bims-microg 2026-10-18 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–10–18
fifteen papers selected by
Marcus Karlstetter, Universität zu Köln

SALL1 as a marker for distinguishing microglia from blood-derived myeloid cells in stroke brain scRNA-seq data.
Preclinical and first-in-human evaluation of VG-3927/SAR448851, an oral small-molecule TREM2 agonist for Alzheimer's disease.
Endothelial cell-microglia crosstalk mediates heart failure-associated synaptic loss and cognitive impairment in male mice.
A cross-species AAV platform for precise microglial interrogation.
ISG15+ Müller glial subtype contributes to early blood-retinal barrier breakdown in diabetic retinopathy.
ApoE lipidation state directs immunometabolic reprogramming of human microglia.
PM2.5 exposure and retinal neurovascular dysfunction: Clinical and mechanistic evidence for complement C3/C3aR pathway involvement.
Blood-brain barrier disruption and microglia-associated synaptic pruning contribute to cognitive decline after electroconvulsive therapy.
Mitochondrial Genetic Background Shapes Baseline Retinal Function, Age-Related Bioenergetic Remodeling, and Microglial STING Phenotypes.
C/EBPβ Drives Ischemia-Induced Microglial Inflammatory Reprogramming Through Transcriptional Activation of ATF3 and Exacerbates Brain Injury.
UBA6 confers neuroprotection against sepsis-associated encephalopathy through facilitating LCN2 ubiquitin-dependent degradation.
Microglial Presenilin-1 modulates neuronal function and memory-associated behaviors.
Wakefulness enhances somatic Ca²⁺ activity of microglia and astrocytes in the auditory cortex via distinct neuronal dependencies.
Spinal microglia mediate chronic itch by promoting ferroptosis.
In vivo virus-free lineage tracing and live imaging reveal that NeuroD1 does not reprogram microglia into neurons.

Mol Neurodegener. 2026 10 15. pii: 67. [Epub ahead of print]21(1):

SALL1 as a marker for distinguishing microglia from blood-derived myeloid cells in stroke brain scRNA-seq data.

Chu-Yan Zhang, Yi-Ming Lu, Heng Zhang, Yi-Sheng Li, Luo-Yi-Fan He, Yi-Yao Gao, Mu-Zhou Xue, Zi-Yu Wang, Zi-Bo Tang, Li-Li Feng, Jiali Wang, Yi-Xuan Zhang.

  Distinguishing resident microglia from infiltrating myeloid cells in stroke scRNA-seq data remains challenging due to shared myeloid markers; SALL1 shows greater specificity for microglia compared with commonly used markers (e.g. TMEM119, CX3CR1, P2RY12), and combining SALL1 with these commonly used markers improves the ability to distinguish microglia from infiltrating myeloid populations in stroke‑associated scRNA‑seq datasets.

Keywords:  Marker gene; Microglia; Myeloid cells; PBMCs; SALL1; ScRNA-seq; Stroke

DOI:  https://doi.org/10.1186/s13024-026-01003-6
Sci Transl Med. 2026 Oct 14. 18(871): eaec5740

Preclinical and first-in-human evaluation of VG-3927/SAR448851, an oral small-molecule TREM2 agonist for Alzheimer's disease.

Borislav Dejanovic, Matthew D Figley, Elizabeth Weisman, Beril Kiragasi, Frederick W Gergits, Kelley Larson, Abigail Renoux, Raj Rajagovindan, Bhaumik Pandya, Jonathan Houze, Liyue Huang, Francois Gaudreault, Ryan O'Mara, Jade H Clarkson, Marion T Turnbull, Andreas Meier, Marco Colonna, Jessica Stromme, David Gray, Evan A Thackaberry, Petra Kaufmann, Christian Mirescu.

