bims-micgli Biomed News
on Microglia
Issue of 2026–04–19
37 papers selected by
Matheus Garcia Fragas, Universidade de São Paulo
  1. A Dynamic Change of Microglial States Occurs During the Transition From Photoreceptor Degeneration to Regeneration in Zebrafish pde6c Mutants.
  2. Immune signaling and function in neurodegeneration.
  3. Two to tango: Microglia in glioblastoma invasion.
  4. Functional genomic profiling of schizophrenia-associated genes reveals key microglial regulators.
  5. Dysfunction of the episodic memory network in the Alzheimer's disease cascade.
  6. Voltage-gated proton channel Hv1/VSOP regulates reciprocal interactions between F-actin and endosomes in microglia.
  7. Microglia detection and phagocytosis of dying neurons is regulated by CX3CR1.
  8. PANoptosis fuels the fire of arthritis.
  9. Repetitive trans-spinal magnetic stimulation promotes repair in inflammatory spinal cord injury through sex-dependent immune modulation.
  10. Astrocyte Mitochondrial UCP4 Reprograms Neuronal Network Oscillations via GDNF-Dependent K+-Ca2+ Signaling in Alzheimer's Disease Mice.
  11. TREM2-mediated microglial phagocytosis of inhibitory synapses contributes to prolonged FS-induced epileptogenesis.
  12. Consensus statement on microglial and macrophage functions in gliomas.
  13. The Microglia Forebrain Assembloid Model Recapitulates Human Brain Development and Neuroimmune Biology.
  14. Single-nucleus brain transcriptomics reveals microglia dysfunction in multiple system atrophy.
  15. Viral Microglia Reprogramming Clears Oligomeric Neurotoxic Debris.
  16. Trem2 exacerbates ischemic brain injury through Gpnmb in a photothrombotic stroke model.
  17. DPP6 Loss Causes Age-Dependent Sleep Dysregulation and Depression-like Phenotypes Linked to Neurodegeneration.
  18. Immune-proteo-metabolomic changes link to Aβ and tau pathology in Alzheimer disease.
  19. Targeted Inhibition of MEGF10-Mediated Astrogliosis Reduces Glial Scar Formation and Promotes Neurofunction Recovery in Mice After Stroke.
  20. A reciprocal glial circuit calibrates injury information and governs the tissue response balance.
  21. The Genotoxic Stress Sensor ZBP1 Drives Tau Pathology.
  22. Microglia respond to and induce anxiety and grooming in mice using calcium signaling.
  23. Mll5 haploinsufficiency attenuates microglial phagocytosis through dysregulated TREM2-SGK3-GSK3β signaling and recapitulates ASD-like behaviors in mice.
  24. Ageing could prime women for autoimmune disorders.
  25. Remodeling synaptic connections via engineered neuron-astrocyte interactions.
  26. Anti-amyloid antibody equilibrium binding to Aβ aggregates from human Alzheimer's disease brain.
  27. Targeted cellular micropharmacies deliver therapeutic agents to the brain.
  28. Serum and CSF cytokine profile impact clinical phenotype in pediatric MOGAD.
  29. Systemic AAV9 Gene Therapy Mitigates Neuromuscular Junction Degeneration and Muscle Atrophy in a Mouse Model of CLN1 Disease.
  30. Folate receptor beta drives NLRP3 inflammasome activation and pyroptosis in macrophages independent of folate binding.
  31. Dysregulation of macrophage lipid metabolism underlies intracellular bacterial neuroinvasion.
  32. The Dual Role of Microglia in Neurodegenerative Diseases: A Review.
  33. From parasite-induced immune activation to neuroinflammation and behavioral dysfunction: convergent mechanisms across protozoa and helminths: a review.
  34. STING signaling in vestibular macrophages underlies Ménière's disease pathogenesis.
  35. Nuclear Translocation of IGF1R Induces Cell Cycle Re-entry via Cyclin D1 Regulation in an Aβ-Driven Alzheimer's Disease Model.
  36. Molecular architecture of the ciliary base in mammalian multiciliated cells.
  37. Signaling cascades shape functional subpopulations of cortical astrocytes in male wild-type mice and APP/PS1dE9 Alzheimer's disease model.
  1. Glia. 2026 Jun;74(6): e70158
    A Dynamic Change of Microglial States Occurs During the Transition From Photoreceptor Degeneration to Regeneration in Zebrafish pde6c Mutants.
    Darshini Ravishankar, Yuki Takeuchi, Ichiro Masai.
      Microglia, brain-resident immune cells, maintain brain homeostasis. However, homeostatic microglia dynamically change into disease-associated microglia in human neurodegenerative diseases. Furthermore, microglia-mediated inflammation is required to initiate neuronal regeneration in zebrafish brain. To understand how functional states of microglia are regulated in response to neuronal degeneration and regeneration, we focused on pde6c mutants, a chronic photoreceptor degeneration zebrafish model. We conducted scRNA-seq analysis on microglia in wild-type sibling and pde6c mutant retinas at the onset of photoreceptor degeneration (5 dpf) and Müller glia-mediated neuronal regeneration (4 wpf). At 5 dpf, retinal microglia consist of three clusters, which correspond to homeostatic, degeneration-response, and stress-response microglia, respectively. The degeneration-response cluster expands in pde6c mutants and expresses genes for neuroprotection and tissue repair. At 4 wpf, retinal microglia comprise four clusters, two of which are specifically produced in pde6c mutants and approach the photoreceptor layer. Furthermore, another cluster is prominently localized in the retinal stem cell niche and shows a transcriptomic profile similar to that of neurogenic-associated microglia (NAM). Comparison of transcriptomic similarity between 4 wpf and 5 dpf microglial clusters revealed that each 4 wpf microglial cluster inherits characteristics of homeostatic, degeneration-response, and stress-response state of 5 dpf microglia in different combinations. Thus, there is a unique heterogeneity of microglia in the initial stage of Müller glia-mediated regeneration. Taken together, our findings reveal a dynamic change of retinal microglia during the transition from photoreceptor degeneration to Müller glia-mediated neuronal regeneration in zebrafish.
    Keywords:  microglia; neuronal regeneration; pde6c; photoreceptor degeneration; zebrafish
    DOI:  https://doi.org/10.1002/glia.70158
  2. J Clin Invest. 2026 Apr 15. pii: e199850. [Epub ahead of print]136(8):
    Immune signaling and function in neurodegeneration.
    Yvonne L Latour, Dorian B McGavern.
      Neurodegenerative diseases arise from interactions among pathogenic proteins, immune responses, and diverse environmental or age-related stressors that disrupt CNS homeostasis. CNS resident microglia detect self-derived danger signals through pattern recognition receptors, and their activation can promote clearance of aberrant proteins, including amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. However, microglial activation may also drive maladaptive states that amplify neuroinflammation. Microglial transitions are further shaped by receptor-mediated signaling and antigen presentation pathways that integrate environmental cues with functional responses. Adaptive immune cells contribute additional layers of regulation, with CD8+ and CD4+ T cells exerting neuroprotective or neurotoxic effects depending on disease context, activation state, and antigen specificity. The identification of granzyme K-expressing CD8+ T cells in several neurodegenerative conditions highlights the growing recognition that distinct T cell subsets may have specialized roles in disease. Aging, repetitive head injury, and viral infection further alter microglial phenotypes, weaken barrier integrity, promote T cell recruitment, and prime the CNS for chronic inflammation. In this review, we synthesize current knowledge of innate and adaptive immune mechanisms in neurodegeneration, examine how external factors influence these responses, and consider how these insights may guide future therapeutic strategies.
    DOI:  https://doi.org/10.1172/JCI199850
  3. Immunity. 2026 Apr 14. pii: S1074-7613(26)00127-5. [Epub ahead of print]59(4): 937-939
    Two to tango: Microglia in glioblastoma invasion.
    Donn A Van Deren, Malay Haldar.
      A lethal feature of glioblastoma is its ability to spread within the brain. In this issue of Immunity, Nebeling et al. use longitudinal three-photon imaging in an immunocompetent glioblastoma model to show that microglial responses at the far infiltration zone are spatially restricted and biphasic, with CX3CR1 signaling modulating tumor invasion dynamics.
