bims-micgli 2026-08-09 papers

bims-micgli

Biomed News

on Microglia

Issue of 2026–08–09
nineteen papers selected by
Matheus Garcia Fragas, Universidade de São Paulo

Immunoproteasome Deficiency Impairs Microglial Clearance and Worsens Tau and Amyloid Pathology.
When less is more and when it isn't: Microglial Spi1 and the limits of what we know.
Predicting Relevant Microglia-Associated Cell-Cell Communication Pathways in Alzheimer's Disease: A Role for SPP1.
Progranulin deficiency-induced lysosomal dysfunction drives maladaptive myeloid cell states through the MITF/TFE transcription factors.
Microglial 5-LOX-activating protein antagonism alleviates leukotriene-driven neuroinflammation.
Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.
Interleukin-6 trans-signalling as a selectively targetable driver of neurodegeneration.
Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases.
CXCL10 contributes to female-specific pathological progression in tauopathy model mice.
Hematopoietic Growth Factors Induce More Extensive Transcriptomic Remodeling in Cerebral Monocytes/Macrophages than in Microglia During the Chronic Phase of Traumatic Brain Injury.
Cholesterol enhances lysosome-autophagosome fusion for better α-synuclein clearance in GBA L444P-mutated Parkinson disease.
Accumulation of Lipid Droplets in Microglia following Neonatal Brain Hypoxia-Ischemia.
A reproducible three-dimensional model of human brain tissue to investigate physiological and disease-associated microglia phenotypes.
Antigen presentation by CD40+MHC-II+ astrocytes promotes CNS autoimmunity.
Microglial CX3CR1 signaling mediates synaptic pruning in degenerative cervical myelopathy.
Tunneling nanotubes in the nervous system: The fourth pillar of brain connectivity.
Organelle contact sites as spatial regulators of lipid fate in adipose tissue metabolic disease.
Optimization of a neuron-microglia co-culture model to explore cell-to-cell interaction dynamics.
Temporal changes in metabolism guide oligodendrocyte precursor cell dynamics in aging and multiple sclerosis.

bioRxiv. 2026 Jul 20. pii: 2026.07.14.738427. [Epub ahead of print]

Immunoproteasome Deficiency Impairs Microglial Clearance and Worsens Tau and Amyloid Pathology.

Malavika Srikanth, Shan Jiang, Steven M Wellman, Shrita Sarkar, Daniella E Lorman, Timothy Lantin, Avery M Runyan, Mayank Kumar, Eric Sydney, Helen Y Figueroa, Mu Yang, Qi Wang, Natura Myeku.

Immunoproteasome induction is prominent in Alzheimer's disease (AD), but whether it protects proteostasis or amplifies neuroinflammation remains unresolved. Here, we generated immunoproteasome-deficient PS19 tauopathy and APP/human tau double-knock-in mice by crossing each disease model with L7M1 mice lacking two immunoproteasome catalytic subunits. Immunoproteasome deficiency increased phospho-tau burden, exacerbated amyloid-β pathology and heightened microglial reactivity without suppressing constitutive 26S proteasome activity. In primary microglia and longitudinal two-photon imaging, immunoproteasome-deficient microglia engaged and engulfed tau aggregate-bearing material but failed to resolve internalized cargo, revealing a post-engulfment degradative checkpoint. Single-nucleus transcriptomics identified a remodeled P2ry12 low /Trem2 high microglial state with impaired phagolysosomal and mitochondrial programs. Reanalysis of human single-nucleus transcriptomic datasets showed that reduced microglial immunoproteasome expression was associated with cargo-processing gene-program changes similar to those observed in immunoproteasome-deficient mouse microglia. Together, these findings identify immunoproteasome biogenesis as a protective glial stress response that supports microglial aggregate clearance in AD.

DOI: https://doi.org/10.64898/2026.07.14.738427
Neuron. 2026 Aug 05. pii: S0896-6273(26)00485-X. [Epub ahead of print]114(15): 2669-2671

When less is more and when it isn't: Microglial Spi1 and the limits of what we know.

Radosveta Koldamova, Nicholas F Fitz, Iliya Lefterov.

Microglia are key players in Alzheimer's disease, but the transcriptional control of their phagocytic function remains unclear. Kim et al. show that mouse microglial Spi1 deletion worsens amyloid pathology by impairing Aβ clearance through Syk, Lyn, and Fcgr1, providing new insight into PU.1-dependent regulatory networks and microglial functions in neurodegeneration.

DOI: https://doi.org/10.1016/j.neuron.2026.06.017
Glia. 2026 Oct;74(10): e70210

Predicting Relevant Microglia-Associated Cell-Cell Communication Pathways in Alzheimer's Disease: A Role for SPP1.

Janssen M Kotah, Marina Trombetta Lima, Esmée C Dragt, Asimenia Voulgaroglou, Nieske Brouwer, Inge R Holtman, Susanne M Kooistra, Bart J L Eggen.