Microglial dysfunction is increasingly implicated in Alzheimer's disease (AD) pathogenesis, with loss-of-function variants in the microglial receptor TREM2 as major risk factors for late-onset AD. We report VG-3927, an oral, CNS-penetrant small-molecule TREM2 agonist that engages the transmembrane domains of TREM2 and its adaptor DAP12 to promote higher-order receptor complex formation and downstream signaling. VG-3927 and tool compound VG-3909 exhibited (sub)nanomolar potency, cooperated with endogenous ligands including amyloid-β (Aβ), and restored signaling in disease-associated TREM2 variants. In human iPSC-derived neuron-microglia-astrocyte cultures, VG-3927 reduced inflammatory cytokines and markers of neuronal damage. In 5xFAD amyloidosis mice expressing the common variant of hTREM2 (5xFAD;hTREM2CV), VG-3909 induced neuroprotective transcriptional reprogramming of microglia, particularly in the plaque niche; enhanced Aβ phagocytosis; and boosted brain glucose metabolism. By contrast, a TREM2 agonist antibody, which may be sequestered by soluble TREM2 (sTREM2), failed to engage plaque microglia. In a first-in-human, randomized, double-blind, placebo-controlled phase 1 trial (NCT06343636, n = 115), VG-3927 was well tolerated across single and multiple ascending doses of up to 140 milligrams. Pharmacokinetics supported once-daily dosing with high CNS penetration (CSF-to-unbound plasma ratio of 0.91). VG-3927 induced dose-dependent reductions in CSF sTREM2, a biomarker of target engagement, consistent across healthy and elderly participants and participants with AD, supporting further clinical development in AD under the new designation SAR448851.

DOI: https://doi.org/10.1126/scitranslmed.aec5740
Nat Commun. 2026 08 14. pii: 10722. [Epub ahead of print]17(1):

Endothelial cell-microglia crosstalk mediates heart failure-associated synaptic loss and cognitive impairment in male mice.

Mengdan Wang, Xiaoxuan Yu, Tursunjan Aziz, Shiyao Zhang, Xiao Wu, Weiyin Wu, Yan Wang, Gang Li, Shuo Zhang.

Cognitive impairment affects 30%-80% of patients with heart failure, yet the mechanisms beyond reduced brain blood flow remain poorly defined. Here we show that circulating factors released during heart failure trigger senescence of brain blood-vessel endothelial cells, which in turn drives synaptic loss and cognitive decline through crosstalk between endothelial cells and microglia, the brain's immune cells. Using a pressure-overload model (transverse aortic constriction) combined with plasma transfer in 8-month-old male mice, we found that elevated circulating TGFβ2 acts on endothelial TGFBR2 and induces the secreted protein SPARC via a non-canonical MEK/ERK-MYC pathway. Endothelial SPARC then activates microglial TLR4, promoting neuroinflammation and abnormal engulfment of synapses. Endothelial deletion of Tgfbr2 or Sparc, and microglial deletion of Tlr4, each preserved synapses and improved cognition, and pharmacological Tlr4 inhibition was protective. These findings define an endothelial-microglia signaling axis and a potential therapeutic target in heart failure-associated cognitive impairment.

DOI: https://doi.org/10.1038/s41467-026-76687-x
Neuron. 2026 Oct 13. pii: S0896-6273(26)00727-0. [Epub ahead of print]

A cross-species AAV platform for precise microglial interrogation.

Fengting Yu, Ruiyu Wang, Run Di, Ke Xu, Jinquan Gao, Huiping Shang, Zhengwei Yuan, Ruicheng Dai, Wenting Wu, Danwei Weng, Xinwei Gao, Heng Li, Tao Yu, Yuanqing Zhang, Xiongfei Wang, Guoming Luan, Fei Zhao, Minmin Luo.

