4 . The origins of human microglia are less clear, but recent evidence suggests that marrow-derived cells may be able to supplement the human microglial pool in certain individuals 5,6 . Here, to investigate the ontogeny of human microglia, we develop a method that uses the collection of accumulated somatic mutations which uniquely labels each clone of cells to track the infiltration of marrow-derived cells into the human brain. Applying this method to 20 aged individuals, we find evidence of an influx of marrow-derived cells into the brain in all examined individuals. Single cell analysis, including single cell lineage tracing using mitochondrial DNA variants, demonstrates that these infiltrating cells are nearly identical to microglia and can comprise a large fraction of the microglial pool. Analysis of large-scale sequencing cohorts demonstrates a protective association between most types of clonal hematopoiesis and Alzheimer's disease. In sum, this work uncovers a widespread influx of myeloid cells into the healthy human brain which serves to reinforce the pool of human microglia and becomes common with aging.

DOI: https://doi.org/10.64898/2026.05.19.726366
Mol Neurodegener Adv. 2026 ;2(1): 24

ApoE expression across the CNS: Who, What, Where, When, and How (much)?

Georgia L Nolt, Chloe C Lucido, Lily M Smith, Lance A Johnson.

  Apolipoprotein E (APOE) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and encodes a major lipid transporter in the central nervous system (CNS). Although apoE has been studied extensively, fundamental questions remain regarding its expression across the CNS. For example, which CNS cell types express APOE? Where is APOE expression enriched across brain regions? When is APOE dynamically regulated - across development, aging, injury, and neurodegeneration? How much apoE is produced at the mRNA and protein level - particularly across the common E2, E3, and E4 isoforms? Here, we synthesize transcriptomic, spatial, biochemical, and genetic evidence to provide an organized framework for the "who, what, where, when, and how (much)" of CNS APOE/apoE. By assessing large-scale single-cell datasets along with in vivo and cell-type-specific genetic studies, we highlight that astrocytes are the predominant source of CNS apoE at baseline, while microglia, oligodendrocyte-lineage cells, vascular-associated populations, and border-interface macrophages exhibit context-dependent induction that is strongly influenced by aging, injury, and AD-related pathology. We also evaluate unresolved discrepancies, such as the extent of neuronal APOE expression and its contribution to total brain apoE, and describe how - across modalities - apoE abundance often follows an isoform-dependent hierarchy (typically E2 > E3 > E4 at the protein level) while transcript-protein discordance and model-specific effects underscore substantial post-transcriptional and contextual regulation. Finally, we discuss how clarifying spatiotemporal, cell-specific, and isoform-dependent apoE expression will enable better informed and more precise apoE-targeted therapeutic strategies.
Graphical abstract:

Keywords:  APOE; Alzheimer's disease; Apolipoprotein E; Brain

DOI:  https://doi.org/10.1186/s44477-026-00028-x
Cell Metab. 2026 Jun 04. pii: S1550-4131(26)00191-9. [Epub ahead of print]

Activity-dependent protein synthesis in neurons requires microglial-metabolic coupling.

Drew Adler, Alejandro Martín-Ávila, Evan Cheng, Mauricio M Oliveira, Muxian Zhang, Harrison T Evans, Deliang Yuan, Richard Sam, Nicole D Zhang, Maria Clara Selles, Olivia Mosto, Wendy J Liu, Victor T Wu, Amy X Guo, Shane A Liddelow, Robert C Froemke, Moses V Chao, Wen-Biao Gan, Eric Klann.

  De novo protein synthesis is required for long-lasting synaptic plasticity and memory, but it comes with a great metabolic cost. In the mammalian brain, it remains unclear which cell types and biological mechanisms are critical for sensing and responding to increased metabolic demand. Here, we demonstrate that microglia, the resident macrophages of the brain, are required for metabolic coupling between endothelial cells, astrocytes, and neurons, which fuels protein synthesis in active neurons. Increasing metabolic demand via a motor task stimulates microglia to secrete the hypoxia-responsive protein CYR61, which increases glucose transporter expression in brain vasculature. Depleting microglia reduces training-induced metabolic fluxes and neuronal protein synthesis, which can be reproduced by blocking CYR61 signaling. Thus, we define a neuroimmune metabolic circuit that is required for on-demand protein synthesis in mouse motor cortex.

Keywords:  astrocyte-neuron-lactate-shuttle; brain immunometabolism; brain metabolism; immunometabolism; mRNA translation; microglia; microglia-endothelial interaction; microglia-neuron interaction; microglial-metabolic coupling; neuroimmunology; protein synthesis

DOI:  https://doi.org/10.1016/j.cmet.2026.05.006
Nat Med. 2026 Jun 04.

Human microglial transitions at the Aβ-tau inflection point associate with divergent pathways to dementia and resilience.

Ashley Lu, Wei-Ting Chen, Maria Dalby, Diego Sainz Garcia, Marisa Vanheusden, Luuk E de Vries, Veerle van Lieshout, Araks Martirosyan, Katleen Craessaerts, Sebastiaan Moonen, Magdalena Zielonka, Iordana Chrysidou, Anke Misbaer, Leen Wolfs, Benjamin Pavie, Dick Swaab, Dietmar Rudolf Thal, Inge Huitinga, Annemieke Rozemuller, Susan Karijn Rohde, Marc Hulsman, Henne Holstege, Rita Balice-Gordon, Niels Plath, Mark Fiers, Bart De Strooper.

Alzheimer's disease (AD) is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau. To disentangle these responses, we combined spatial transcriptomics and single-nucleus RNA sequencing of the superior frontal cortex from octogenarians living with or without dementia and from cognitively intact centenarians with comparable Aβ accumulation. We identified six distinct tissue domains representing a spatial pathological continuum of AD, with a key inflection point marked by a shift from Aβ-associated inflammatory changes to tau-associated cellular programs. This transition was accompanied by a change in microglial states, from early inflammatory to late antigen-presenting phenotypes, termed early and late plaque-induced gene (PIG) programs. Resilient individuals showed distinct pathological patterns: octogenarians without dementia lacked late PIGs, whereas centenarians showed late PIG activation that was uncoupled from tau accumulation. Together, these findings highlight divergent resilience-associated mechanisms in human aging and position microglial state transitions at the Aβ-tau interface as candidate points of resilience with potential therapeutic relevance.

DOI: https://doi.org/10.1038/s41591-026-04393-8
bioRxiv. 2026 May 24. pii: 2024.09.19.609743. [Epub ahead of print]

FcγR- and CD9-dependent synapse engulfing microglia in the thalamus drives cognitive impairment following cortical brain injury.

Ken Matoba, Takahiro Kochi, Yassin R Mreyoud, Jana H Badrani, Hency Patel, Hiroshi Tsujioka, Toshihide Yamashita, David K Crossman, Minae Niwa, Shin-Ichi Kano.