  Microglia play a key role in the pathophysiology of Alzheimer's Disease (AD) and their increased heterogeneity likely affects disease progression. We previously identified distinct microglial signatures that were enriched in AD donors and associated with amyloid and tau, respectively. Here we generated a snRNAseq dataset from postmortem control and AD cases and analyzed alterations in cell-cell communication pathways that might be relevant to AD pathophysiology. One signaling pathway perturbed in AD cases involved SPP1, and while this pathway was also present in control samples, microglia-microglia SPP1 signaling was restricted to AD donors. Further analyses within microglia-microglia signaling predict AD-specific induction of GAS6-AXL signaling (from inflammatory and ribosomal microglia), and SPP1-ITGAV/ITGB5 signaling (from disease-associated and inflammatory microglia, among others). Together, these findings might in part explain the increased microglia phagocytic profile described in AD. RNAscope confirmed enrichment of SPP1 expressing microglia near amyloid plaques in AD brain tissue samples. These data indicate altered cellular communications between microglia in the AD brain.

Keywords:  Alzheimer's disease; SPP1; cell–cell communication; microglia; single nucleus RNA sequencing

DOI:  https://doi.org/10.1002/glia.70210
Immunity. 2026 Aug 03. pii: S1074-7613(26)00308-0. [Epub ahead of print]

Progranulin deficiency-induced lysosomal dysfunction drives maladaptive myeloid cell states through the MITF/TFE transcription factors.

Leon Tejwani, Catherine M Heffner, Christopher Balak, Lukas L Skuja, David Tatarakis, Anil Rana, Seungyoon B Yu, Gabriel A Fitzgerald, Connie Ha, Gabrielly Lunkes de Melo, Elizabeth W Sun, Matthew J Simon, Jason C Dugas, Johann Chow, Elliot Thomsen, Lily Sarrafha, Eric Liang, Neal Gould, Jung Suh, Thomas Sandmann, Christopher K Glass, Gilbert Di Paolo.

  Lysosomal dysfunction in myeloid cells is increasingly implicated in neurodegenerative diseases. To examine the interplay between lysosomal health and cellular state, we performed multi-omic profiling of myeloid cells from brains of aged mice lacking progranulin (Grn-/- mice), a lysosomal protein linked to neurodegeneration. Single-cell RNA sequencing identified a microglial subpopulation defined by GPNMB expression, which displays hallmarks of lysosomal stress, including altered lysosomal protein expression, lipofuscinosis, and metabolic and lipid dysregulation. Epigenetic profiling of Grn-/- microglia revealed an enrichment of MITF/TFE transcription factor motifs at active enhancers, and deletion of these factors reversed the Grn-/--specific myeloid cell transcriptional signature. Diverse lysosomal perturbations drove a common transcriptional and functional signature, with conditions that induce lysosomal deacidification closely phenocopying progranulin deficiency. Finally, compensatory GPNMB induction in Grn-/- myeloid cells promoted lysosomal acidification, and loss of myeloid cell GPNMB exacerbated neurotoxicity. Our findings link lysosomal health with epigenetic, transcriptional, and functional myeloid cell states associated with neurodegeneration.

Keywords:  disease-associated microglia; epigenetics; frontotemporal dementia; granulin; lipids; lipofuscin; lysosomal pH; lysosomes; macrophages; microglia

DOI:  https://doi.org/10.1016/j.immuni.2026.07.009
Acta Neuropathol. 2026 Aug 04. pii: 16. [Epub ahead of print]152(1):

Microglial 5-LOX-activating protein antagonism alleviates leukotriene-driven neuroinflammation.

Julia Konings, Fleur Mingneau, Serhii Chornyi, Cathrin E Hansen, Rianne T M van der Brugt, Tessa G van Elk, Laura Bolkaerts, Bo Batens, Gábor Tóth, Ingela Lanekoff, Frédéric M Vaz, Alessio Cardilli, Marie Sels, Susanne M A van der Pol, Helga E de Vries, Martin Giera, Oliver Werz, Sofie Kessels, Sanne G S Verberk, Jeroen F J Bogie, Merel Rijnsburger, Jerome J A Hendriks, Gijs Kooij.