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.016
  4. Neuropsychopharmacology. 2026 Apr 16.
    Functional genomic profiling of schizophrenia-associated genes reveals key microglial regulators.
    Joy E Horng, Liam T McCrea, Rebecca E Batorsky, Joshua J Bowen, Camilla Boschian, Yoonjae Song, Roy H Perlis, Steven D Sheridan.
      Microglia are increasingly recognized as key regulators of neural circuit development and putative contributors to the pathophysiology of neuropsychiatric disorders such as schizophrenia (SCZ). However, the functional impact of SCZ-associated genes in microglia remains largely unexplored. Here, we performed an arrayed CRISPR targeting screen of 30 SCZ-associated genes predicted to be differentially expressed in human microglia-like cells. Target genes were prioritized based on post-mortem transcriptomic relevance and predicted ontology-based roles in phagocytosis pathways. We quantified phagocytic activity and morphological changes following gene targeting using high-content confocal imaging. Key targets, including CYFIP1, MSR1, TREM2, SYK, ITGB2, ITGAM, and IRF8, modulated phagocytosis and altered morphological properties consistent with activation states, validating their functional roles in microglia. To elucidate transcriptional impact, we further applied a multiplexed RNA sequencing platform across gene targets. These analyses revealed gene-specific transcriptional signatures, implicating divergent pathways related to phagocytic, activation, cytoskeletal, and lysosomal function. Together, these findings demonstrate the utility of CRISPR-based functional genomics in characterizing microglia function and identifying new target genes and mechanisms that may underlie their contributions to SCZ pathophysiology.
    DOI:  https://doi.org/10.1038/s41386-026-02406-1
  5. Nat Commun. 2026 Apr 17. pii: 3578. [Epub ahead of print]17(1):
    Dysfunction of the episodic memory network in the Alzheimer's disease cascade.
    René Lattmann, Niklas Vockert, Jose Bernal, Judith Wesenberg, Yanin Suksangkharn, Renat Yakupov, Hartmut Schütze, Wenzel Glanz, Enise Incesoy, Michaela Butryn, Falk Lüsebrink, Matthias Schmid, Melina Stark, Luca Kleineidam, Annika Spottke, Marie Coenjaerts, Frederic Brosseron, Klaus Fliessbach, Anja Schneider, Peter Dechent, Klaus Scheffler, Stefan Hetzer, Alfredo Ramirez, Christoph Laske, Sebastian Sodenkamp, Slawek Altenstein, Luisa-Sophie Schneider, Daria Gref, Eike Jakob Spruth, Andrea Lohse, Björn H Schott, Jens Wiltfang, Ingo Kilimann, Doreen Goerss, Ayda Rostamzadeh, Josef Priller, Oliver Peters, Julian Hellmann-Regen, Stefan Teipel, Michael Wagner, Frank Jessen, Anne Maass, Gabriel Ziegler, Emrah Düzel.
      Alzheimer's disease (AD) is a major cause of dementia and cognitive decline. Here, we assessed how episodic memory (EM) network dysfunction, a hallmark of AD, is related to the longitudinal progression of AD biomarkers, neurodegeneration and cognition using data from the DZNE DELCODE study. This data set includes over 1000 longitudinal functional magnetic resonance imaging measurements of EM network function. We related activation and deactivation of EM to individual disease progression scores from a disease progression model. Voxel-wise analyses revealed widespread loss of deactivation and activation with disease progression. Trajectories for the loss of deactivation were nonlinear, associated with amyloid- and tau-positivity and visually preceded trajectories of cognitive decline. The relationship between deactivation and cognitive decline was partly independent of neurodegeneration. Our results provide evidence that synaptic dysfunction and neurodegeneration are independent drivers of cognitive decline, providing a rationale for targeting synaptic dysfunction along the AD cascade.
    DOI:  https://doi.org/10.1038/s41467-026-71831-z
  6. Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2521977123
    Voltage-gated proton channel Hv1/VSOP regulates reciprocal interactions between F-actin and endosomes in microglia.
    Takafumi Kawai, Daisuke Yoshioka, Pattama Wiriyasermkul, Risa Mori-Kreiner, Rizki Tsari Andriani, Megumi Kobayashi, Manabu Abe, Kenji Sakimura, Kazuki Nagayasu, Shushi Nagamori, Yasushi Okamura.
      Voltage-gated proton channel Hv1/VSOP has long been regarded as a plasma membrane protein that modulates intracellular pH and membrane potential to support immune cell function. Here, we reveal an unexpected intracellular pool of Hv1 on endosomal membranes in microglia, where it orchestrates a reciprocal interplay between endosomal trafficking and the actin cytoskeleton. Combining endosome patch-clamp recordings with high-resolution imaging, we demonstrate that functional endosomal Hv1 forms tight and dynamic associations with F-actin. Genetic deletion of Hv1 markedly elongates actin filaments, a phenotype that appears to depend on intracellular rather than plasma membrane Hv1 activity. Heterologous expression of wild-type Hv1, but not a proton-non-conducting mutant, reduced the F-actin staining, indicating that the ion-conducting function is required for this regulation. Live-cell imaging reveals that Hv1-positive endosomes move in concert with F-actin networks and frequently engage with their terminal regions, suggesting that filament barbed ends are trapped at Hv1-positive endosomes. Proximity-labeling proteomics identifies the actin-capping protein CAPZ as a critical mediator of Hv1-dependent actin remodeling, and genetic ablation of CAPZ abolishes the actin phenotype in Hv1-deficient microglia. These findings uncover a previously unrecognized ion channel-cytoskeleton crosstalk that shapes endosomal function and microglial physiology, redefining the functional landscape of voltage-gated proton channels.
    Keywords:  F-actin; endosome; microglia; voltage-gated proton channel
    DOI:  https://doi.org/10.1073/pnas.2521977123
  7. bioRxiv. 2026 Apr 06. pii: 2026.04.02.716180. [Epub ahead of print]
    Microglia detection and phagocytosis of dying neurons is regulated by CX3CR1.
    Maryanne N Barasa, Alicia N Pietramale, Robert A Hill.
      Neuronal cell death is a hallmark of many neurodegenerative diseases. Effective detection and clearance of cell debris generated during cell death events is essential to prevent a degenerative cascade. Brain resident microglia are responsible for performing these functions through complex cell-cell signaling involving both "find-me" and "eat-me" cues. To examine microglial responses to neuronal cell death in vivo, we investigated neuron/microglia CX3CL1/CX3CR1 signaling using intravital optical imaging in mouse cortex and a single-cell ablation technique called 2Phatal. We find that CX3CL1 aggregates as puncta on microglia and that this pattern is maintained when microglia engulf dying neurons. Additionally, disruption of this signaling via Cx3cr1 deletion when both few and many neurons are dying leads to delayed cell corpse clearance, partly due to a delay in microglial engagement with the dying cells. Overall, our work uncovers a precise role for CX3CL1/CX3CR1 signaling in regulating the microglial response to dying neocortical neurons.
    DOI:  https://doi.org/10.64898/2026.04.02.716180
  8. Immunity. 2026 Apr 14. pii: S1074-7613(26)00128-7. [Epub ahead of print]59(4): 931-933
    PANoptosis fuels the fire of arthritis.
    Nagakannan Pandian, Thirumala-Devi Kanneganti.
      Innate immune cell death is critical for host defense but drives inflammatory disease when dysregulated. In this issue of Immunity, Huang et al. report that the complement protein C1q activates macrophage mitochondrial SARM1 to deplete NAD+ and produce cADPR, triggering NLRC5/NLRP12-PANoptosome formation, PANoptosis, and synovial inflammation in rheumatoid arthritis; targeting this pathway reduces inflammation.
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.017
  9. J Neuroinflammation. 2026 Apr 15.
    Repetitive trans-spinal magnetic stimulation promotes repair in inflammatory spinal cord injury through sex-dependent immune modulation.
    Fannie Semprez, Inès Ziane, Alexandre Du, Inès Istre, Léo Dupuis, Laurine Moncomble, Pauline Neveu, Clémence Raimond, Antoine Fernandes, Jessy Dorange, Quentin Delarue, Nicolas Guérout.