Various states of microglia appear in neuroinflammation, but their impact on brain function and behavior is not fully understood. Here we report that synapse engulfing microglia in the thalamus are crucial for cognitive impairment after cortical brain injury. Region-specific manipulations of reactive microglia in the chronic phase of injuries showed that microglial changes in the thalamus, but not in the hippocampus, impaired recognition memory. Single-cell RNA-sequencing analysis revealed the enrichment of synapse engulfing microglia in the thalamus, which developed in a CD9-dependent manner and caused synaptic loss and recognition memory deficits. In the thalamus, the blood-brain barrier was disrupted, and extravasated γ-immunoglobulins (IgG) co-localized with synapse engulfing microglia. Fc γ receptor III blockade in the thalamus reduced synapse engulfing microglia, synapse loss, and recognition memory deficits. These findings demonstrate that the induction of synapse engulfing microglia in the thalamus by extravasated IgG/Fc γ RIII and CD9 signals causes recognition memory deficits after cortical brain injury.

DOI: https://doi.org/10.1101/2024.09.19.609743
Cell Rep. 2026 Jun 04. pii: S2211-1247(26)00560-7. [Epub ahead of print]45(6): 117482

Elevated phagocytic capacity directs innate spinal cord repair.

Dana Klatt Shaw, Vishnu Muraleedharan Saraswathy, Anthony R McAdow, Lili Zhou, Dongkook Park, Ridim Mote, Amulya Saini, Ashley J Douthitt, Katerina Stepankova, Brittney Unverzagt, Cédric G Geoffroy, Aaron N Johnson, Mayssa H Mokalled.

  Immune cells elicit a continuum of transcriptional states after spinal cord injury (SCI). In mammals, inefficient debris clearance and chronic inflammation impede recovery and overshadow pro-regenerative immune functions. We found that zebrafish SCI elicits transient immune activation and efficient debris clearance. Transcriptomics and genetic ablation showed zebrafish macrophages are highly phagocytic and required for regeneration. Comparisons between zebrafish and mammalian macrophages identified transcription and immune response regulator (tcim) as an immune-enriched regenerative gene. Deletion of zebrafish tcim impairs phagocytosis and regeneration and activates a pro-inflammatory signature in leukocytes. Tcim expression in zebrafish and mouse macrophages establishes its conserved roles by promoting lipid metabolism and the reprogramming of myeloid precursors into activated phagocytes. This study underscores a requirement for elevated phagocytic capacity to achieve innate spinal cord repair and identifies a gene with conserved function in mammalian cells.

Keywords:  CP: Immunology; CP: Neuroscience; immune clearance; lipid metabolism; macrophages; microglia; neuroimmunology; phagocytosis; spinal cord injury; spinal cord regeneration; zebrafish

DOI:  https://doi.org/10.1016/j.celrep.2026.117482
bioRxiv. 2026 May 22. pii: 2026.05.22.726347. [Epub ahead of print]

APOE4 and INPP5D converge on membrane mechanics to regulate endocytosis in human astrocytes.

Artur S Gevorgyan, Lila M Gordon, Christian A Combs, Adrian Lita, Linda G Yang, Carla Cuní-López, Jessica T Root, Mioara Larion, Justin W Taraska, Priyanka S Narayan.

Disrupted endocytosis is an early feature of Alzheimer's disease (AD), but how genetic risk factors functionally impact this pathway remains unclear. Using isogenic human iPSC-derived astrocytes, we show that the AD risk variant, APOE4, impairs clathrin-mediated membrane curvature, clathrin-mediated endocytosis, and alters plasma membrane lipid saturation and tension. Compared to APOE3 astrocytes, APOE4 cells display an accumulation of flat clathrin structures, reduced maturation of clathrin-coated pits, decreased early endosomes, and reduced endocytic uptake. We then identify the AD risk gene INPP5D as a modifier that restores early endocytosis in APOE4 astrocytes by promoting clathrin curvature and maturation through a mechanism distinct from membrane tension regulation. Beyond effects on trafficking, INPP5D overexpression also reduces lipid droplet accumulation and attenuates inflammatory signaling, linking membrane dynamics to disease-associated astrocytic phenotypes. Together, these findings establish altered membrane mechanics as a proximal consequence of the APOE4 variant and identify endocytosis as a common node linking AD risk genes.

DOI: https://doi.org/10.64898/2026.05.22.726347
bioRxiv. 2026 May 28. pii: 2026.05.27.728269. [Epub ahead of print]

Neuronal UBE3A loss engages a TNF-driven neuron-to-microglia axis that promotes synapse remodeling.

Xin Yang, Xu Zhang, Yu-Wen Alvin Huang.

Neuron-microglia communication shapes neuroimmune homeostasis and circuit maturation, yet the neuron-derived cues that tune microglial inflammatory state and phagocytic programs remain incompletely defined. The E3 ubiquitin ligase UBE3A is critical for brain development and synaptic function, and altered UBE3A dosage or activity is linked to neurodevelopmental phenotypes with emerging connections to inflammation. Using Angelman syndrome (AS), where UBE3A loss is largely neuron-selective due to imprinting, as a tractable framework, we investigated how neuronal UBE3A deficiency engages microglial programs. In human iPSC-derived neuron-microglia co-cultures, neuronal UBE3A depletion induced a TNF-associated secretory signature and was accompanied by increased microglial inflammatory markers, including complement components. Neuron-conditioned media was sufficient to elicit microglial cytokine/complement transcripts, supporting a role for soluble neuron-derived cues. In these co-cultures, neuronal UBE3A loss increased synapse engulfment by microglia, which was reduced by TNF receptor pathway inhibition with the TNFR1 antagonist R7050 alongside decreased microglial inflammatory readouts. In vivo, juvenile AS mouse hippocampus showed early microglial dysregulation, and reanalysis of a maternal-deletion AS pig single-nucleus RNA-seq dataset revealed enrichment of microglial activation and phagosome/lysosome pathways. Together, these findings implicate a TNF-linked neuron-to-microglia signaling axis downstream of neuronal UBE3A loss that can be pharmacologically modulated during development.

DOI: https://doi.org/10.64898/2026.05.27.728269
Cell Rep. 2026 May 29. pii: S2211-1247(26)00496-1. [Epub ahead of print]45(6): 117418

Astrocyte-microglia crosstalk via CSF1 and IFN-β promotes central nervous system repair.

Tuoxin Cao, Matin Hemati-Gourabi, Yongliang Liu, Anna E Mills, Lauren Baur, Ellie P Rice, Theo Klippel, Yiwen Yan, Xiu Xu, William K Fenske, Jean X Jiang, Meifan Chen.

  Despite accumulating evidence of functional interactions between astrocytes and microglia in central nervous system (CNS) injury and disease, mechanisms coordinating their response to CNS insults remain incompletely understood. We report that injury-reactive astrocytes at the lesion border upregulate colony-stimulating factor 1 (CSF1) required for microglial proliferation, wound closure, and motor recovery after focal spinal cord injury (SCI). Intriguingly, astrocyte-targeted deletion of CSF1 also reduces the cell number of border-forming astrocytes, revealing positive feedback regulation between astrocytes and microglia. We further show that microglia produce interferon β (IFN-β), which reciprocally supports astrocyte survival. Genetic disruption of interferon signaling in astrocytes in turn impairs astrocytic border formation, coordination with microglia in wound healing, and motor recovery. This work uncovers astrocyte-microglia crosstalk via CSF1 and IFN-β that synergizes the acute injury response of these cells for neural repair, providing insights into fundamental biology of astrocyte-microglia communication and its therapeutic potential.