  In multiple sclerosis (MS), the chronic, unresolved nature of neuroinflammation within the central nervous system (CNS) remains a major obstacle for effective therapeutic intervention. This challenge arises primarily due to an incomplete understanding of the dysregulated inflammatory and pro-resolving pathways underlying MS lesion progression. Bioactive lipid mediators (LMs), biosynthesized through the coordinated actions of specific enzymes like lipoxygenases (LOX) and cyclooxygenases (COX), are key regulators of both the initiation and resolution of an inflammatory response; however, their spatial organization and functional role during MS pathology have not been fully elucidated. Here, by using pneumatically assisted nanospray desorption electrospray ionization (PA nano-DESI) mass spectrometry imaging and immunohistochemistry, we reveal an increase in the LM leukotriene B4 (LTB4) in human MS white matter compared to controls, with further enrichment in MS lesions relative to perilesional areas, alongside elevated microglial 5-LOX activating protein (FLAP) expression. Pharmacological antagonism of FLAP suppresses LTB4 biosynthesis in human-induced pluripotent stem cell (iPSC)-derived microglia with only marginal effects on the microglia transcriptional phenotype as determined by RNA sequencing. Moreover, in vivo FLAP antagonism ameliorates disease severity and spinal cord inflammatory gene expression in the experimental autoimmune encephalomyelitis (EAE) model, an animal model of MS, in both a prophylactic and therapeutic settings. This coincided with reduced local LTB4 biosynthesis and reduced levels of inflammatory monocytes within the spinal cord during EAE. Together these findings establish the FLAP/LTB4 axis as a driver of neuroinflammation and a druggable therapeutic target for chronic inflammatory CNS disorders like MS.

Keywords:  5-Lipoxygenase activating protein (FLAP); Experimental autoimmune encephalomyelitis (EAE); Leukotriene B4 ; Lipidomics; Microglia; Multiple sclerosis; Neuroinflammation; PA nano-DESI MSI,

DOI:  https://doi.org/10.1007/s00401-026-03055-w
Mol Neurobiol. 2026 Aug 01. pii: 800. [Epub ahead of print]63(1):

Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.

Mengqi Chu, Miaomiao Tan, Xulin Gan, Shumao Cui, Liyun Shi.

  Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose an urgent global health challenge. Growing evidence establishes microglia-driven neuroinflammation as a key driver of disease onset and progression, with mitochondrial dysfunction emerging as an early trigger of microglial activation. This review comprehensively summarizes current progress on how mitochondrial alterations regulate microglial activation across AD, PD, and ALS. We identify conserved mechanisms including metabolic reprogramming, impaired mitophagy, and inflammatory signaling, though Aβ, α-synuclein, and TDP-43 engage these pathways through disease-specific molecular routes. Therapeutic strategies targeting microglial mitochondria, including cGAS-STING and NLRP3 inhibitors, TREM2 agonists, and mitochondrial transplantation, remain largely preclinical. Emerging targets such as OLFML3 and GPNMB require functional validation in microglia. Collectively, this review underscores that preserving microglial mitochondrial health represents a promising therapeutic frontier and identifies key priorities for translating these strategies toward clinical application.

Keywords:  Microglia; Mitochondria; Neurodegenerative diseases

DOI:  https://doi.org/10.1007/s12035-026-06091-5
Trends Neurosci. 2026 Aug 07. pii: S0166-2236(26)00140-2. [Epub ahead of print]

Interleukin-6 trans-signalling as a selectively targetable driver of neurodegeneration.

Grace Risby-Jones, John D Lee, Jenny N Fung.

  Interleukin-6 (IL-6) exerts protective and pathogenic effects in the central nervous system through distinct receptor-signalling modes. Classical signalling via membrane-bound IL-6 receptor (IL-6R) is often associated with homeostatic and reparative functions, whereas trans-signalling, mediated by soluble IL-6R, expands IL-6 responsiveness to gp130-expressing cells and may promote chronic inflammation. Emerging evidence implicates dysregulated IL-6 trans-signalling in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Here, we review mechanisms linking IL-6 trans-signalling to immune, glial, neuronal, and vascular dysfunction in neurodegeneration. We highlight key knowledge gaps and discuss whether selective targeting of trans-signalling can limit inflammatory pathology while preserving beneficial classical IL-6 functions.

Keywords:  astrocytes; biomarker stratification; blood–brain barrier; cytokine signalling; microglia; neuroinflammation

DOI:  https://doi.org/10.1016/j.tins.2026.07.002
Immunity. 2026 Aug 03. pii: S1074-7613(26)00307-9. [Epub ahead of print]

Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases.

Christopher D Balak, Johannes C M Schlachetzki, Addison J Lana, Elizabeth West, Christine Hong, Jordan DuGal, Yi Zhou, Benjamin Li, Nathanael J Spann, Payam Saisan, Vishal Sarsani, Kilian L Kleemann, Xiaoming Zhang, Martina P Pasillas, Sydney O'Brien, Juliette A Bokor, Philip L S M Gordts, Oleg Butovsky, Beth Stevens, Fredrik Kamme, Christopher K Glass.