  Targeting microglia with adeno-associated viruses (AAVs) remains challenging because of inefficient transduction, off-target expression, and inconsistent payload performance. Here, we develop an integrated, Cre-independent AAV platform that combines a compact 446-bp microglia-specific regulatory element (MSRE), a high-yield AAV2/9.m capsid, microRNA-mediated neuronal de-targeting, and a microglia-tailored codon-optimization strategy. Following direct intracranial delivery, the optimized vector achieves robust, long-lasting transgene expression with greater than 90% microglial specificity across multiple mouse brain regions, including in an Alzheimer's disease model. With doxorubicin-assisted delivery, the platform also enables efficient and selective microglial targeting in rats, rhesus macaques, and human ex vivo brain slices. Codon optimization supports the expression of otherwise challenging functional payloads, enabling calcium imaging, chemogenetic manipulation, and CRISPR-Cas9-mediated genome editing. This cross-species toolkit provides a versatile resource for investigating microglial biology and developing microglia-directed therapeutic strategies.

Keywords:  CRISPR-Cas9; calcium imaging; capsid engineering; chemogenetics; codon optimization; gene therapy; human tissue; nonhuman primate; regulatory element; viral vector

DOI:  https://doi.org/10.1016/j.neuron.2026.09.017
J Clin Invest. 2026 Oct 15. pii: e205800. [Epub ahead of print]136(20):

ISG15+ Müller glial subtype contributes to early blood-retinal barrier breakdown in diabetic retinopathy.

Tian Niu, Yan Jiang, Xindan Xing, Qian Zhu, Xinyi Liu, Kangjia Lv, Junwei Fang, Kun Liu.

  Diabetic retinopathy features early glial stress and neurovascular dysfunction, yet Müller glial programs linking inflammatory cues to oxidative injury remain unclear. We identify a spatially clustered interferon-stimulated gene 15 (ISG15)+ Müller glial subtype expanded in streptozotocin-induced diabetic mice. High glucose alone did not increase basal free ISG15 or detectable ISGylation (ISG15-dependent protein modification) in primary Müller glia, whereas conditioned medium from high glucose-exposed microglia induced both, recapitulated by IFN-β and attenuated by type I interferon receptor 1 inhibition. In vivo, Ifnb1 RNAscope signals were associated with microglia, retinal Ifnb1 expression increased in diabetic retinas, and microglial depletion reduced Ifnb1 expression and limited the expansion of ISG15+ Müller glia. Müller glia-specific Isg15 deletion preserved blood-retinal barrier integrity, reduced acellular capillaries and Evans blue leakage, and mitigated oxidative stress, lipid peroxidation, and glutathione redox imbalance. Loss of ISG15 or disruption of ISGylation blunted interferon-driven oxidative stress in Müller glia and reduced Müller glia-conditioned medium-dependent endothelial migration and tube formation. Mechanistically, IFN-β promoted peroxiredoxin 6 (PRDX6) ISGylation and proteasome-dependent degradation without altering Prdx6 transcripts. Thus, microglial IFN-β promotes an ISG15+ Müller glial subtype that compromises antioxidant defense and promotes early barrier injury in diabetic retinopathy.

Keywords:  Cell biology; Cell stress; Innate immunity; Ophthalmology; Retinopathy; Vascular biology

DOI:  https://doi.org/10.1172/JCI205800
Alzheimers Dement. 2026 Oct;22(10): e71882

ApoE lipidation state directs immunometabolic reprogramming of human microglia.

Tsion G Shiferaw, Snigdha Sarkar, Katelyn M Baker, Rowan S Wooldridge, Hannah M Binfet, Victoria N Prozapas, Chinemerem P Ogbu, Athena A Schepmoes, Isaac K Attah, Christy S Niemeyer, Kayla G Sprenger, James E Hassell, Robert H Eckel, John T Melchior, Kimberley D Bruce.