Keywords:  CNS injury; CNS repair; CP: neuroscience; CSF1; IFN-β; astrocyte-microglia interaction; glia crosstalk; interferon response; reactive astrocytes; spinal cord injury; wound repair astrogliosis

DOI:  https://doi.org/10.1016/j.celrep.2026.117418
Cell Mol Immunol. 2026 Jun 04.

Microglia and neuroinflammation: function, heterogeneity, and crosstalk.

Shuai Zong, Xiaolin Cui, Shuang Wu, Zhiming Lu.

  Microglia, the resident innate immune cells of the central nervous system (CNS), are indispensable for maintaining brain homeostasis, conducting immune surveillance, and responding to injury. Recent single-cell sequencing studies have revealed that activated microglia exhibit a spectrum of activation states that extend well beyond the classical proinflammatory/anti-inflammatory dichotomy, encompassing distinct subpopulations such as disease-associated microglia (DAMs), termed interferon-responsive microglia (IRMs), and lipid-droplet-accumulating microglia (LDAMs). Their remarkable plasticity enables microglia to adopt dual functional roles-either neuroprotective or neurotoxic-depending on the context of neuroinflammatory disease progression. Furthermore, microglia do not act in isolation but serve as central communicators within a dynamic cellular network of the CNS, interacting with neurons, astrocytes, oligodendrocytes, and peripheral immune cells to regulate processes such as synaptic pruning, inflammatory amplification, and myelin integrity and repair. This review provides a comprehensive overview of microglial origin, development, and classification, as well as the dynamic spectrum of microglial cellular states. Furthermore, we discuss the classical and latest mechanisms of microglia-mediated neuroinflammation and focus on the crosstalk between microglia and other cells of the CNS. The hub position of microglia within neuroinflammatory networks, together with their unique cellular characteristics, may unlock a promising frontier for the development of precision therapeutic strategies against neuroinflammatory disorders.

Keywords:  Cellular heterogeneity; Microglia; Neuroimmune crosstalk; Neuroinflammation

DOI:  https://doi.org/10.1038/s41423-026-01438-3
Front Cell Neurosci. 2026 ;20 1852176

Microglial state transitions are constrained by developmental and metabolic checkpoints.

Adil El Mesaoudi, Dong Won Kim.

  Single-cell transcriptomic and epigenomic profiling has revealed extensive microglial heterogeneity across development, homeostasis, and disease. However, one recurring observation remains unexplained. Only subsets of microglia adopt expected transcriptional programs in a given context, and transcriptional activation often fails to translate into functional execution. Current frameworks describe microglial states, but they do not explain why individual cells differ in their ability to access, sustain, or complete state transitions. Here, we propose a checkpoint framework for microglial state transitions. In this model, transitions depend on prerequisite conditions that must be met before a response can proceed. We use the term checkpoint in the sense of cell-cycle biology, where progression depends on prior conditions, rather than in the signal-integration sense used for peripheral immune checkpoints. We first consider the peripheral checkpoint model, in which transitions are driven mainly by activating and inhibitory receptor signaling. In that system, continuous hematopoietic renewal buffers many individual cell-level constraints. We then argue that this logic is modified in microglia. Their embryonic origin, lifelong residence in the CNS, and limited replacement capacity make cellular history a more durable determinant of responsiveness. Within this framework, we define three non-redundant classes of checkpoint-like constraints. The first is developmental licensing, which establishes accessible response space through lineage specification, postnatal maturation, and age-dependent stabilization. The second is metabolic and proteostatic capacity, which determines whether cells can meet the energetic and protein-handling demands required for execution. The third is tissue-derived gating, in which neuronal, astrocytic, and extracellular matrix signals set permissive or non-permissive conditions for transition. Together, these constraints help explain why microglial responses are heterogeneous, why transcriptional state and functional output can diverge, and why disease-associated profiles may reflect stalled or incomplete transitions rather than stable functional identities. This framework shifts attention from descriptive states to constrained transitions. It also suggests that therapy should focus on restoring transition competence rather than simply suppressing or inducing specific microglial states.

Keywords:  checkpoint; developmental licensing; metabolic capacity; microglia; neurodegeneration; neuroimmunology; state transitions; tissue gating

DOI:  https://doi.org/10.3389/fncel.2026.1852176
Front Cell Neurosci. 2026 ;20 1798151

Defining functional states and roles of microglia in neuropsychiatric disorders.

Kinga Szydlowska, Renan Tivanello, Bozena Kaminska.

  Microglia are myeloid cells of the central nervous system (CNS) that acquire a context-specific phenotype and adjust their functions to microenvironmental cues. They participate in immune signaling, synaptic remodeling, and circuit functions, and have emerged as key culprits in neurodevelopmental and psychiatric disorders such as depression, anxiety, autism spectrum disorder (ASD), and schizophrenia. We characterize and discuss different functional state of microglia defined by sc-omics approaches that bring a high resolution to cell functionalities. Subsequently, we review the evidence of microglial states, microglia-driven mechanisms and their impacts on development and progression of neuropsychiatric disorders. In affective mood disorders, chronic stress, glucocorticoid dysregulation, and peripheral inflammation drive microglial nefarious activation. This leads to excessive synaptic pruning, impaired neurotrophic support, glutamate excitotoxicity, and circuit dysfunction in mood-related brain regions, with strong modulation by circadian mechanisms and sex-dependent factors. In ASD, microglia adopt a hybrid activation state characterized by altered inflammatory signaling, dysregulated phagocytosis, and aberrant synaptic pruning, driven by genetic and epigenetic mechanisms, including TREM2, ARID1A, complement components, and calcium-dependent glial signaling, which together disrupt network connectivity and social behavior. In schizophrenia, genetic risk factors related to C4 and DISC1, along with inflammatory and metabolic stress, promote excessive microglia-mediated synapse elimination, cytoskeletal and motility deficits, and secondary neuronal metabolic dysfunction, which correlate with cognitive and negative symptoms. These findings strongly position microglia as a hub and key determinants of CNS homeostasis whose context-dependent dysregulation links immune, genetic, and environmental risk factors to synaptic and behavioral pathology. We discuss which microglial signaling pathways are shared and identify promising therapeutic targets across the neuropsychiatric disease spectrum.

Keywords:  disease-associated microglia; mass cytometry; microglia heterogeneity; microglia plasticity; mood disorders; single-cell RNA sequencing

DOI:  https://doi.org/10.3389/fncel.2026.1798151
J Neuroinflammation. 2026 Jun 02.

Placental and juvenile immune responses to maternal immune activation are differentially regulated by sex chromosomes and gonads across gestation.

Stephanie Salia, Nadine T Burry, Meagan E Hinks, Kerri M Sparkes, Alison M Randell, Alexandre S Maekawa, Nicole Reid, Lucas F Fowler, Rachel Q Kelly, Jai-Lynn Francis, Madison C Youden, Stephanie H G Pelley, Susan G Walling, Ashlyn Swift-Gallant.