      
    Keywords:  Demyelination; Immune modulation; Repetitive magnetic Stimulation; Sex differences; Spinal cord injury; Transverse myelitis
    DOI:  https://doi.org/10.1186/s12974-026-03803-5
  10. Cells. 2026 Mar 27. pii: 597. [Epub ahead of print]15(7):
    Astrocyte Mitochondrial UCP4 Reprograms Neuronal Network Oscillations via GDNF-Dependent K+-Ca2+ Signaling in Alzheimer's Disease Mice.
    Aisylu Gaifullina, Chaima Belhi, Leonardo Restivo, Jean-Yves Chatton.
      Neuron-targeted therapies for Alzheimer's disease (AD) have shown limited efficacy, highlighting the need to explore glial-based mechanisms of neuroprotection. Here, we show that astrocyte mitochondrial uncoupling via viral overexpression of uncoupling protein 4 (UCP4) restores neuronal circuits and ion channel function in aged 3xTG AD mice with overt symptoms. Spontaneous local field potential recordings revealed a partial recovery of hippocampal and subicular sharp wave ripple oscillations, electrophysiological signatures of neuronal circuits known to be altered in AD. Combined whole-cell patch-clamp electrophysiology with two-photon Ca2+ imaging further demonstrated that UCP4 modulates activity-dependent Ca2+ influx, A-type potassium channel function, and enhances glial cell line-derived neurotrophic factor (GDNF) signaling. These findings identify astrocytic mitochondrial uncoupling as a potent mechanism enhancing neuronal resilience and restoring circuit function in symptomatic AD brains.
    Keywords:  Alzheimer’s disease; GDNF; astrocyte; mitochondria; sharp wave ripples; uncoupling protein
    DOI:  https://doi.org/10.3390/cells15070597
  11. Cell Death Discov. 2026 Apr 11.
    TREM2-mediated microglial phagocytosis of inhibitory synapses contributes to prolonged FS-induced epileptogenesis.
    Xiaoqian Wang, Hua Zhou, Yujie Zhai, Yunrong Zhang, Yao Cheng, Yi Yuan, Wenxiao Cao, Anqing Gao, Mengshuang Liu, Qiaoyun Wang, Hongliu Sun.
      Febrile seizures (FS) are common convulsive episodes in childhood and an important etiological component in epilepsy. However, most currently available antiepileptic drugs cannot prevent epileptogenesis and may even exacerbate it. Triggering receptor expressed on myeloid cell 2 (TREM2)-mediated microglial phagocytosis of inhibitory synapses may play a pivotal role in epileptogenesis; however, the role of TREM2 in FS-induced epilepsy remains unclear. We established a Sprague-Dawley rat model of juvenile prolonged FS to analyze the associated molecular changes, epileptic susceptibility, and seizures. Our results confirmed that prolonged FS resulted in increased TREM2 levels, excessive phagocytosis by activated microglia targeting inhibitory synapses, and elevated epileptic susceptibility and seizures. Administration of a CD33 agonist (monosialoganglioside 1, GM1), a negative moderator of TREM2 that reduces its levels, attenuated microglial phagocytosis of inhibitory synapses and weakened susceptibility to epilepsy and seizures. The inhibitory effects of TREM2 knockdown were similar to those of CD33 activation. Blocking the outward-facing region of phosphatidylserine (PtdSer) to prevent TREM2 recognition resulted in increased TREM2 levels and deteriorated microglial activation. Finally, although vesicular GABA transporter (VGAT) levels were higher in the prolonged FS rats treated with annexin V, susceptibility to epilepsy and seizures were aggravated. This study revealed that reducing TREM2 levels may inhibit prolonged FS-induced epileptogenesis by alleviating the phagocytic function of activated microglia targeting inhibitory synapses, while preventing TREM2 from recognizing PtdSer has the opposite effect.
    DOI:  https://doi.org/10.1038/s41420-026-03118-7
  12. Acta Neuropathol. 2026 Apr 16. pii: 39. [Epub ahead of print]151(1):
    Consensus statement on microglial and macrophage functions in gliomas.
    Yuqi Zheng, Islam Alzoubi, Manuel B Graeber, Atul Anand, Lara Barazzuol, Mario Dorostkar, Karl Frontzek, Anna Golebiewska, Costas G Hadjipanayis, Tibor Hortobagyi, Azzam Ismail, Gerard H Jansen, Bozena Kaminska, Daniel Kirschenbaum, Yoshihiro Komohara, Bjarne Winther Kristensen, Kevin S Lee, Emilie Le Rhun, Q Richard Lu, Kaspar Matiasek, Christian Mawrin, Alessandro Michelucci, Nicola Montemurro, Marc-André Mouthon, Quan Liu, Regina Reimann, Roman Sankowski, Alejandro Schcolnik-Cabrera, Michael Schulz, Christian M Schürch, Marius Schwabenland, Aurélie Tchoghandjian, Indrė Valiulytė-Simaitė, Mariano S Viapiano, Tobias Weiss, Michael Weller, Max Wintermark.
      This international consensus statement synthesizes key findings on the complex roles of microglia and macrophages (tumor-associated microglia/macrophages or TAMs) in glioma progression and therapeutic resistance. Recent advances have highlighted the cellular, spatial, and temporal heterogeneity of TAMs, their functional plasticity, and the intricate interactions between TAMs, glioma stem cells, and the neuronal microenvironment, challenging the M1/M2 classification paradigm for TAMs in gliomas and other misconceptions. The statement emphasizes that glioma cells manipulate TAMs to suppress anti-tumor functions, while microglia-mediated modulation of neuron-glioma cell interactions promotes tumor progression. Furthermore, glioblastoma-derived extracellular vesicles (EVs) reprogram microglia to support tumor progression, offering novel therapeutic targets. To advance research and develop more effective treatments, the statement advocates for precision therapies targeting specific TAM subsets or functions, the use of bioengineered EVs as a therapeutic approach, and a shift away from simplistic terminology like "M1/M2" and "neuroinflammation". Ultimately, this new understanding can support innovative strategies to modulate the tumor microenvironment, turning immunosuppression into immunostimulation and improving outcomes for patients with glioblastoma and other types of gliomas.
    Keywords:  Glioma; Immunotherapy; Macrophages; Microglia; Neurooncology
    DOI:  https://doi.org/10.1007/s00401-026-02999-3
  13. bioRxiv. 2026 Apr 09. pii: 2026.04.08.717256. [Epub ahead of print]
    The Microglia Forebrain Assembloid Model Recapitulates Human Brain Development and Neuroimmune Biology.
    Zeinab Tashi, Kaila Gemenes, Santiago Ochoa, Mauri Spendlove, Mischa Ellison, Rose Graf, Madeline G Andrews, Benjamin B Bartelle.
      Microglia are innate immune cells of the CNS whose dysfunction contributes to inflammation and metabolic changes across neurodegenerative and CNS disorders. Across all stages of life, microglia are essential for immune surveillance, neural homeostasis, and synaptic pruning; however, their role in neurodevelopment is less understood. Microglia invade the brain during early neurogenesis, prior to neuronal/glial differentiation, but their potential role at this stage remains undescribed. To model neuroimmune interactions during human cortical development, we created an "assembloid" of human ESC-derived forebrain organoids combined with developmentally matched microglia during cortex formation. Functional contributions of microglia were compared to control organoids using histology and metabolomics.
    DOI:  https://doi.org/10.64898/2026.04.08.717256
  14. Nat Commun. 2026 Apr 15.
    Single-nucleus brain transcriptomics reveals microglia dysfunction in multiple system atrophy.
    Rasmus Rydbirk, Frederik Nørby Friis Sørensen, Jonas Folke, Henriette Haukedal, Andrea Asenjo Martinez, Irene Lisa Vargas, Simone McGarry, Oline Chantell Hollmann, Camila Gherardelli, Sofia Sepulveda, Adam T Szafran, Michael A Mancini, Sanne Simone Kaalund, Tomasz Brudek, Lisette Salvesen, Sara Bech, Justyna Okarmus, Peter Kharchenko, Morten Meyer, Claudio Soto, Kristine Freude, Abhisek Mukherjee, Susana Aznar, Konstantin Khodosevich.