   INTRODUCTION: ApoE ε4 is the strongest genetic risk factor for Alzheimer's disease (AD). Emerging evidence suggests that ApoE4 increases AD risk by disrupting microglial metabolism and function. However, whether ApoE lipidation state contributes to microglial dysfunction remains poorly understood.
METHODS: Human microglia were treated with lipid-free (LF) or lipid-bound ApoE3 or ApoE4. Label-free, live-cell holotomography and global proteomics were used to assess isoform- and lipidation-specific effects on lipid droplet (LD) dynamics, mitochondrial morphology, and microglial phenotype.
RESULTS: ApoE4 treatment resulted in fewer but enlarged LDs and increased mitochondrial fragmentation compared to ApoE3, effects that were enhanced by lipid-bound ApoE4. Proteomic analyses revealed a strong type I interferon response in cells exposed to LF-ApoE, which was exacerbated by LF-ApoE4.
DISCUSSION: These findings indicate that lipid-bound ApoE4 drives metabolic reprogramming, whereas LF-ApoE4 promotes inflammatory signaling, identifying ApoE lipidation as a critical modifier of ApoE4-associated AD risk.

Keywords:  APOE ε4; Alzheimer's disease; apolipoprotein E; holotomography; lipid metabolism; microglia

DOI:  https://doi.org/10.1002/alz.71882
J Hazard Mater. 2026 Oct 04. pii: S0304-3894(26)02787-1. [Epub ahead of print]518 143806

PM2.5 exposure and retinal neurovascular dysfunction: Clinical and mechanistic evidence for complement C3/C3aR pathway involvement.

Yi Tian, Yixiang Zhu, Xinyao Yu, Ji Zhou, Haidong Kan, Xinghuai Sun, Yuan Lei.

  PM2.5 is a pervasive environmental toxicant associated with retinal neurodegeneration, yet the mechanisms remain unclear. This study combined clinical, animal, and cellular approaches to investigate whether C3/C3aR signaling mediates PM2.5‑induced retinal neurovascular damage. In retrospective longitudinal glaucoma cohort, a linear mixed‑effects model analyzed PM2.5 effects on inflammatory markers. In mice, we examined PM2.5 effects on retinal complement, microglia activation, neurovascular function, and vision. The protective effect of the C3aR blocker SB290157 was also evaluated. BV2 and retinal endothelial cells were used to study C3‑dependent microglial polarization and its vasoregulatory effects. In clinical experiment, we identified a significant association between short-term PM2.5 exposure and systemic complement dysregulation, characterized by a decrease in serum C3c. In mice, PM2.5 exposure induced marked retinal C3 activation. This change was characterized by microglial activation, vascular dysfunction, and retinal structural and functional impairment. In vitro, PM2.5 directly induced C3/C3aR-dependent microglial M1 polarization and stimulated endothelial vasoconstrictor secretion via microglial crosstalk. Treatment with C3aR inhibitor attenuated the vicious cycle, preserving retinal structure and visual function. In conclusion, C3/C3aR axis serves as a key mechanistic link between PM2.5 exposure and retinal neurodegeneration. Targeting this pathway may offer a therapeutic strategy for mitigating pollution-related retinal damage.

Keywords:  Complement C3; Glaucoma; Microglia; Neurovascular dysfunction; PM(2.5)

DOI:  https://doi.org/10.1016/j.jhazmat.2026.143806
Brain Behav Immun. 2026 Oct 12. pii: S0889-1591(26)00811-1. [Epub ahead of print] 107063

Blood-brain barrier disruption and microglia-associated synaptic pruning contribute to cognitive decline after electroconvulsive therapy.

Yanzhang Li, Si Xu, Mengyao Dai, Tianfeng Wang, Yang Ji, Yue Wu, Wentao Dai, Yanghua Tian.