  Sex differences are a defining feature of neurodevelopmental disorders (NDDs), with males diagnosed up to four times more frequently than females. Gestational maternal immune activation (MIA) is an environmental risk factor for NDDs that produces stronger behavioral alterations among male offspring. To identify the contributions of sex chromosomes (XX vs. XY) and gonadal development (ovaries vs. testes) in this sex bias, we used the Four Core Genotypes (FCG) mouse model. We assessed placental, fetal, and juvenile brain immune responses, along with juvenile behavioral outcomes, following early (E12.5) or late (E17.5) gestational exposure to Poly(I: C), eliciting a robust systemic maternal immune response. Placental immune profiling revealed distinct sex-specific strategies: XX gonadal females mounted coordinated pro- and anti-inflammatory responses, whereas XY offspring and gonadal males exhibited relative immune suppression, particularly in late gestation, coinciding with the testicular androgen surge. Conversely, fetal brain chemo-cytokine responses 24 h post-MIA were similar across XX females and XY males. However, XY offspring juvenile neuroimmune alterations were associated with increased social avoidance. Early MIA eliminated the typical social advantage of gonadal females, shifting behavior toward male-typical patterns. Together, we identify the placenta as a key site of sex-specific immune responses to MIA and demonstrate that gestational timing, sex chromosome complement, and gonadal signals interact to shape long-term neuroimmune and behavioral outcomes relevant to sex-bias in NDDs.

Keywords:  Cytokines; Fetal brain; Four-core genotypes; Maternal immune activation; Microglia; Neurodevelopmental disorders; Placenta; Sex differences

DOI:  https://doi.org/10.1186/s12974-026-03881-5
J Neuroinflammation. 2026 Jun 02.

GPNMB modulates neutrophil extracellular trap formation: therapeutic implications for ischemic stroke.

Ningning Zong, Jian Chen, Yang Geng, Lixuan Yang, Shengnan Xia, Haiyan Yang, Xinyu Bao, Yun Xu.

  Microglia are key immune-competent cells responding immediately to manipulate post-stroke neuroinflammation to shape the prognosis of stroke. GPNMB was reported to be upregulated after ischemic stroke and might influence the outcome. However, its detailed biological function and mechanism remain elusive. Here, we found that GPNMB was remarkably elevated in the ischemic brain and mainly distributed in microglia. Combining GPNMB knockout mice and recombinant GPNMB protein, we found that GPNMB could alleviate ischemic brain injury. Recombinant GPNMB (rGPNMB) administration could reduce neutrophil extracellular traps (NETs) formation, while knockout of GPNMB promoted NET formation in ischemic stroke. In addition, we found that CD44 functioned importantly in mediating the role of GPNMB inhibiting NET formation and alleviating ischemic brain injury. Depletion of neutrophils or inhibition of NET formation with DNase I could reduce the neuroprotective impact of GPNMB. Mechanistically, GPNMB might inhibit NET formation partly via modulating the Rac-ROS pathway after binding to the CD44 receptor. Finally, our data indicated that delayed rGPNMB administration retained neuroprotective impact in ischemic stroke. Our study revealed the importance of GPNMB in modulating NET formation and suggested a potential target for manipulating post-stroke neutrophil-associated neuroinflammation.

Keywords:  GPNMB; Ischemic stroke; Microglia; NETs; Neutrophil

DOI:  https://doi.org/10.1186/s12974-026-03894-0
Sci Transl Med. 2026 Jun 03. 18(852): eaeb8517

Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction.

Caiwei Guo, Kuchuan Chen, Sarat Vatsavayai, Tetsuya Akiyama, Chang Liu, Yi Zeng, Odilia Sianto, Edith Yang, Juliane Bombosch, Rasheen Powell, Shannon Zhen, Shila Mekhoubad, Ryan D Morrie, Georgiana Miller, Dragana Ilic, Moritz Boll, Euan Parnell, Peter Penzes, Noa Lipstein, Eric M Green, Leonard Petrucelli, William W Seeley, Aaron D Gitler.

TAR DNA binding protein 43 (TDP-43) pathology is a defining pathological hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major feature of TDP-43 pathology is its nuclear depletion, leading to the aberrant inclusion of cryptic exons during RNA splicing. STMN2 and UNC13A have emerged as prominent TDP-43 splicing targets, but the broader impact of TDP-43-dependent cryptic splicing on neuronal function remains unclear. Here, we report previously unidentified TDP-43 splicing targets critical for membrane excitability and synaptic function, including KALRN, RAP1GAP, SYT7, and KCNQ2. Using human stem cell-derived neurons, we showed that TDP-43 reduction induces cryptic splicing and down-regulation of these genes, resulting in impaired excitability and synaptic transmission. In postmortem brains from patients with FTD, these cryptic splicing events occurred selectively in neurons with TDP-43 pathology. Suppressing individual cryptic splicing events using antisense oligonucleotides partially restored neuronal function, and combined targeting almost fully rescued the synaptic deficit caused by TDP-43 loss. Together, our findings provide evidence that cryptic splicing in these synaptic and membrane excitability genes is not only a downstream marker but instead a direct driver of neuronal dysfunction, establishing a mechanistic link between TDP-43 pathology and neurodegeneration in ALS and FTD.

DOI: https://doi.org/10.1126/scitranslmed.aeb8517
bioRxiv. 2026 May 21. pii: 2026.05.20.726454. [Epub ahead of print]

Astrocytic ACSBG1 depletion improves lipid-cytokine signaling and attenuates α-Synuclein pathology in a Parkinson's disease mouse model.

YoungDoo Kim, Bhupesh Vaidya, Jiyoen Kim, Sara Bitar, Femil Joseph Shajan, Ajay Kumar Verma, Hari Krishna Yalamanchili, Shubham Singh, Huda Y Zoghbi.

Astrocytes are key regulators of lipid metabolism, and dysregulated astrocytic lipid processing is implicated in Parkinson's disease (PD) pathogenesis. Our prior genome-wide screens identified ACSBG1, an astrocyte-enriched acyl-CoA synthetase, as a candidate regulator of α-synuclein (α-Syn) levels. However, how ACSBG1 links lipid reprogramming to inflammatory astrocyte activation and α-Syn pathology remains unknown. We compared the transcriptomic, cytokine, and lipid secretomes of TNF-α and IL-1α stimulated primary astrocytes from wild-type (WT) and Acsbg1 knockout (KO) mice. In vivo, we crossed Acsbg1 KO mice with a Thy1-α-Syn PD model to assess behavior, neuroinflammation, synaptic integrity, and α-Syn levels. Following cytokine exposure, Acsbg1 KO astrocytes mounted an attenuated inflammatory transcriptional response, secreting significantly fewer inflammatory mediators (e.g., IL-6, RANTES, MIP-3α) and less long-chain Sphingosine 20:1 than WT astrocytes. Importantly, exogenous Sphingosine 20:1 or cytokines from WT reactive astrocytes induced neuronal α-Syn phosphorylation (pS129). In vivo, Acsbg1 deletion in Thy1-α-Syn mice reduced astrogliosis, rescued synaptic and behavioral deficits, and decreased total and pS129-α-Syn. These findings establish ACSBG1 as a key regulator of inflammatory astrocyte signaling that contributes to α-Syn phosphorylation via specific cytokine and lipid mediators, identifying ACSBG1 as a novel therapeutic target for modulating astrocyte-neuron communication in PD.