  Lysosomal dysfunction is causally linked to neurodegeneration in many lysosomal storage disorders and is associated with various age-related neurodegenerative diseases. Here, we investigated the question of underlying mechanisms using a mouse model of mucopolysaccharidosis type IIIA caused by deficiency of the lysosomal hydrolase SGSH. Systematic imaging and transcriptomic and epigenetic studies revealed microglia to be the most profoundly impacted cell type in brains of Sgsh-deficient mice. Further investigation identified dominant and context-dependent roles of members of the MITF/TFE family as major drivers of microglia-specific epigenetic and transcriptional changes resulting from lysosomal stress that are dependent on collaborative interactions with AP-1/ATF, C/EBP, and PU.1/ETS transcription factors. Features of the transcriptomic and epigenetic alterations observed in murine Sgsh deficiency were also observed in microglia derived from mouse models of age-related neurodegeneration and in human Alzheimer's disease patients. These findings reveal common and disease-specific transcriptional mechanisms associated with disease-associated microglia phenotypes.

Keywords:  ChIP-seq; MITF; MPS-IIIA; TFE3; disease-associated microglia; epigenetics; lysosomal storage disorder; lysosome; microglia; neurodegeneration

DOI:  https://doi.org/10.1016/j.immuni.2026.07.008
J Neuroinflammation. 2026 Aug 05. pii: 268. [Epub ahead of print]23(1):

CXCL10 contributes to female-specific pathological progression in tauopathy model mice.

Ryohei Uenishi, Rinna Kawata, Tatsuya Manabe, Yukio Matsuba, Naomi Mihira, Toru Takeo, Takaomi C Saido, Masanori Hijioka, Takashi Saito.

  Neuroinflammation plays a central role in the progression of tauopathy via the glial activation and T cell accumulation in the brain parenchyma. However, the key molecular mediators that link these processes to tau pathology remain poorly understood.Here, we identify C-X-C motif chemokine ligand 10 (CXCL10) as a critical inflammatory mediator that is markedly upregulated in the brains of P301S-mutant tau transgenic mice and associated with regions of severe tau pathology. Spatial transcriptomics revealed that CXCL10 is mainly expressed by disease-associated astrocytes, defining an astrocytic CXCL10-rich inflammatory niche within the tauopathy brain.Genetic ablation of Cxcl10 significantly attenuated soluble and insoluble tau accumulation selectively in 9-month-old female mice, whereas no attenuation of tau accumulation was observed at 11-12 months of age. In addition, Cxcl10 deficiency significantly prolonged survival specifically in female tauopathy mice. Although Cxcl10 deficiency reduced the number of parenchymal T cells in both sexes, this reduction did not explain the female-specific effects. Furthermore, Cxcl10 deficiency did not alter neurodegeneration and motor dysfunction, suggesting that downstream sex-dependent regulatory mechanisms govern tauopathy progression. Moreover, CXCL10-dependent inflammatory activation within the local microenvironments was observed in both sexes. Although the molecular mechanisms underlying the sex-dependent effects of CXCL10 remain unclear, these findings suggest that CXCL10 contributes to tau pathology through multiple inflammatory pathways.In summary, our findings identify CXCL10 as a key inflammatory mediator of sex specific tau-associated pathology.

Keywords:  CXCL10; Disease associated astrocytes; Sex differences; Spatial transcriptome; Tauopathy

DOI:  https://doi.org/10.1186/s12974-026-03989-8
Mol Neurobiol. 2026 Aug 06. pii: 815. [Epub ahead of print]63(1):

Hematopoietic Growth Factors Induce More Extensive Transcriptomic Remodeling in Cerebral Monocytes/Macrophages than in Microglia During the Chronic Phase of Traumatic Brain Injury.

Sushil Gaire, Robert S Gardner, Michele Kyle, Xuecheng Qiu, William Miller, Lawrence S Chin, Li-Ru Zhao.

  Previous studies show that combined treatment with stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) enhances brain repair and functional recovery during the chronic phase of severe traumatic brain injury (TBI), but the underlying mechanisms remain unclear. Here, we investigated whether SCF + G-CSF modulates brain immune cell states during chronic TBI. In a controlled cortical impact mouse model, SCF + G-CSF was administered subcutaneously for 5 consecutive days beginning 8 months post-injury. CD11b⁺ brain immune cells, including microglia and monocytes/macrophages (Mo/Mac), were isolated one day after the final injection and analyzed by single-cell RNA sequencing. Integrated analyses revealed more extensive transcriptomic changes in Mo/Mac than in microglia following SCF + G-CSF treatment. Flow cytometry confirmed a significant increase in the CD11b+/CD45high Mo/Mac population following treatment. In microglia, SCF + G-CSF modestly upregulated genes such as S100a8, S100a9, Mir682, and Rpl37rt. In contrast, Mo/Mac showed robust upregulation of genes including Wfdc17, Ifitm1/2/3, Tspo, Lrg1, and Igfbp6, consistent with transcriptomic signatures associated with antiviral defense, anti-inflammatory regulation, and acquisition of reparative phenotypes. Volcano plot analysis demonstrated more extensive transcriptomic remodeling in infiltrating peripheral immune cells than in resident microglia. Pathway analysis identified interleukin-17 signaling as a candidate pathway associated with SCF + G-CSF treatment, along with enrichment of programs related to protein synthesis, detoxification, and glial development. Together, these findings demonstrate that the transcriptomic response to SCF + G-CSF treatment is more pronounced in cerebral monocyte/macrophage populations than in microglia, providing insight into candidate immunomodulatory mechanisms associated with brain repair in chronic TBI.