      Multiple system atrophy (MSA) is a rare, age-related neurodegenerative disease that shares clinical and pathological features with Parkinson's disease (PD) but presents a more devastating disease course. To elucidate the distinct cellular pathophysiology, we performed single-nucleus RNA sequencing on postmortem striatal brain tissue from 7 MSA and 12 PD patients, and 10 non-neurological cases. Here, we show significant compositional differences in astroglia and microglia subtypes, while oligodendroglia and neurons are comparable. PD brains show abundant microglia expressing MHC class II HLA haplotypes, indicative of a proinflammatory state, alongside more homeostatic astrocytes. In contrast, MSA lack activated microglia but has more reactive astrocytes compared to PD. Transcriptomic analysis suggests compromised oligodendrocyte signaling in MSA, with microglia being in a state of immune tolerance or exhaustion. Microglia derived from iPSC exposed to patient cerebrospinal fluid exhibit reduced phagocytic activity, especially in MSA. These findings underscore a dysfunctional immune response in MSA as a potential contributor to the more severe pathophysiology of MSA.
    DOI:  https://doi.org/10.1038/s41467-026-71525-6
  15. bioRxiv. 2026 Apr 08. pii: 2026.04.06.716590. [Epub ahead of print]
    Viral Microglia Reprogramming Clears Oligomeric Neurotoxic Debris.
    Griffin P Carter, Zachary P McKay, Mark A Katz, Lisbeth Disla, Dasean T Nardone-White, Derek Southwell, Michael C Brown, Matthias Gromeier.
      Owing to pivotal roles in CNS debris clearance and homeostasis, microglia are central targets for the therapy of neurodegenerative diseases. Intricate proximity to neurons, the inherent danger of neuroimmune toxicity, and intrinsically high plasticity and adaptability, impose high hurdles on microglia modulation. Attenuated viruses are being tested extensively against CNS malignancies (i.e., cancer virotherapy); yet, aside from viral vector-mediated payload delivery, virotherapy for non-neoplastic CNS disease remains unexplored. Here we report disseminated targeting of microglia with the highly attenuated polio:rhinovirus chimera, PVSRIPO, that culminated in profound, durable microglia reprogramming. This phenotype, rooted in extended cytoplasmic viral (v)RNA replication, was non-cytopathogenic and did not yield virus progeny or dissemination. vRNA replication in microglia triggered selective interferon (IFN) regulatory factor (IRF) 3/IRF7 transcriptional programs in the relative absence of NFκB-driven proinflammatory cytokine responses and elicited robust phagocytosis of both tumor cells and amyloid-beta. Targeting of microglia with PVSRIPO mediated immunotherapy in a mouse glioma model and the clearance of oligomeric amyloid-beta deposits in an injectable model of neurotoxic amyloid accumulation. This work identifies attenuated virotherapy as an approach to safely and effectively invigorate microglia function in immune surveillance and neurotoxic debris clearance.
    DOI:  https://doi.org/10.64898/2026.04.06.716590
  16. Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2523148123
    Trem2 exacerbates ischemic brain injury through Gpnmb in a photothrombotic stroke model.
    Xuezhen Chen, Kunyu Li, Siyu Liu, Junyi Zhao, Sagun Tiwari, Fan Zeng, Yue Zhao, Pingping Zhang, Han Tang, Hong Zhao, Helmut Kettenmann, Xianyuan Xiang, Xinzhou Zhu.
      Ischemic stroke is a major public health challenge, with microglia-mediated neuroinflammation exerting both protective and detrimental effects on neuronal survival. The Triggering receptor expressed on myeloid cells 2 (Trem2), predominantly expressed by microglia, has been reported to confer neuroprotection in the middle cerebral artery occlusion (MCAO) model. Paradoxically, in patients, elevated plasma soluble Trem2 (sTrem2) levels correlate with increased risk and poor outcomes. To test the impact of Trem2 function in the context of stroke, we utilized the photothrombotic stroke model which elicited strong Trem2 upregulation, a clinical feature which is not mimicked in MCAO models. Trem2 depletion reduced infarction volume, suppressed proinflammatory cytokine production, preserved neuronal survival, and lessened motor and neurological impairment. Conversely, intracerebral administration of sTrem2 exacerbated neuronal loss, amplified inflammation, and worsened neurological deficits. Integrated mouse-human transcriptomic analyses identified glycoprotein nonmetastatic B (Gpnmb) as a conserved downstream effector of Trem2. Soluble Gpnmb (sGpnmb) administration abolished the protective effects of Trem2 depletion, promoting microglial activation, lipid accumulation, and neuronal damage. Additionally, plasma sTrem2 and sGpnmb levels were elevated in stroke patients, positively correlated, and may serve as biomarkers of poor prognosis. These findings uncover a detrimental role for Trem2 in ischemic stroke, provide mechanistic insight into the link between sTrem2 and poor clinical outcomes, and identify the Trem2-Gpnmb axis as a potential therapeutic target to mitigate poststroke neuroinflammation.
    Keywords:  Trem2; blood biomarker; ischemic stroke; middle cerebral artery occlusion model; photothrombotic model
    DOI:  https://doi.org/10.1073/pnas.2523148123
  17. Int J Mol Sci. 2026 Apr 02. pii: 3224. [Epub ahead of print]27(7):
    DPP6 Loss Causes Age-Dependent Sleep Dysregulation and Depression-like Phenotypes Linked to Neurodegeneration.
    Lin Lin, Ashley E Pratt, Dax A Hoffman.
      Sleep disturbances are early hallmarks of Alzheimer's disease (AD) and other dementias, yet the molecular mechanisms remain poorly understood. We previously showed that dipeptidyl aminopeptidase-like protein 6-knockout (DPP6-KO) mice exhibit accelerated neurodegeneration with synaptic loss, neuronal death, and circadian dysfunction resembling AD pathology. Here, we investigate whether DPP6 deficiency directly causes sleep dysregulation and assess age-dependent effects using wireless EEG/EMG telemetry, behavioral monitoring, and body temperature recordings. We found striking age-dependent sleep phenotypes in DPP6-KO mice. Adult (3-month) DPP6-KO mice showed hyperactivity-driven REM sleep increases, while aged (12-month) DPP6-KO mice developed insomnia with fragmented sleep architecture. Critically, aged DPP6-KO mice exhibited decreased REM latency, a biomarker of depression, which we confirmed by behavioral assays. Conversely, DPP6 overexpression in aged wild-type mice increased NREM duration and reduced sleep fragmentation, demonstrating a protective effect. Throughout aging, DPP6-KO mice showed dysregulated locomotor activity and body temperature rhythms, suggesting broader disruption of circadian and metabolic homeostasis. These findings establish DPP6 as a critical regulator of sleep architecture whose loss recapitulates key sleep disturbances observed in AD/dementia. The progressive nature of sleep dysfunction in DPP6-KO mice, from REM abnormalities to insomnia, parallels human disease progression and positions DPP6 as a potential therapeutic target for sleep-related symptoms in neurodegenerative disorders.
    Keywords:  Alzheimer’s disease; DPP6; NREM; REM; body temperature; dementia; depression; neurodegeneration; sleep disorders
    DOI:  https://doi.org/10.3390/ijms27073224
  18. Alzheimers Dement. 2026 Apr;22(4): e71359
    Immune-proteo-metabolomic changes link to Aβ and tau pathology in Alzheimer disease.
    Meng Wang, Maria Buthut, Jenny Meinhardt, Carolin Otto, Gerardina Gallaccio, Camila Fernández-Zapata, Matteo Teves, Claudia Samol, Katja Dettmer, Simon Heckscher, Sakshi Kamboj, Yozlem Bahar, Christian Conrad, Christian Böttcher, Desiree Kunkel, Klemens Ruprecht, Friedemann Paul, Peter J Oefner, Helena Radbruch, Wolfram Gronwald, Harald Prüß, Chotima Böttcher.
       INTRODUCTION: Tryptophan metabolism is increasingly implicated in Alzheimer's disease (AD), particularly through aryl hydrocarbon receptor (AhR) ligands that influence neuroinflammation. However, their relationships with core AD pathology-amyloid-β (A) and tau (T) deposition-and associated immune-proteomic alterations remain unclear.