DOI: https://doi.org/10.64898/2026.05.20.726454
Neurobiol Dis. 2026 Jun 03. pii: S0969-9961(26)00212-3. [Epub ahead of print] 107467

Early-onset neuroinflammation drives neurodegeneration caused by lysosomal PI(3,5)P2 insufficiency.

Bridget Wong, Morgan Payne, Alexander Silva, Emma Kurniawan, Alison S Eidman, Donald Pizzo, Rachana Rajupalem, Guy M Lenk, Joao A Paulo, Taimur Khan, Eeva-Liisa Eskelinen, Steve P Gygi, Nicholas G Brown, Miriam H Meisler, Andrew S Mendiola, Brandon M Gassaway, Cole J Ferguson.

  Phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] is a lysosomal signaling lipid whose deficiency, caused by mutations in the PIKfyve complex subunits Fig. 4 or VAC14, underlies a spectrum of fatal neurologic diseases including Charcot-Marie-Tooth type 4 J (CMT4J) and amyotrophic lateral sclerosis (ALS). To map the molecular consequences of PI(3,5)P2 insufficiency in the brain, we performed quantitative proteomic and transcriptomic analyses of three mouse lines bearing distinct loss-of-function mutations in Fig. 4 or Vac14, examining the brain at the presymptomatic and end stages. Strikingly, profound neuroinflammation was already present at postnatal day 5 (before significant neurodegeneration), characterized by complement activation, interferon signaling, and parenchymal infiltration of peripheral myeloid cells and T-cells. Isolated mutant microglia exhibited a markedly pro-oxidative transcriptional state with elevated reactive oxygen species, a partly non-cell-autonomous phenotype, being present in microglia from mice with conditional Fig. 4 inactivation in just neurons and astrocytes. Comparison of early (P5) and late (P25) proteomics data revealed that PI(3,5)P2 insufficiency impairs developmental remodeling of the brain proteome: proteins typically upregulated during postnatal maturation failed to accumulate, implicating lysosomal function in neurodevelopment. We identify coordinated elevation of p53, Fas receptor, inflammatory caspases, Gasdermin D, RIPK1, and ZBP1, consistent with multifactorial inflammatory cell death with features of apoptosis, pyroptosis, and necroptosis. Many of the dysregulated proteins are encoded by genes mutated in lysosomal storage disorders, ALS, CMT, Alzheimer's and Parkinson diseases, extending the pathogenic relevance of PI(3,5)P2 insufficiency. Together, these findings establish that early neuroinflammation is a defining - and likely initiating - feature of neurodegeneration caused by disruption of lysosomal PI(3,5)P2.

Keywords:  Astrocyte; Fas; Fig4; Lysosome; Microglia; Neuroinflammation; PI(3,5)P2; PIKfyve; Phosphoinositide; Reactive oxygen species; Vac14; cGAS-STING; p53

DOI:  https://doi.org/10.1016/j.nbd.2026.107467
Neurochem Int. 2026 Jun 04. pii: S0197-0186(26)00084-7. [Epub ahead of print] 106193

Disturbed lipid metabolism in microglia after cerebral ischemia-reperfusion.

Xinyu Li, Shifeng Chu, Zhao Zhang, Naihong Chen.

  Cerebral ischemia-reperfusion injury (CIRI) frequently compromises neurological outcomes in stroke patients despite successful recanalization therapy. While the brain's dense lipid network is integral to immune regulation and tissue repair, the spatiotemporal disruption of lipid metabolism during CIRI remains incompletely synthesized. This review critically evaluates the dynamic alterations in brain lipid profiles following ischemic injury, with a specific focus on the microglial niche. We detail how the excessive influx of extracellular lipid debris forces microglia into maladaptive, lipid-droplet-accumulating states, thereby amplifying lipotoxicity, the neuroinflammatory storm, and microglial vulnerability to ferroptosis. By integrating current evidence on lipid-driven microglial dysfunction, this review highlights the "lipid-inflammation-ferroptosis" axis as a contributing pathogenic mechanism in CIRI. Finally, we discuss the translational potential and current limitations of targeting microglial lipid metabolism, offering a balanced perspective on developing targeted metabolic interventions to enhance stroke recovery.

Keywords:  brain ischemia; ferroptosis; inflammation; lipid metabolism; microglia

DOI:  https://doi.org/10.1016/j.neuint.2026.106193
Mol Neurodegener. 2026 Jun 03.

Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer's knock-in mouse phenotypes.

LaShae Nicholson, Si Jie Tang, Tejaswini Karra, Habiba Abouelatta, Stephen M Strittmatter.

   BACKGROUND: Metabolic dysfunction contributes to the risk and progression of Alzheimer's disease (AD), yet the cellular mechanisms linking impaired insulin signaling and systemic metabolic stress to brain dysfunction remain incompletely defined.
METHODS: We examined the impact of chronic high-fat, high-sugar (HFHS)-induced insulin resistance on metabolic parameters, spatial learning and memory, and in vivo glial activation and neuropathology in Alzheimer's disease knock-in mice expressing human mutant APP and wild-type (WT) tau. Single-nucleus RNA sequencing was performed to resolve cell-type-specific transcriptional responses.
RESULTS: HFHS-diet induced weight gain, hyperglycemia, and glucose intolerance in WT and AD knock-in mice as compared to control diet-fed mice. However, impaired spatial learning was observed only in AD knock-in mice on the HFHS diet, even though there was no greater amyloid-β deposition or tau phosphorylation than in control diet AD knock-in mice. Transcriptomic profiling revealed that HFHS-fed AD mice engaged a distinct glial program, which we termed the metabolic impairment in neurodegeneration (MinD) state, characterized by upregulation of genes involved in synaptic targeting and trans-synaptic signaling shared across microglia, astrocytes, and oligodendrocytes. In parallel, we identified selective induction of the transcription factor Meis2 in cortical Layer 2 inhibitory neurons, which exhibited HFHS-diet transcriptional remodeling enriched for pathways regulating vesicle release, synaptic organization, and membrane excitability. These coordinated glial and neuronal transcriptional changes were associated with reduced inhibitory synapse density in HFHS-fed AD mice.
CONCLUSION: Diet-induced insulin resistance in AD knock-in mice is associated with coordinated glial and inhibitory neuron transcriptional remodeling and cognitive impairment, without alteration of the classical amyloid and tau pathology present in the AD mice fed a lean diet. These findings define cellular programs linking systemic insulin metabolic dysfunction to cortical circuity vulnerability in AD.