Keywords:  Chronic traumatic brain injury; Hematopoietic growth factor; Macrophages; Microglia; Transcriptomic analysis; Traumatic brain injury

DOI:  https://doi.org/10.1007/s12035-026-06096-0
Cell Rep. 2026 Aug 06. pii: S2211-1247(26)00878-8. [Epub ahead of print]45(8): 117800

Cholesterol enhances lysosome-autophagosome fusion for better α-synuclein clearance in GBA L444P-mutated Parkinson disease.

Mingjia Chen, Fengtao Liu, Yujie Yang, Ruibo Chen, Linhua Gan, Yimin Sun, Yuchen Yan, Sisi Xie, Chenwei Zhu, Xiaoting Sun, Yang Li, Shun Zhu, Wen Liu, Ji Zuo, Yunlong Yang, Jian Wang.

  Mutations in lysosomal enzyme glucocerebrosidase (GBA), the most common genetic risk factor for Parkinson disease (PD), exacerbate α-synuclein pathology through unclear mechanisms. Here, we report, in a large cohort, that GBA-mutated PD patients exhibit lower serum cholesterol levels. By introducing the most common GBA variant in our cohort, L444P, into human α-synuclein knock-in mice, we noted that the mice exhibited behavioral and molecular pathological PD features at 12 months of age. Mechanistically, lysosomal proteomics identified the loss of lysosome-cytoplasmic vesicle interactions and cholesterol-containing lipid microdomains in both PD patients and mice. Autophagic flux monitoring revealed impaired autophagosome-lysosome fusion in GbaL444P/+ neurons. Gain- and loss-of-function experiments uncovered cholesterol synthesis impairment via glycosphingolipid-reduced SREBP2 levels. Importantly, cholesterol supplementation was found to enhance the autophagic flux and mitigate α-synuclein accumulation in vitro, whereas AAV-Srebp2 delivery increased α-synuclein clearance in GbaL444P/+ mice. Our study provides animal models and mechanistic insights into GBA-associated PD and offers a therapeutic paradigm by facilitating cholesterol-associated α-synuclein autophagic clearance.

Keywords:  CP: metabolism; CP: neuroscience; GBA; PD; Parkinson disease; autophagy; cholesterol; glucocerebrosidase; mouse model; α-synuclein

DOI:  https://doi.org/10.1016/j.celrep.2026.117800
bioRxiv. 2026 Jul 22. pii: 2026.07.18.739219. [Epub ahead of print]

Accumulation of Lipid Droplets in Microglia following Neonatal Brain Hypoxia-Ischemia.

Fan Li, Yuqing Lei, Sihao Li, Gui Zhang, Yinuo Li, Beiyan Wu, Donna M Ferriero, Peipei Pan, Zhonghui Guan, Xiangning Jiang.

Background: Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal mortality and neurodevelopmental impairments. Following brain hypoxia-ischemia (HI), microglia face substantial metabolic stress; and upon phagocytosis, they become overloaded with lipids derived from engulfed dead neurons and myelin debris. It is unclear how microglia respond to and process the lipid cargo, and whether lipid accumulation may affect microglia function following neonatal HI.
Methods: The postnatal day 10 mice were subjected to HI using the Vannucci model. Lipid droplets (LD) were assessed by histology and immunofluorescent staining. Single-nucleus RNA sequencing (snRNA-seq) was performed using brain tissue from HI-injured and sham-operated mice at 72 hours after HI. LD-accumulating microglia (LDAM) were identified by a specific LD marker gene perilipin 2 ( Plin2 ). Differential gene expression was analyzed between Plin2 -positive and Plin2 -negative microglia after HI. Human HIE brain sections were also examined for LD accumulation. The dynamic changes of PLIN2-expressing microglia and infiltrating monocyte-derived macrophages (MDM) at 24 hours, 72 hours and 7 days after HI were compared using flow cytometry. In addition, mouse BV2 microglia were subjected to oxygen-glucose deprivation (OGD) to study phagocytosis and cytokine expression.
Results: Lipid droplets accumulated primarily in microglia after HI in neonatal mice and in human HIE brain. LD were not found in astrocytes or neurons. Plin2 -expressing LDAM emerged as new microglia clusters after HI. Compared with microglia without LD, LDAM showed a distinct transcriptional profile with upregulation of genes linked to microglial activation, enhanced cholesterol and lipid processing, and a shift towards phagocytic and pro-inflammatory state. Blocking LD biogenesis reduced elevated phagocytosis and IL-1β expression in BV2 cells following OGD.
Conclusion: Our study revealed that microglia accumulate lipid droplets as part of their metabolic responses to HI in the neonatal brain. Microglial lipid droplet formation is associated with a pro-inflammatory phenotype at early stage after HI, and increased phagocytosis in vitro. The lipid metabolic changes may regulate microglial function and influence HI outcomes.