    METHODS: We performed integrative multi-omics/high-dimensional profiling of cerebrospinal fluid (CSF) and peripheral blood from A-T- (n = 19) and A+T+ (n = 35) individuals, classified based on CSF Aβ and pTau181 levels. Analyses included targeted metabolomics, mass cytometry, and NULISA-based proteomics, and inter-compartmental correlation analysis. Brain-derived tryptophan catabolism was investigated using single-nucleus RNA sequencing (snRNA-seq).
    RESULTS: Thirteen differentially expressed CSF proteins in A+T+ individuals correlated positively with tryptophan metabolites and pyroglutamate, and negatively with regulatory T cells, isobutyrate, and dendritic cells. Similar patterns were observed in blood. snRNA-seq suggested partial brain origin of metabolites.
    DISCUSSION: Our findings highlight conserved immune-metabolic-proteomic signatures in AD and implicate tryptophan metabolism as a cross-compartmental factor relevant for biomarker and therapeutic development.
    HIGHLIGHTS: Thirteen cerebrospinal fluid (CSF) proteins involved in metabolism and neuronal function link to Alzheimer's disease (AD) pathology Intergrative analysis reveals shared and compartment-specific AD signatures Tryptophan-kynurenine metabolites correlate with AD pathology Indole metabolites show CSF-plasma coupling in A+T+ individuals Immune signatures diverge across CSF (regulatory T cells [Tregs], dendritic cells [DCs]) and blood (B and myeloid cells).
    Keywords:  Alzheimer's disease; amyloid‐beta; aryl hydrocarbon receptor; mass cytometry; tau pathology; tryptophan
    DOI:  https://doi.org/10.1002/alz.71359
  19. Glia. 2026 Jun;74(6): e70159
    Targeted Inhibition of MEGF10-Mediated Astrogliosis Reduces Glial Scar Formation and Promotes Neurofunction Recovery in Mice After Stroke.
    Jingjing Xu, Tongtong Xu, Lin Gan, Shiyu Deng, Qianyuan Lian, Jing Ye, Yiyan Guo, Hanlai Li, Yanqin Geng, Huaitong Yao, Enkhbat Myagmartsend, Wanlu Li, Zhijun Zhang, Guo-Yuan Yang, Won-Suk Chung, Jianfeng Li, Yaohui Tang, Jixian Wang.
      The formation of glial scar at the chronic stage of neurological disease is mainly attributed to the activation and proliferation of astrocytes, termed astrogliosis. It is documented that astrogliosis-induced glial scar formation following stroke severely impairs neurological recovery. However, the mechanisms underlying astrogliosis remain poorly understood. Herein, we discovered that knockdown of MEGF10, a well-known phagocytic receptor that mediates astrocyte-dependent synapse engulfment, caused G1 phase arrest in astrocytes and downregulated cell cycle-related genes, leading to reduced astrocyte proliferation and activation. Genetic deletion of MEGF10 in astrocytes reduced astrocyte proliferation and activation, glial scar formation, and extracellular matrix deposition, subsequentially decreased brain atrophy and promoted neurofunction recovery of mice after stroke. Leveraging on these findings, we further developed a clinically applicable lipid nanoparticle (LNP) system with good biocompatibility, capable of targeted delivery of MEGF10 siRNA to astrocytes. Injecting these LNPs effectively reduced astrocyte proliferation and activation, minimized glial scar formation, and enhanced neurobehavioral recovery of mice after stroke. Our study unveils a previously unrecognized role of MEGF10 in regulating astrogliosis and provides a clinically translatable strategy for targeted modulating glial scar formation and promoting neurofunction recovery after stroke, suggesting that targeting MEGF10 may represent a new therapeutic approach for treating stroke.
    Keywords:  MEGF10; astrogliosis; glial scar; lipid nanoparticles; stroke
    DOI:  https://doi.org/10.1002/glia.70159
  20. Neuron. 2026 Apr 15. pii: S0896-6273(26)00222-9. [Epub ahead of print]
    A reciprocal glial circuit calibrates injury information and governs the tissue response balance.
    Pengwei Luan, Jianming Jia, Yue Chen, Fengxue Xi, Anett D Schwarcz, Xiujie Jiang, Zsuzsanna Környei, Balázs Kalmár, Ya Wang, Ádám Dénes, Miao Jing.
      Brain injury elicits complex tissue responses that are dynamically regulated between activation and resolution, yet the mechanisms that govern this balance remain elusive. We show that acute injury evokes focal extracellular ATP events (Inflares) with characteristic spatiotemporal signatures that scale quantitatively with injury severity, suggesting a glial mechanism for damage calibration. We further reveal that microglia exert negative feedback on Inflares by tuning interleukin (IL)-1β output based on extracellular ATP levels and cellular state. The IL-1β signal is directly received by astrocytes through IL-1R1 and intracellular Ca2+-calcineurin signaling, where it converges with injury input to shape Panx1-dependent ATP release. These bidirectional interactions form a reciprocal glial circuit that enforces a balanced injury response, while disrupting the circuit destabilizes the dynamic control, impairing the cellular reactivity and worsening early injury outcomes. Our findings uncover a glial circuit and molecular players that dynamically regulate tissue injury responses.
    Keywords:  ATP Inflare; IL-1β; astrocyte; brain injury; feedback control; glial circuit; microglia; purinergic signaling
    DOI:  https://doi.org/10.1016/j.neuron.2026.03.031
  21. Cells. 2026 Mar 26. pii: 591. [Epub ahead of print]15(7):
    The Genotoxic Stress Sensor ZBP1 Drives Tau Pathology.
    Jessica M Thanos, Olivia C Campbell, Nick R Natale, Ana Royo Marco, Michael A Puchalski, John R Lukens.
      Genotoxic stress, which includes DNA damage and the mis-localization of DNA and RNA, is a defining feature of tauopathies, Alzheimer's disease, and several other neurodegenerative disorders. Recent findings indicate that activation of the innate immune system in response to genotoxic stress can drive harmful neuroinflammation, compromise neuronal integrity, and promote neurodegeneration. Multiple innate immune sensors of genotoxic stress have recently been discovered, but the contributions of many of these emerging nucleic acid-sensing pathways in neurodegenerative disease pathogenesis remain largely unexplored. Z-DNA binding protein 1 (ZBP1) is one such recently discovered genotoxic stress sensor that has been shown to incite various forms of cell death as well as proinflammatory cytokine production in response to left-handed Z conformations of DNA (Z-DNA) and RNA (Z-RNA). Here, we show that ZBP1 deletion provides protection against tau pathology and neuronal loss in the PS19 mouse model of tauopathy. Moreover, we find that this rescue of tauopathy seen with ZBP1 ablation is associated with dampened activation of microglia and astrocytes. These findings identify ZBP1 as a pivotal genotoxic stress sensor that drives tau pathology, gliosis, and neuronal loss in tauopathy. This work further suggests that targeting ZBP1 may offer a therapeutic strategy to treat tau-mediated neurodegenerative disease.
    Keywords:  Alzheimer’s disease; ZBP1; genotoxic stress; innate immunology; neurodegenerative disease; neuroinflammation; nucleic acid sensing; tauopathy
    DOI:  https://doi.org/10.3390/cells15070591
  22. Mol Psychiatry. 2026 Apr 13.
    Microglia respond to and induce anxiety and grooming in mice using calcium signaling.
    Naveen Nagarajan, Mario R Capecchi.
      Disruption of the mouse Hoxb8 gene causes chronic anxiety and pathological over-grooming resulting from defective Hoxb8 microglia. Furthermore, optogenetic stimulation of Hoxb8 microglia in specific regions of the brain induces elevated anxiety and/or grooming. Herein we show that the molecular signals for inducing anxiety and/or grooming in response to optogenetic activation are calcium ions. Conversely, induction of grooming and anxiety in mice produces calcium transients within microglia. Unexpectedly, calcium transients are not produced in Hoxb8 mutant mice in response to the induction of these behaviors. The likely cause for this lack of response by Hoxb8 mutant mice to induced grooming is the presence of high constitutive levels of free calcium within Hoxb8 mutant microglia resulting from the gene disruption. These calcium ions, in turn, serve as relentless signals to increase anxiety and grooming leading to chronic anxiety and pathological overgrooming in Hoxb8 mutant mice. Thus, we have shown that calcium signaling is used by microglia: 1) to induce anxiety and/or grooming by optogenetic stimulation of Hoxb8 microglia in WT mice, 2) to respond by microglia to the induction of both behaviors in WT mice and 3) as the causative agent for producing chronic anxiety and pathological overgrooming in Hoxb8 mutant mice.