Keywords:  Alzheimer’s; Diabetes; Glucose; Inhibitory neurons; Insulin resistance; Microglia; Obesity; snRNA-seq

DOI:  https://doi.org/10.1186/s13024-026-00946-0
Mol Neurobiol. 2026 Jun 03. pii: 671. [Epub ahead of print]63(1):

Soluble TREM1 Contributes to Aging-Related Neurodegeneration via ROBO2/ERK Pathway.

Jing-Wen Qi, Xin-Yu He, Yu-Cheng Gu, Zi-Jian Luo, Rui Duan, Ying-Dong Zhang, Yi Xie, Teng Jiang.

  Aging is recognized as the most significant risk factor for neurodegenerative diseases. Emerging evidence indicates that inflammation contributes to the progression of aging-related neurodegeneration. As a transmembrane immune receptor, triggering receptor expressed on myeloid cells 1 (TREM1) plays a crucial role in the regulation of inflammatory responses. Previously, our research group and others showed that the levels of a soluble form of TREM1 (sTREM1) were increased in the plasma or cerebrospinal fluid (CSF) of patients with Alzheimer's disease, the most common type of neurodegenerative disease among the elderly. Moreover, the elevated levels of CSF sTREM1 were closely associated with a more rapid rate of hippocampal degeneration in cognitively impaired older adults. However, the precise mechanisms by which sTREM1 contributes to aging-related neurodegeneration remain largely unclear. In this study, by utilizing senescence accelerated mouse prone 8 mice, an animal model of accelerated aging, we confirmed that serum sTREM1 levels were significantly increased during the aging process. Importantly, we demonstrated that roundabout guidance receptor 2 (ROBO2) functioned as a receptor for sTREM1 in hippocampal neurons, and its expression was also upregulated with aging. Additionally, we revealed for the first time that knockdown of neuronal ROBO2 mitigated aging-related hippocampal synaptic degeneration and cognitive impairments. Furthermore, we provided the first evidence that sTREM1 reduced the expression of synaptic proteins via the ROBO2/extracellular signal-regulated kinase pathway. These findings elucidated the mechanisms through which sTREM1 contributed to aging-related neurodegeneration and suggested that the inhibition of sTREM1-mediated signaling might represent a novel therapeutic strategy for the treatment of neurodegeneration and cognitive decline induced by aging.

Keywords:  Aging; Alzheimer’s disease; Inflammatory marker; Neurodegeneration; ROBO2; sTREM1

DOI:  https://doi.org/10.1007/s12035-026-05987-6
Nat Commun. 2026 Jun 05.

Microglial CD31 suppresses Aβ clearance and promotes Alzheimer pathology in 5×FAD mice.

Qiuzhi Zhou, Fei Sun, Yao Zhang, Xiaojian Cao, Mengzhu Li, Haitao Yu, Tao Jiang, Shihong Li, Weixia Wang, Jiazhao Xie, Ting He, Yanchao Liu, Dan Ke, Xiao-Chuan Wang, Peng Xu, Enjie Liu, Hong Chen, Jian-Zhi Wang.

Microglia play crucial roles in Alzheimer's disease (AD), yet the molecular mechanisms are unclear. Here, we show that CD31, a recognized endothelial marker, is predominantly expressed in microglia but not in neurons or astrocytes, and it is significantly elevated in the brains of AD patients and mouse models. Microglia-specific CD31 knockdown in 5xFAD mice substantially attenuated the dysregulated transcription networks, suppressed microglia hyperactivation and the disease-associated microglia (DAM), mitigated Aβ deposition and inflammation, and eventually improved cognitive functions in mice. Mechanistically, CD31 knockdown damaged the simultaneous recruitment of Src homology phosphatase 2 (SHP2) and STAT3, leading to a reduced dephosphorylation and enhanced activation of STAT3, a transcription factor. STAT3 activation increased transcription of membrane metalloendopeptidase (MME) and promoted Aβ clearance. Collectively, this study identifies microglial CD31, by regulating SHP2-STAT3-MME axis, plays a role in AD pathogenesis and targeting CD31 is promising in AD drug development.

DOI: https://doi.org/10.1038/s41467-026-74037-5
J Biomed Sci. 2026 Jun 01. pii: 57. [Epub ahead of print]33(1):

Distinct and combined interferon-ɑ/β-receptor-1 loss in neurons and astrocytes disrupt brain energy metabolism and drive Parkinsonian dementia.

Erika B Villanueva, Zala Zebec, Marina Cisquella-Serra, Jon Lundstrøm, Jens V Andersen, Filippa L Qvist, Emil W Westi, Andrea Marin, Gisela Jimenez-Duran, Lluís Riera-Ponsati, Emilie Tresse, Oliver Kretz, Desiree Loreth, Tobias Goldmann, Thomas Blank, Marco Prinz, Blanca I Aldana, Matthias Mann, Niels H Skotte, Shohreh Issazadeh-Navikas.

   BACKGROUND: Dysregulated interferon-alpha/beta-receptor 1 (IFNAR1) signaling was recently identified to contribute to the development of sporadic Parkinson's disease (PD) into PD with Dementia (PDD). The molecular, cellular, and phenotypic impacts of brain IFNAR1 loss in aging have not been explored in vivo, which may reveal novel disease mechanisms and therapeutic targets.
METHODS: Single nuclei RNA sequencing (snRNA-seq), liquid chromatography tandem mass spectrometry (LC-MS/MS), functional metabolic mapping, flow cytometry, quantitative PCR (qPCR), in situ hybridization, immunofluorescence and immunohistochemistry, Western blotting, and behavior analyses were used to investigate the molecular, cellular, and phenotypic impacts of IFNAR1 loss in vivo.
RESULTS: Baseline IFNAR1 expression varies among major brain cell types, including neurons and astrocytes, and is differentially affected in PD and Lewy Body Dementia patients compared to unaffected controls. Neuron- and astrocyte-specific transcriptomic and proteomic alterations in Ifnar1-/- mice implicate mitochondrial defects, defective mitophagy, and synergistic dysfunctional neurotransmission upon IFNAR1 loss, leading to glucose hypermetabolism measured by functional metabolic analysis. Consequently, Ifnar1-/- mice exhibited PDD-like pathogenesis, including dopaminergic cell loss in the substantia nigra, cortical neurodegeneration, Lewy-body-like inclusions, neuroinflammation, and progressive PDD-like behavior deficits. Brain cell-specific IFNAR1 loss examined in vivo revealed delayed but distinct development of PDD-like phenotypes, where neuropathology, motor, and cognitive behavior deficits were recapitulated only in mice lacking neuronal IFNAR1, and behavior resembling neuropsychiatric abnormalities recapitulated only in mice lacking astrocytic IFNAR1.
CONCLUSIONS: IFNAR1 plays a crucial role in brain and mitochondrial homeostasis, loss of which results in neurodegeneration and neuropathology resembling PDD. Differential neuropathology and behavioral outcomes upon neuronal vs astrocytic IFNAR1 loss emphasizes a need for understanding neurodegenerative pathophysiology in cell-specific contexts. Trial registration Not applicable as the study does not include a clinical trial.