DOI: https://doi.org/10.64898/2026.07.18.739219
Nat Neurosci. 2026 Aug 04.

A reproducible three-dimensional model of human brain tissue to investigate physiological and disease-associated microglia phenotypes.

Julien Klimmt, Carolina Cardoso Gonçalves, Jessica Valentina Montgomery, Stephan A Müller, Merle Bublitz, Severin Filser, Lars Paeger, Brigitte Nuscher, Angelika Dannert, Sigrun Roeber, Veronica Pravata, Martina Schifferer, Joshua J Shrouder, Nathalie Schulz, Judit González-Gallego, Silvia Cappello, Thomas Misgeld, Nikolaus Plesnila, Eduardo Beltrán, Jochen Herms, Elena De Domenico, Marc D Beyer, Joachim L Schultze, Christian Haass, Stefan F Lichtenthaler, Caterina Carraro, Dominik Paquet.

Stem-cell-based in vitro models offer promising potential to elucidate human brain cell functions and interactions, but limitations in reproducibility, maturation and cell-type diversity persist. Especially, prolonged incorporation of mature microglia and studies of neuroinflammation have proven challenging. Here, we developed a human induced pluripotent stem cell-based three-dimensional cortical brain tissue model (3BTM) containing neurons, astrocytes and microglia with high reproducibility, maturity and viability. 3BTMs show morphological, functional and proteomic maturation of all cell types, leading to high similarity to their in vivo counterparts. Incorporated microglia survive for over 6 months and display mature morphology, functions and gene expression. Importantly, when engineered to model Alzheimer's disease pathology, 3BTMs recapitulate key disease hallmarks, including amyloid deposition, increased phospho-tau levels and neuroinflammation, with microglia shifting their transcriptional landscape to disease-relevant signatures. Treatment of Alzheimer's disease 3BTMs with anti-Aβ immunotherapy cleared deposits and largely reversed disease signatures in glia. Together, our microglia-containing model provides a platform for studying physiological and pathological states of human brain tissue.

DOI: https://doi.org/10.1038/s41593-026-02367-0
Nature. 2026 Aug 05.

Antigen presentation by CD40+MHC-II+ astrocytes promotes CNS autoimmunity.

Joon-Hyuk Lee, Zhaorong Li, Joselyn S Soto, Ah-Ram Kim, Tomer Illouz, Carolina M Polonio, Michael Kilian, Jessica E Kenison, Anton M Schüle, Camilo Faust Akl, Hong-Gyun Lee, Brian M Andersen, Jessica J Ye, Joseph M Rone, Gavin Piester, Lena Srun, Jazmin Martinez, Austin Danko, Jinsu Lee, Tae Hyun Heo, Elizabeth N Chung, Landon K Oetjen, Pere Duart-Abadia, Nakyung Koo, Norbert Perrimon, Michael A Wheeler, Baljit S Khakh, Stephanie E J Zandee, Alexandre Prat, Francisco J Quintana.

Astrocytes contribute to the pathology of multiple neurological disorders, including the T cell-driven autoimmune disease of the central nervous system (CNS) multiple sclerosis and its mouse model, experimental autoimmune encephalomyelitis1. However, little is known about functional interactions between astrocytes and CD4+ T cells. Here using rabies barcode interaction detection followed by sequencing2, in combination with single-cell RNA sequencing, in vitro co-culture systems and cell-specific in vivo CRISPR-Cas9-based genetic perturbation studies, we established that astrocytes expressing CD40 and MHC-II promote CNS T cell autoimmunity. We harnessed universal labelling immune partnerships by SorTagging intercellular contacts3 to analyse astrocyte-interacting CD4+ T cells, finding that direct astrocyte-CD4+ T cell interactions enhance pathogenic T helper 17 cell responses in experimental autoimmune encephalomyelitis. In addition, we studied the effect of these interactions on astrocytes. Using in vivo subproteomic approaches4 and AlphaFold-Multimer predictions5, we established that CD40 activation in astrocytes by CD40L expressed by CD4+ T cells induces the accumulation of PLIN4-positive lipid droplets, which provide acetyl-CoA to promote p65 acetylation-dependent NF-κB activation and antigen presentation. Finally, we detected CD40+MHC-II+LD+ astrocytes in multiple sclerosis samples by single-nucleus RNA sequencing and immunohistochemistry. In summary, these studies define a previously unrecognized mechanism by which astrocytes promote CNS autoimmunity.