    DOI:  https://doi.org/10.1038/s41380-026-03572-w
  23. Nat Commun. 2026 Apr 17.
    Mll5 haploinsufficiency attenuates microglial phagocytosis through dysregulated TREM2-SGK3-GSK3β signaling and recapitulates ASD-like behaviors in mice.
    Shumin Gao, Qingxiu Lin, Xiaotong Liu, Meixiang Jia, An-Yi Zhang, Zhendong Feng, Lei Han, Nianzhuang Qiu, Xiao-Xing Liu, Huajie Zhai, Haizhen Zhang, Jing Zhang, Xiaodan Ding, Yan Zhang, Lin Lu, Jie Shi, Jia Jia Liu, Ya Bin Wei.
      Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by persistent deficits in social communication and repetitive behaviors. Recent studies have indicated that heterozygous mutations in the mixed lineage leukemia 5 (MLL5) gene are implicated in ASD susceptibility and associated with neurodevelopmental abnormalities. However, the detailed mechanisms remain unclear. Here, we demonstrate that Mll5 haploinsufficiency in mice impairs microglial phagocytosis, drives neuronal hyperexcitability, and recapitulates core ASD-like behaviors. We also show that Mll5 acts as an epigenetic regulator, modulating microglial phagocytosis via the TREM2-SGK3-GSK3β signaling axis, which is associated with deficient glucose metabolism. Furthermore, microglia derived from individual with ASD exhibit parallel reductions in MLL5 expression and phagocytic function. By targeting this pathway, lithium chloride, a GSK3β inhibitor, rescues both microglial phagocytosis deficits and behavioral abnormalities in Mll5 haploinsufficienct mice. Our findings highlight MLL5's critical role in ASD and its potential as a therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-026-71922-x
  24. Nature. 2026 Apr 16.
    Ageing could prime women for autoimmune disorders.
      
    Keywords:  Ageing
    DOI:  https://doi.org/10.1038/d41586-026-01213-4
  25. Nat Commun. 2026 Apr 15. pii: 3490. [Epub ahead of print]17(1):
    Remodeling synaptic connections via engineered neuron-astrocyte interactions.
    Shin Heun Kim, Woojin Won, Gyu Hyun Kim, Yeon Hee Kook, Seungkyu Son, Songhee Choi, Dong Yeop Kang, Mingu Gordon Park, Young-Jin Choi, Seong Su Won, Juhee Shin, Yong Jeong, Kea Joo Lee, C Justin Lee, Sangkyu Lee.
      Information flow through synapses in the central nervous system is regulated by both rapid electrochemical activity and slower structural remodeling. While technological advances allow precise manipulation of synaptic activity, methods for structural remodeling remain limited. Here, we present SynTrogo (Synthetic Trogocytosis), a synthetic molecular approach for modulating synaptic connections. By engineering complementary ligand and receptor proteins, we enable physical interaction between two defined cell populations in culture, leading to a trogocytosis-like process in which receptor-expressing cells internalize membrane fragments and adjacent cytosolic material from ligand-expressing cells. Applying SynTrogo to hippocampal CA3 neurons and CA1 astrocytes in adult male mice results in ultrastructural changes at axon-astrocyte interfaces, accompanied by significantly reduced synaptic connectivity. The remaining synapses exhibit coordinated pre- and post-synaptic structural changes and reorganization of synaptic components and organelles, and are associated with enhanced synaptic plasticity and memory performance. These findings suggest that neural circuits can undergo adaptive reshaping under conditions of synaptic reduction and may provide a foundation for editing synaptic architecture with therapeutic potential for connectopathies.
    DOI:  https://doi.org/10.1038/s41467-026-71440-w
  26. Alzheimers Dement. 2026 Apr;22(4): e71350
    Anti-amyloid antibody equilibrium binding to Aβ aggregates from human Alzheimer's disease brain.
    Katrine D Bjørnholm, P Monroe Butler, Anna E Francis, Curran Varma, Emma T Spooner, Martine B Grenon, Yi Ran Xu, Youqi Tao, Angela L Meunier, Amirah K Anderson, Elizabeth L Hennessey, Michael B Miller, Dennis J Selkoe, Cynthia A Lemere, Andrew M Stern.
       INTRODUCTION: Lecanemab binds "protofibrils," which are poorly characterized in human brain. It is unknown why lecanemab caused fewer amyloid-related imaging abnormalities (ARIAs) than other antibodies in trials. The apolipoprotein E (APOE) ε4 allele increases ARIA risk through unknown mechanisms.
    METHODS: Equilibrium binding constants (KD) and total amyloid beta (Aβ) binding (Bmax) of aducanumab, lecanemab, and donanemab equivalents to soluble and insoluble amyloid plaque-enriched and cerebral amyloid angiopathy (CAA)-enriched Aβ were compared across 17 Alzheimer's disease (AD) cases by mixed models. Titrated immunofluorescence (IF) staining compared antibody binding.
    RESULTS: Lecanemab and aducanumab had indistinguishable preference for "protofibrils." Antibody preference for plaque-enriched versus CAA-enriched Aβ did not differ in soluble extracts or by IF staining but differed slightly in insoluble extracts. The APOE ε4 allele was associated with more soluble antibody-accessible Aβ.
    DISCUSSION: Lecanemab's binding target is similar to other antibodies'. Differences in antibody preference for plaque versus CAA Aβ may not explain differences in ARIA with edema rates.
    Keywords:  Alzheimer's disease; aducanumab; affinity; amyloid; amyloid‐related imaging abnormalities; apolipoprotein E; brain tissue; cerebral amyloid angiopathy; donanemab; fibril; immunotherapy; lecanemab; protofibril; solubility
    DOI:  https://doi.org/10.1002/alz.71350
  27. EMBO Mol Med. 2026 Apr 14.
    Targeted cellular micropharmacies deliver therapeutic agents to the brain.
    Manish Malviya, Subha Baniya, Eitan Wong, Tanya Jain, Branavan Manoranjan, Kristen C Vogt, Zoe Kehs, Pedro C Silberman, Tao Dao, Yueming Li, David A Scheinberg.
      The systemic administration of therapeutic agents, particularly large, charged molecules such as antibodies, has limited efficacy in treating central nervous system (CNS) disorders. In addition, the slow progression of neurodegenerative diseases makes repeated intrathecal injections unfeasible. Alzheimer's disease is characterized by the accumulation of Aβ amyloid plaques. Microglia contribute to the clearance of Aβ, but are inhibited by the expression of CD33. Therefore, antibody blocking of CD33 may enhance the phagocytosis of Aβ by microglial cells, slowing AD progression. Here, we use cells as "targeted cellular micropharmacies" that are retained in the CNS to deliver therapeutic proteins directly into the brain. To achieve this, we genetically engineered CD4 T-cells to express: (1) a chimeric antigen receptor against GD2 to retain the cells in the brain, (2) ectopic FoxP3 to reduce inflammation, (3) secreted IL-2 to promote cell longevity, and (4) secreted anti-CD33 scFv antibody. Our proof-of-concept demonstrates that therapeutic antibodies can be delivered to the brain for at least 8 weeks to treat neurological disorders. Other agents could be similarly delivered into the brain by this platform.
    DOI:  https://doi.org/10.1038/s44321-026-00421-9
  28. J Neuroinflammation. 2026 Apr 14.
    Serum and CSF cytokine profile impact clinical phenotype in pediatric MOGAD.
    Eri Ohashi, Kuniko Kohyama, Takayuki Mori, Shinpei Matsuda, Hiroya Nishida, Sahoko Miyama, Itaru Hayakawa, Yuichi Abe, Naoki Yamada, Motomasa Suzuki, Kohei Matsubara, Masataka Fukuoka, Takeshi Inoue, Ichiro Kuki, Hiroshi Sakuma.