Keywords:  Brain energy metabolism; IFNAR1; LC–MS/MS; Mitochondria; Parkinson’s disease dementia; SnRNA-seq

DOI:  https://doi.org/10.1186/s12929-026-01257-8
Cell Death Dis. 2026 May 30. pii: 517. [Epub ahead of print]17(1):

Microglia in diffuse midline glioma contribute to extracellular matrix remodelling and cancer cell invasion.

Lily Keane, Martin Škandík, Mercedes Posada-Pérez, Raj Bose, John Desito, Esmee van der Linde, Pinelopi Engskog-Vlachos, Sandra Ceccatelli, Adam L Green, Bertrand Joseph.

Diffuse midline glioma, H3K27-altered (DMG), is an aggressive and uniformly fatal paediatric brain tumour arising in midline structures and characterised by substantial microglial infiltration. We investigated whether microglia adopt a reactive state in response to DMG cells that functionally contributes to tumour progression. Transcriptomic profiling of microglia exposed to DMG, H3K27M cells, together with analysis of tumour associated myeloid cells isolated from DMG patient biopsies, revealed a pronounced upregulation of extracellular matrix (ECM) components, including fibronectin. Single cell transcriptomic analysis further identified microglia as the primary fibronectin expressing cell population within human DMG, H3K27M tumours. Functional invasion assays using a panel of patient-derived DMG, H3K27M cells, revealed that microglia-derived fibronectin significantly enhances tumour cell invasiveness, while its chemical inhibition with RGDS peptide or Avapritinib or its genetic silencing using small-interfering RNAs effectively suppresses invasion. Across independent patient cohorts (Kids First, PNOC, and CBTTC), and in archival tissues, DMG tumours were found to exhibit elevated expression of ECM components, and high fibronectin expression that correlated with poor prognosis. These findings suggest that microglia actively contribute to DMG invasiveness through ECM component production, identifying fibronectin as a potential therapeutic target in this lethal paediatric cancer.

DOI: https://doi.org/10.1038/s41419-026-08891-y
Nat Commun. 2026 Jun 02.

Pre-treatment bacterial cell states shape antibiotic-induced transcriptional reprogramming and survival.

Qiang Liu, Zehui Yu, Xiaoli Liu, Amy Iverson, Tyler Simmons, Jason W Rosch, Peijun Ma.

Bacteria can survive antibiotic treatment through phenotypic adaptation, a process that is often transient and involves heterogeneous transcriptional reprogramming. However, how this transcriptional heterogeneity is generated and how it influences antibiotic survival remains unclear. Here, we use bacterial single-cell RNA sequencing and functional assays in Klebsiella pneumoniae to characterize transcriptional heterogeneity and examine how pre-treatment cell states are associated with antibiotic-induced responses and survival outcomes. Using growth phase as a biologically meaningful axis of transcriptional variation, we reveal that even within an isogenic population, distinct transcriptional responses can be induced and co-contribute to survival. These responses are shaped by the cell's pre-treatment transcriptional state and the mechanism of antibiotic action. Genetic and environmental perturbations, such as rpoS deletion and nutrient supplementation, shift pre-treatment cell states and alter survival frequencies. Our findings establish the biological significance of transcriptional heterogeneity shaped by pre-treatment cell states, providing a systems-level framework for understanding bacterial antibiotic response and suggesting strategies to enhance antibiotic efficacy by modulating cell states.

DOI: https://doi.org/10.1038/s41467-026-73949-6
J Neuroinflammation. 2026 Jun 05.

Microglial galectin-3 disrupts parvalbumin interneurons and hippocampal synchrony, driving cognitive deficits.

Min Jia, Hua Shao, Si-Qi Ma, Wen-Xue Liu, Meng Cai, Tong Zhu, Shan Xu, Gui-Zhou Li, Shuai-Fei Lu, Jin-Chun Shen, Jiang Chen, Yun Stone Shi, Kenji Hashimoto, Guang-Fen Zhang, Mu-Huo Ji, Jian-Jun Yang.

  Sepsis-associated encephalopathy (SAE), a devastating neurological complication of systemic inflammation, affects approximately 70% of patients with sepsis. It not only increases mortality but also leaves survivors with persistent cognitive deficits. However, the mechanisms underlying SAE progression remain incompletely understood. Here, using a lipopolysaccharide (LPS)-induced mouse model of SAE, we identify microglial galectin-3 (Gal-3) as a central pathogenic mediator driving systemic inflammation-induced cognitive impairment. Mechanistically, systemic LPS challenge robustly upregulates microglial Gal-3, which in turn activates Toll-like receptor 2 (TLR2) signaling and promotes NLRP3/AIM2 inflammasome assembly. This microglia-driven inflammatory cascade substantially exacerbates local oxidative stress, leading to selective structural and functional impairment of hippocampal parvalbumin (PV) interneurons. Dysfunction of these critical interneurons disrupts theta/gamma oscillations, impairs excitatory/inhibitory (E/I) balance and synaptic plasticity, and ultimately results in severe cognitive decline. Supporting this pathogenic cascade, pharmacological inhibition of Gal-3 with TD139 effectively suppresses TLR2/inflammasome activation, attenuates oxidative stress, and prevents memory deficits. Conversely, targeted rAAV-mediated overexpression of Gal-3 in microglia is sufficient to recapitulate neuroinflammation, PV-interneuron injury, oscillatory abnormalities, and cognitive impairment. Finally, chemogenetic reactivation of hippocampal PV interneurons using DREADDs restores theta/gamma oscillations and ameliorates LPS-induced cognitive deficits. Together, our findings define a coherent pathogenic axis linking microglial Gal-3 upregulation to PV interneuron-dependent network desynchronization and highlight Gal-3 as a promising therapeutic target for inflammation-associated cognitive disorders.

Keywords:  Cognitive impairments; Galectin-3; Hippocampal oscillations; Microglia; Neuroinflammation; PV interneurons

DOI:  https://doi.org/10.1186/s12974-026-03889-x
bioRxiv. 2026 May 18. pii: 2026.05.14.725257. [Epub ahead of print]

Integrated Lipidomics and Nitro-Fatty Acid Profiling Link Adipose Redox Imbalance to Alzheimer's Disease-Related Neurovascular Injury.

Sukkum Ngullie Chang, Praveen Kumar Guttula, Kirti Agrawal, Elnaz Sheikh, William N Beavers, Timothy D Allerton, Manas Ranjan Gartia.