DOI: https://doi.org/10.1038/s41586-026-10860-6
Neurobiol Dis. 2026 Aug 05. pii: S0969-9961(26)00312-8. [Epub ahead of print] 107567

Microglial CX3CR1 signaling mediates synaptic pruning in degenerative cervical myelopathy.

Cindy M Zhou, Azam Asgarihafshejani, James Hong, Sydney T Brockie, Mandana Movahed, Sarah Sadat, Sogolie Kouhzaei, Michael G Fehlings.

  Degenerative cervical myelopathy (DCM) encompasses several conditions that cause compression of the cervical spinal cord. While the pathobiology underlying compression-induced neural degeneration remains incompletely understood, microglial synaptic pruning, driven by CX3CR1, is thought to be a main contributor. The current study builds on previous work demonstrating that Cx3cr1-/- mice exhibit improved gait following DCM and seeks to determine if CX3CR1-mediated synaptic pruning underlies this improvement. We compared C57BL/6 (WT, wild-type) and Cx3cr1-/- mice across 12-weeks of DCM. Locomotor and pain function were assessed using CatWalk and Von Frey outcome measures, respectively. Synaptic and electrophysiological changes were characterized at baseline and after 4-weeks of DCM using pre- and post-synaptic markers, motor evoked potentials (MEPs), and whole-cell patch-clamp recordings. Cx3cr1-/- and WT mice showed differences in locomotion at baseline. Normalization of all groups revealed that Cx3cr1-/- mice exhibited improved locomotion across 12-weeks and greater mechanical sensitivity on Von Frey. 4-weeks post-DCM induction, the microglia of Cx3cr1-/- mice displayed reduced engulfment of excitatory and inhibitory synapses in the dorsal and ventral horns. This was accompanied by a disruption to the dorsal horn excitation-to-inhibition (E/I) balance, driven primarily by a loss of inhibitory transmission as confirmed by whole-cell patch clamp recording, and altered corticospinal-neuromuscular excitability, as confirmed by motor evoked potentials. Together, our findings reveal CX3CR1-mediated microglial synaptic pruning as a potential novel contributor to early DCM pathobiology. Specifically, our results suggest that an absence of pruning shifts the synaptic E/I balance in the dorsal horn, which may underlie the gait benefits observed in Cx3cr1-/- mice.

Keywords:  CX3CR1; Degenerative cervical myelopathy (DCM); Fractalkine signaling; Knockout model; Microglia; Synaptic pruning

DOI:  https://doi.org/10.1016/j.nbd.2026.107567
Neuron. 2026 Aug 03. pii: S0896-6273(26)00539-8. [Epub ahead of print]

Tunneling nanotubes in the nervous system: The fourth pillar of brain connectivity.

Dimitri Budinger, Michael T Heneka.

  Tunneling nanotubes (TNTs) are thin, actin-based membranous conduits that enable direct and indirect cytoplasmic exchange between distant cells. Once considered a rare in vitro phenomenon, TNTs are increasingly recognized as dynamic intercellular communication routes in the central nervous system. Here, we discuss emerging evidence supporting the presence and functional relevance of TNTs in the brain, their roles in physiological coordination and pathological spread, and the conceptual shift they demand in how we understand neural connectivity. We argue that TNTs represent a previously underappreciated layer of brain organization-one that may critically shape neurodegeneration, neuroinflammation, and repair-and outline key experimental and theoretical directions to move the field forward.

Keywords:  brain connectome; neurodegeneration; neuroinflammation; organelle transfer; tunneling nanotubes

DOI:  https://doi.org/10.1016/j.neuron.2026.07.010
Life Sci. 2026 Aug 07. pii: S0024-3205(26)00433-9. [Epub ahead of print] 124624

Organelle contact sites as spatial regulators of lipid fate in adipose tissue metabolic disease.

Yiqin Yan, Lupeng Chen.

  Adipose tissue protects metabolic homeostasis by storing excess fatty acids, releasing fuels during energy demand and coordinating endocrine and inflammatory signals. These functions are often described as linear pathways of lipogenesis, lipolysis, fatty acid oxidation and thermogenesis. However, lipid handling in adipocytes is spatially organized by organelle contact sites. The endoplasmic reticulum (ER), lipid droplets (LDs), mitochondria, peroxisomes and lysosomes form dynamic interfaces that determine whether fatty acids are stored safely, mobilized for oxidation, processed into specialized lipid species or redirected toward lipotoxic intermediates. In this review, we synthesize evidence that ER-LD and LD-mitochondria contacts coordinate lipid storage and oxidative use, whereas peroxisome-centred contacts connect lipolysis, very-long-chain and branched-chain fatty acid processing, plasmalogen metabolism and mitochondrial remodelling. We further discuss how autophagy and lysosomal pathways maintain adipocyte quality control by regulating LD turnover, mitophagy and membrane renewal. Finally, we propose that obesity, insulin resistance, ectopic lipid deposition, lipodystrophy and adipose inflammation can be viewed as different manifestations of impaired spatial lipid routing. This framework does not replace classical metabolic models, but provides a mechanistic layer that may help identify contact-site-dependent vulnerabilities in metabolic disease.