      
    Keywords:  Chemokines; Cytokines; Interleukin-6 (IL-6); Myelin oligodendrocyte glycoprotein IgG (MOG IgG); Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD)
    DOI:  https://doi.org/10.1186/s12974-026-03795-2
  29. Int J Mol Sci. 2026 Mar 28. pii: 3080. [Epub ahead of print]27(7):
    Systemic AAV9 Gene Therapy Mitigates Neuromuscular Junction Degeneration and Muscle Atrophy in a Mouse Model of CLN1 Disease.
    Ewa A Ziółkowska, Albina Jablonka-Shariff, Letitia L Williams, Elizabeth M Eultgen, Matthew D Wood, Daniel A Hunter, Mark S Sands, Alison K Snyder-Warwick, Jonathan D Cooper.
      CLN1 disease, caused by mutations in the PPT1 gene, is a fatal neurodegenerative lysosomal storage disorder. While central nervous system (CNS) pathology is well documented, the impact on peripheral tissues remains unclear. Having previously described severe spinal cord pathology, we investigated whether PPT1 deficiency also impacts the neuromuscular junction (NMJ) and skeletal muscle, and whether early systemic gene therapy can prevent these disease manifestations. NMJ morphology, terminal Schwann cell (tSC) coverage, and skeletal muscle structure were examined in symptomatic and end-stage Ppt1-/- mice. Neonatal mice received systemic AAV9-hCLN1 gene therapy via intravenous injection. Untreated Ppt1-/- mice exhibited pronounced NMJ pathology, including progressive tSC loss, apparently reduced innervation, and increased abnormal acetylcholine receptor clustering. In parallel, we observed skeletal muscle atrophy, with decreased myofiber diameter and reduced myonuclear content, despite preserved sciatic nerve morphology. Systemic AAV9-hCLN1 therapy partially prevented or ameliorated these phenotypes, preserving NMJ innervation and muscle fiber structure. These findings identify peripheral NMJ and muscle abnormalities as previously unrecognized features of CLN1 disease and provide proof-of-concept that early systemic gene therapy can mitigate these effects. Our results highlight the systemic nature of CLN1 pathology and support the need for treatments that address both CNS and peripheral targets for comprehensive disease modification.
    Keywords:  AAV9 gene therapy; CLN1 disease; muscle atrophy; neuromuscular junction; peripheral nervous system; terminal Schwann cells
    DOI:  https://doi.org/10.3390/ijms27073080
  30. J Immunol. 2026 Apr 15. pii: vkag051. [Epub ahead of print]215(4):
    Folate receptor beta drives NLRP3 inflammasome activation and pyroptosis in macrophages independent of folate binding.
    Lisa M Rogers, Kyle Firestone, Riya Chinni, Anna C Branco, Kayla Wrobleski, Teresa Chou, Jeffery A Goldstein, Xiaoping Gu, Emily Mason, Shaoyou Chu, Michael Rubart-von der Lohe, Philip Low, David M Aronoff.
      Folate receptor beta (FRβ), encoded by FOLR2, is selectively expressed in monocytes and macrophages, yet its function in innate immune signaling remains poorly defined. Here, we identify FRβ as a novel regulator of NLRP3 inflammasome activation and pyroptosis in human THP-1 macrophages. Using CRISPR/Cas9-mediated gene deletion, we show that loss of FOLR2 severely impaired caspase-1 activation, gasdermin D cleavage, and IL-1β release in response to multiple NLRP3 stimuli, without altering pro-IL-1β induction. These defects were not rescued by exogenous folate and were independent of extracellular folate concentrations. Mechanistically, FOLR2/FRβ appears to potentiate potassium efflux and the expression of multiple potassium channel-encoding genes. Single-cell RNA sequencing revealed broad transcriptional repression in FRβ-deficient macrophages, including genes involved in inflammasome signaling and ion transport. Genome-wide methylation profiling showed increased CpG hypermethylation in FOLR2-deficient cells, consistent with reduced transcriptional activity. Our findings indicate that FRβ promotes NLRP3 activation in a folate-independent manner potentially by regulating DNA methylation, gene transcription, and K+ efflux in macrophages. These findings uncover a previously unrecognized immunoregulatory function for FRβ, positioning it as a potential modulator of macrophage-driven inflammation in contexts such as host defense, autoimmunity, and tissue-specific immune responses at the tumor and maternal-fetal interface.
    Keywords:  DNA methylation; FRβ; NLRP3 inflammasome; folate receptor beta; macrophage activation
    DOI:  https://doi.org/10.1093/jimmun/vkag051
  31. Nat Commun. 2026 Apr 14.
    Dysregulation of macrophage lipid metabolism underlies intracellular bacterial neuroinvasion.
    Zhou Sha, Kun Yang, Shoupeng Fu, Xiaoyong Tong, Hui Yang, Huiling Fang, Qianqian He, Ning Li, Xinyu Shu, Qi Liu, Beibei Fu, Jin Liu, Qian Li, Hao Zeng, Xiaokai Zhang, Rui Yao, Xushuo Zhang, Wenjin Guo, Xuhu Mao, Mian Long, Xiaoyuan Lin, Quanming Zou, Haibo Wu.
      Acute central nervous system infection is highly lethal, yet the mechanisms by which intracellular bacteria infiltrate the brain remain unclear. Phagocytes are central to host defense, but how infected cells facilitate bacterial access to the brain is poorly defined. In this study, we characterize a CD36+ Fabp4+ Pparg+ macrophage subset that mediates bacterial penetration of the brain without disrupting the blood-brain barrier. Biomechanical analysis reveals that CD36+ macrophages exhibit abundant protrusions and adhesion molecules, enabling resistance to blood flow shear stress and promoting endothelial adhesion. Metabolomic profiling reveals dysregulated lipid metabolism during neuroinvasion, with β-hydroxybutyrate promoting the differentiation and survival of CD36+ macrophages. Importantly, ketogenesis exacerbates symptoms during bacterial neuroinvasion, which could be halted by physiological glucose supplementation. Here, we show that intracellular bacteria exploit metabolically reprogrammed macrophages to access the brain, highlighting glycolipid metabolic homeostasis as a potential therapeutic target in bacterial neuroinvasion.
    DOI:  https://doi.org/10.1038/s41467-026-71791-4
  32. Brain Res Bull. 2026 Apr 13. pii: S0361-9230(26)00173-5. [Epub ahead of print] 111887
    The Dual Role of Microglia in Neurodegenerative Diseases: A Review.
    Nanke Zhang, Nan Xiong, Yanlin He, Lele Zhou.
       BACKGROUND: Microglial activation has increasingly been recognized as a central hub in the pathogenesis of neurodegenerative diseases, where it exerts dynamic regulatory roles characterized by a contest between neuroprotective and neurotoxic actions. However, the precise process underlying this interplay between the two opposing effects remains incompletely elucidated.
    RESULTS: Moderate activation of microglia prevents the accumulation of neurotoxic substances, such as cellular debris and misfolded proteins, promotes neuronal survival by secreting neurotrophic factors, and induces self-limiting inflammation that exerts neuroprotective and repair-promoting effects. In contrast, chronic and persistent microglial activation driven by sustained elevations of pro-inflammatory cytokines, cGAS-STING-mediated DNA sensing, hyperactivation of membrane receptors (e.g., TREM2 and CX3CR1), mitochondrial dysfunction, accumulation of disease-associated proteins, and the emergence of regulatory lectins like Galectin-3, accelerates the progression of neurodegenerative diseases. Through multi-targeted and multi-mechanistic interventions aimed at enhancing microglial phagocytic activity, inhibiting aberrant complement-mediated synaptic pruning (C1q/C3/CR3), reducing neuroinflammation, modulating immune checkpoints (e.g., CD33 and TIM-3)-it is possible to preserve microglial clearance of pathological factors and support neuronal repair. These precision strategies prevent the erroneous engulfment of healthy synapses and promote M2-like polarization，thereby optimizing neuroprotective effects, and delaying or ameliorating the progression of neurodegenerative diseases.
    CONCLUSIONS: This review outlines the dynamic "double-edged sword" role of microglia in neurodegenerative diseases and systematically summarizes the clinical and multi-targeted intervention strategies designed to precisely modulate their functions and skew them toward a neuroprotective phenotype.