Alzheimer's disease (AD) is increasingly recognized as a systemic disorder in which peripheral metabolic and redox dysfunction affects neurovascular injury and amyloid pathology. However, the lipid-redox mechanisms linking adipose tissue dysfunction to AD are less explored. Here, we applied an integrated multi-omics and imaging approach to investigate adipose lipid remodelling that leads to nitric oxide (NO)-derived nitro-fatty acid modifications and their effects on β-amyloid and VEGF in the hippocampus of APP/PS1 mice. Targeted lipidomics revealed broad suppression of lysophospholipids and membrane phospholipids (LPC, PC, PE, PG) in gonadal white adipose tissue (gWAT), consistent with impaired membrane turnover and mitochondrial lipid deficiency. Untargeted lipidomics demonstrated accumulation of ceramides, triacylglycerols, monoacylglycerols, and phosphatidic acids, indicating lipotoxicity and disrupted lipid flux. Oxidized lipid mediator profiling showed increased 13-HODE, 12-HETE, and 14-HDHA. Further, Raman microscopy mapping revealed a shift from protective nitro-oleic acid toward increased nitration of polyunsaturated fatty acids. These lipid abnormalities coincided with increased adipose expression of redox and inflammatory markers, including NOX4 and TNF-α, and impaired mitochondrial redox metabolism assessed by fluorescence lifetime imaging (FLIM). Citrulline and nitrite treatments partially normalized adipose lipid-redox signatures. Citrulline restored phospholipid remodeling and nitro-oleic acid signaling, whereas nitrite preferentially enhanced stress-associated signaling lipids. Importantly, both interventions reduced hippocampal β-amyloid burden and restored VEGF expression, with citrulline producing the strongest neurovascular rescue. These findings identify adipose lipid-redox imbalance as a systemic contributor to neurovascular pathology in AD and highlight NO-directed metabolic modulation as a strategy to mitigate disease-associated lipid dysfunction.

DOI: https://doi.org/10.64898/2026.05.14.725257
Nat Cell Biol. 2026 Jun 01.

Emerging roles of ferroptosis in modulating the immune landscape of glial tumours.

Michael G Argenziano, Taruna V Neelakantan, Colin Sperring, Oluwaseyi Adeuyan, Dominique M O Higgins, Jeffrey N Bruce, Betty Y S Kim, Athanassios Dovas, Peter Canoll, Michael Lim, Brent R Stockwell, Matei A Banu.

The brain offers a unique environment for cancer, with limited access to nutrients and highly regulated immune surveillance. Here we explore the role of ferroptosis, a form of metabolically regulated cell death driven by iron-mediated lipid peroxidation, in shaping immune-cell composition and function in glial tumours. We review the complex metabolic crosstalk between cell populations regulating ferroptosis in the glioma milieu. Ferroptosis induces polarization of resident microglia and controls the cytotoxic roles of CD8+ T cells and the immunosuppressive effects of regulatory T cells. We discuss recently uncovered mechanisms of ferroptosis-driven immune evasion and the impact on tumour evolution. Additionally, we analyse mechanisms of synergy in combinations incorporating ferroptosis-inducing agents and immunotherapies, including immune checkpoint blockade and adoptive cell therapies, which aim to induce effective immune responses and durable control in gliomas.

DOI: https://doi.org/10.1038/s41556-026-01972-2
Alzheimers Dement. 2026 Jun;22(6): e71542

Stress, stress systems, and Alzheimer's disease.

Stephanie G Eberly, Chayarndorn Phumsatitpong, Catherine E Munro, Thomas C Neylan, Daniela Kaufer, Alexander J Ehrenberg.

  Stress is increasingly recognized as an important, modifiable factor for Alzheimer's disease (AD), yet its roles in initiation, progression, and outcomes remain incompletely elucidated. Epidemiologic studies link chronic stress, early-life adversity, and trauma to increased AD risk, while experimental models have uncovered mechanisms by which stress hormones directly drive core AD pathological processes, including amyloid beta and tau aggregation, neuroinflammation, and neurodegeneration. Complicating the relationship, brain structures that regulate the stress response are themselves selectively vulnerable to early degeneration in AD. As these circuits degenerate, interpreting changes in stress biomarkers becomes more challenging, with physiological measures potentially decoupling from perceived stress. Here, we review evidence connecting stress to AD pathophysiology as both a risk factor and a driver, examine how the degeneration of stress neuroendocrine systems accelerates disease progression, and discuss implications for intervention and clinical trial design.

Keywords:  Alzheimer's disease; cortisol; dementia; hypothalamus‐pituitary‐adrenal axis; neuromodulatory systems; stress; sympathetic‐adrenal‐medullary axis

DOI:  https://doi.org/10.1002/alz.71542
Autophagy. 2026 Jun 03.

Reticulophagy limits Alzheimer's disease pathology through FAM134B-dependent APP clearance.

Yuting Zhang, Jun Sun, Yixian Cui.

  Selective autophagy maintains organelle and proteome homeostasis through receptor-mediated degradation of damaged membranes and aggregation-prone proteins. Although autophagy dysfunction and endoplasmic reticulum (ER) abnormalities are prominent features of Alzheimer's disease (AD), whether reticulophagy directly contributes to amyloid precursor protein (APP) turnover has remained unclear. We identify FAM134B/RETREG1 as a specific receptor that recognizes ER-localized APP and promotes its lysosomal degradation through LC3-dependent reticulophagy. In AD patient samples and 5XFAD mice, epigenetic repression of FAM134B limits TFEB/TFE3-dependent transcription, resulting in impaired ER turnover, APP accumulation, and exacerbated amyloid pathology. Restoration of wild-type, but not LIR-mutant, FAM134B rescues reticulophagy, reduces APP and Aβ accumulation, preserves neuronal integrity, and improves cognition in 5XFAD mice. These findings establish impaired reticulophagy as an upstream pathogenic mechanism in AD and highlight FAM134B-mediated ER turnover as a potential therapeutic strategy for limiting amyloidogenic APP accumulation.

Keywords:  5XFAD mice; FAM134B/RETREG1; MAP1LC3B/LC3B; TFE3; TFEB; amyloid beta precursor protein; autophagy; epigenetic modification; lysosome; receptor

DOI:  https://doi.org/10.1080/15548627.2026.2684514
J Neurochem. 2026 Jun;170(6): e70467

Brain Bioenergetics in Aging: Neurovascular and Neurometabolic Coupling and Fuels: 15th International Conference on Brain Energy Metabolism.

Kelly L Drew, Robert Zorec, Nina Vardjan, Marko Kreft, Mary C McKenna.

This Preface introduces the Special Issue entitled, "Brain Bioenergetics in Aging: Neurovascular and Neurometabolic Coupling and Fuels," which is comprised of manuscripts contributed by invited speakers and program/organizing committee members who participated in the 15th International Conference on Brain Energy Metabolism (ICBEM) held on September 17-21, 2024, in Ljubljana, Slovenia. The conference covered the latest developments in research related to (i) coordination of neurometabolic and neurovascular coupling and homeostasis of energy metabolism in healthy aging and Alzheimer's disease, (ii) in vivo imaging modalities for study of neurometabolic and neurovascular coupling, (iii) mitochondrial and metabolic alterations and resilience in injured and aging brain, (iv) astrocyte metabolism in Alzheimer's and other neurodegenerative diseases, (v) microglial support of neuronal metabolism and role in neurodegeneration, (vi) neuronal mitochondria and disease, (vii) lipids and transporters in brain function, metabolism and Alzheimer's disease, and (viii) metabolic regulation of cognition. The special issue contains 19 manuscripts on these topics.

DOI: https://doi.org/10.1111/jnc.70467
Nature. 2026 Jun 02.

Bang! Exploding immune cells splatter potent toxins everywhere.

Amanda Heidt.



Keywords:  Cell biology; Immunology

DOI:  https://doi.org/10.1038/d41586-026-01766-4