Keywords:  Adipose tissue; Lipid droplets; Lipophagy; Metabolic disease; Mitochondria; Organelle contact sites; Peroxisomes

DOI:  https://doi.org/10.1016/j.lfs.2026.124624
Front Immunol. 2026 ;17 1850795

Optimization of a neuron-microglia co-culture model to explore cell-to-cell interaction dynamics.

Stefania Vogiatzis, Martina Severa, Agostina Pietrantoni, Giada Cairo, Roberta Pia Falco, Caterina Veroni, Angela Lanciotti, Marilena Paola Etna, Davide Antonio Abate, Lucia Nencioni, Marta Trevisan, Eliana Marina Coccia, Luisa Barzon.

   Introduction: The dialogue between the immune and nervous systems in the central nervous system (CNS) is a fundamental challenge in neuroscience and neuroimmunology. Microglia, the brain's resident immune cells, continuously communicate with neurons to maintain brain homeostasis, support development, and orchestrate responses to injury.
Methods: We adapted the CEBPA/SPI1 transcription factor overexpression approach to generate induced microglia-like cells (iMG) from human embryonic stem cells (hESCs), establishing a reproducible and standardized baseline framework for neuron-microglia co-culture. iMG characterization included assessment of key microglial markers (GPR34, MMP9, TMEM119, IBA1, P2Y12), phagocytic capability benchmarked against the human microglial cell line HMC3, and high-resolution scanning electron microscopy (SEM). iMGs were then co-cultured with hESC-derived NGN2-induced neurons (iNeu), with systematic optimization of seeding ratios and temporal parameters.
Results: iMGs expressed key microglial markers and demonstrated phagocytic capabilities comparable to HMC3 cells. In co-culture, iMGs exhibited remarkable phenotypic plasticity, with upregulation of both homeostatic and activation-associated microglial genes. Reciprocally, neurons showed increased expression of maturation and synaptic markers, indicating a bidirectional crosstalk. SEM revealed spatially variable iMG morphology - transitioning from ramified to amoeboid forms depending on proximity to neuronal structures.
Discussion: This contact-based in vitro system provides a versatile platform for investigating neuroimmune interactions, designed to be further integrated with additional CNS cell types, and applicable to the study of microglial activation, neuron-microglia signalling, and the impact of infections on CNS homeostasis.

Keywords:  in vitro modelling; microglia; neuroinflammation; neuron-microglia co-culture system; stem cell differentiation

DOI:  https://doi.org/10.3389/fimmu.2026.1850795
Neuron. 2026 Aug 07. pii: S0896-6273(26)00570-2. [Epub ahead of print]

Temporal changes in metabolism guide oligodendrocyte precursor cell dynamics in aging and multiple sclerosis.

Tess Dierckx, Sarah E Wilson, Rebecca Buchanan, Themistoklis M Tsarouchas, Yuhsiang Cheng, Maria Sacconi Nunez, Kelly Strickland, Dena Kumsa, Yohan S S Auguste, Sam Vanherle, Sander Bouwman, Daniela Rojo, Louisa Dal Cengio, Celia Lerma-Martin, Yassene Mohammed, Lucas Schirmer, Jeroen F J Bogie, Bart J L Eggen, Erin M Gibson.

  Impaired oligodendrocyte precursor cell (OPC) differentiation limits myelin renewal in aging and contributes to multiple sclerosis (MS) progression. How aging drives OPC deficits remains incompletely understood. We find dysregulation of genes associated with the circadian clock, including Bmal1, and metabolism in aged compared with young OPCs. Targeted loss of Bmal1 in OPCs drives metabolic dysfunction, leading to cellular senescence and impaired dynamics. OPC proliferation and differentiation occur at different rates throughout the day in young adult mice and become disrupted with aging. Chronotherapeutic targeting of BMAL1-controlled sirtuin signaling restores Bmal1-disrupted OPC dynamics after demyelination via sirtuin 2 (Sirt2)-dependent mechanisms. Induced pluripotent stem cell (iPSC)-derived OPCs from MS patients and MS lesion oligodendroglia recapitulate BMAL1 and SIRT2 disruptions. These findings establish BMAL1 as a key regulator of OPC energy metabolism, sirtuin homeostasis, and senescence. We anticipate that this work will provide a foundation for future studies investigating the interconnected roles of aging, circadian disruption, and myelin biology.

Keywords:  BMAL1; OPCs; aging; circadian; iPSC; metabolism; multiple sclerosis; myelination; oligodendrocyte precursor cells; oligodendrocytes

DOI:  https://doi.org/10.1016/j.neuron.2026.07.015