    Keywords:  Dual role; Microglia; Neurodegenerative diseases; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.brainresbull.2026.111887
  33. J Neuroinflammation. 2026 Apr 17. pii: 129. [Epub ahead of print]23(1):
    From parasite-induced immune activation to neuroinflammation and behavioral dysfunction: convergent mechanisms across protozoa and helminths: a review.
    Al-Shaimaa Mohsen Sadek, Reem Hamada Mahmoud.
      
    Keywords:  Cytokines; Epigenetics; Global mental health; Gut–brain axis; Microbiota dysbiosis; Neuroinflammation; Neuromodulators; Neuropsychiatric disorders; Parasitic infections
    DOI:  https://doi.org/10.1186/s12974-026-03804-4
  34. J Neuroinflammation. 2026 Apr 14.
    STING signaling in vestibular macrophages underlies Ménière's disease pathogenesis.
    Jiahui Liu, Na Li, Yurong Mu, Yongdong Song, Yao Lu, Xiaoxuan Xu, Na Zhang, Jing Wang, Xiaofei Li, Hanyue Wang, Yan Wang, Zhaomin Fan, Yafeng Lyu, Yuechen Han, Daogong Zhang, Haibo Wang.
      
    Keywords:  CUL4B-DDB1-ROC1 complex; Hearing loss; Ménière’s disease; STING; Vertigo
    DOI:  https://doi.org/10.1186/s12974-026-03812-4
  35. Mol Neurobiol. 2026 Apr 15. pii: 563. [Epub ahead of print]63(1):
    Nuclear Translocation of IGF1R Induces Cell Cycle Re-entry via Cyclin D1 Regulation in an Aβ-Driven Alzheimer's Disease Model.
    Priyanka Sengupta, Debashis Mukhopadhyay.
      Alzheimer's disease (AD) involves progressive neurodegeneration, with abnormal receptor signaling and disrupted cell-cycle activity leading to neuronal loss. Here, we identify a previously unknown mechanism linking β-amyloid (Aβ) exposure to the nuclear translocation of the Insulin-like Growth Factor 1 Receptor (IGF1R) in differentiated SH-SY5Y neuronal cells. The differentiated cholinergic model induced by retinoic acid and BDNF expresses acetylcholinesterase (AChE) and indicates that under amyloidogenic stress, IGF1R may transition from homeostatic membrane and vesicular signaling to a nuclear-centric function. We show that prolonged Aβ treatment causes phosphorylation-dependent nuclear import of IGF1R, confirmed by confocal imaging and biochemical fractionation. IGF1R is conventionally located in the membrane and vesicular membranes; however, under amyloidogenic stress, we show here that it is imported to the nucleus and exerts transcriptional control. The buildup of nuclear IGF1R coincided with increased Cyclin D1 levels and redistribution of neurons into S and G₂ phases, indicating abnormal cell-cycle re-entry. Chromatin immunoprecipitation demonstrated increased IGF1R binding at the CCND1 and JUN promoters after Aβ exposure, suggesting a direct role in gene transcription. Pharmacological blockade of IGF1R phosphorylation by PPP or SUMOylation by Ginkgolic acid significantly reduced Cyclin D1 elevation, implying that both post-translational modifications are involved in receptor nuclear trafficking. Co-immunoprecipitation and confocal imaging identified Nucleophosmin (NPM1) as a putative IGF1R interacting partner, potentially contributing to its nuclear transport and stabilizing receptor-chromatin complexes. These results establish IGF1R as a signaling-transcription connector linking extracellular amyloid stress to nuclear gene regulation, providing a mechanistic explanation for faulty neuronal cell-cycle re-entry in AD. We suggest that abnormal IGF1R-NPM1 interactions contribute to receptor mislocalization and cell-cycle failure, highlighting new targets for therapeutic intervention aimed at receptor trafficking and neuroprotection in Alzheimer's disease.
    Keywords:  Alzheimer’s disease; Cell cycle re-entry; IGF1R; NPM1; Transcriptional control
    DOI:  https://doi.org/10.1007/s12035-026-05865-1
  36. bioRxiv. 2026 Apr 07. pii: 2026.04.05.716577. [Epub ahead of print]
    Molecular architecture of the ciliary base in mammalian multiciliated cells.
    Caitlyn L McCafferty, Marine Brunet, Hugo van den Hoek, Garrison Buss, Olivier Mercey, Philippe Van der Stappen, Danilo Ritz, Adrian Müller, Ricardo Righetto, Paul Guichard, Virginie Hamel, Tim Stearns, Benjamin D Engel.
      Multiciliated epithelial cells (MCCs) generate tens to hundreds of motile cilia to drive fluid flow in diverse physiological contexts. While the axonemal structure of motile cilia has been described extensively in recent years, the molecular architecture of the transition zone, basal body, and surrounding ciliary environment of MCCs remain more elusive. Here, we use cryo-focused ion beam (cryo-FIB) milling and cryo-electron tomography (cryo-ET) to obtain in situ 3D views of the ciliary base within intact MCCs from mammalian trachea, complemented by in situ cross-linking mass spectrometry (XL/MS) and ultrastructure expansion microscopy (U-ExM) for molecular identification. Our data reveal spatially-defined modifications of microtubule architecture from the proximal centriole to the early axoneme, including transition zone-specific features such as an A-B linker bridging microtubule doublets and a helical assembly of microtubule inner proteins (MIPs). We show that the ciliary necklace, a feature observed in many motile cilia, is spatially aligned with the transition zone and quantify its regular organization within the membrane. Our in situ data capture rarely observed events, including intraflagellar transport (IFT) trains connecting to ciliary vesicles tethered to undocked centrioles. The surrounding ciliary environment contains intermediate filaments that encircle the basal bodies and bundled actin filaments that elaborate microvilli structures between the cilia. Integration of XL/MS and U-ExM identified novel microtubule associated proteins (MAPs), MIPs, and membrane-associated proteins localized to these distinct subdomains. This work provides a molecular and structural map of the mammalian MCC ciliary base, revealing architectural principles that underlie its assembly, organization, and function.
    DOI:  https://doi.org/10.64898/2026.04.05.716577
  37. Nat Commun. 2026 Apr 14.
    Signaling cascades shape functional subpopulations of cortical astrocytes in male wild-type mice and APP/PS1dE9 Alzheimer's disease model.
    Yiannis Poulot-Becq-Giraudon, Océane Guillemaud, Elisa Degl'Innocenti, Vivien Letenneur, Karouna Bascarane, Tony Barbay, Mie Møller Clausen, Céline Derbois, Martine Guillermier, Ludmila Juricek, Miriam Riquelme-Perez, Tom Lakomy, Lucile Benhaim, Noëlle Dufour, Pauline Gipchtein, Fanny Petit, Léa Siron, Gwennaëlle Aurégan, Nathalie Dechamps, Marie-Claude Gaillard, Alexis-Pierre Bemelmans, Rémi Bos, Maria-Angeles Carrillo-de Sauvage, Giampaolo Milior, Nathalie Rouach, Solène Brohard, Kevin Muret, Eric Bonnet, Carole Escartin.
      Astrocytes are key partners for neurons and can impact diseases such as Alzheimer's disease (AD), as they exhibit multiple reactive changes. Recent single cell/nucleus genomics analyses evidence astrocyte subpopulations coexisting in normal and AD brains. However, the signaling cascades controlling them, their functional characteristics and roles in AD are still unknown. Here, thanks to astrocyte-specific reporters for STAT3 and NF-kB signaling pathways, two regulators of astrocyte reactivity, we report the presence of three astrocyte subpopulations defined by their signaling activity, in the prefrontal cortex of male APP/PS1dE9 mice. These subpopulations are not triggered by amyloid deposition and are also observed in wild-type mice. They show distinct morphologies, molecular signatures and functional profiles. While NF-kB+ astrocytes have larger territories and higher lysosomal activity, STAT3+ astrocytes display enhanced hemichannel activity. Specific inhibition of these subpopulations reduces amyloid plaque size and impacts anxiety, social preference and social memory in AD but not wild-type mice. Our results show how innate signaling shapes astrocyte subpopulations in the mouse cortex, with distinct functions in health and disease.
    DOI:  https://doi.org/10.1038/s41467-026-71826-w
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