   BACKGROUND: Modified electroconvulsive therapy (MECT) is a highly effective intervention for major depressive disorder (MDD), yet its broader clinical application is constrained by poorly understood cognitive side effects. We hypothesized that MECT disrupts hippocampal blood-brain barrier (BBB) integrity, permitting extravasation of peripheral factors that activate microglia, drive synaptic phagocytosis, and precipitate cognitive decline.
METHODS: We employed a multi-modal translational approach integrating: (1) clinical neuroimaging (rs-fMRI and DCE-MRI) and cognitive assessments in 41 MDD patients undergoing MECT (including 9 with DCE-MRI); (2) a chronic restraint stress (CRS) mouse model subjected to electroconvulsive shock (ECS), with behavioral, molecular, and transcriptomic analyses; and (3) causal validation via microglial depletion (PLX5622) and targeted BBB repair (Axitinib). In vitro, HT22 hippocampal neurons were stimulated with soluble inflammatory mediators released by primed microglia to assess direct synaptic injury.
RESULTS: MECT significantly impaired immediate and delayed associative memory and reduced left hippocampal ALFF in MDD patients; memory decline correlated with ALFF reduction. In a paired subgroup of patients, DCE-MRI revealed increased hippocampal Ktrans after MECT, providing preliminary clinical imaging support for treatment-associated BBB hyperpermeability. In CRS mice, ECS downregulated tight junction proteins (Claudin-5, ZO-1, Occludin), induced Evans blue extravasation, and promoted hippocampal deposition of fibrinogen and complement C3. ECS also triggered microglial activation, enhanced PSD95 synaptic phagocytosis, elevated IL-6/IL-1β, and reduced synaptic proteins. Critically, both PLX5622-mediated microglial depletion and Axitinib-mediated BBB repair reversed these pathological changes and rescued cognitive function, establishing a dual causal validation system. Axitinib failed to suppress LPS-induced microglial activation, suggesting its protective effects were mediated via BBB restoration rather than direct immunomodulation.
CONCLUSIONS: In conclusion, this study identifies a hippocampus-centered neurovascular-immune mechanism underlying MECT/ECS-related cognitive impairment. Our findings demonstrate that BBB disruption is an early upstream event that permits peripheral factors to enter the brain, activate microglia, and drive synaptic injury and cognitive decline. These results establish a novel mechanistic framework for the cognitive side effects of MECT and highlight BBB protection and microglial modulation as potential strategies for cognitive protection.

Keywords:  Blood-brain barrier; Cognitive impairment; DCE-MRI; Electroconvulsive therapy; Microglial activation; Synaptic pruning

DOI:  https://doi.org/10.1016/j.bbi.2026.107063
Aging Cell. 2026 Oct;25(10): e70771

Mitochondrial Genetic Background Shapes Baseline Retinal Function, Age-Related Bioenergetic Remodeling, and Microglial STING Phenotypes.

McKenna M Somerville, Sydney S Lin, Scott W Ballinger, Alecia K Gross.

  Mitochondria are central regulators of retinal bioenergetics and innate immune signaling, yet how mitochondrial genetic background and aging jointly influence immunometabolic responses in the retina remains poorly defined. Here, we investigated the effects of mitochondrial DNA (mtDNA) variation on retinal function and the combined effects of mtDNA variation and age on bioenergetic composition, mtDNA damage, and the microglial expression and intracellular localization of stimulator of interferon genes (STING) protein. Using mitochondrial-nuclear eXchange (MNX) mice harboring identical C57BL/6J nuclear genomes but distinct C57 or C3H mtDNA haplotypes, we assessed oxidative phosphorylation complex composition, electrophysiological function, mtDNA damage, and microglial STING dynamics across the lifespan and following acute intraocular pressure (IOP) elevation. Aging was associated with increased mtDNA damage and remodeling of oxidative phosphorylation complex composition, characterized by reduced Complex III and V abundance and increased Complex IV. Despite these age-associated changes, photoreceptor- and retinal ganglion cell-associated retinal responses were preserved at early ages, whereas bipolar cell-associated responses differed by mtDNA background. Microglial STING expression increased with age. Acute IOP elevation was associated with differential microglial STING dynamics and STING association with lysosomal compartments decreased with age. Together, these findings demonstrate that mitochondrial genetic background and aging influence retinal bioenergetics and neuroimmune protein expression and identify mtDNA variation as a modifier of age-associated microglial STING expression in the retina.

Keywords:  metabolism; microglia; neuroinflammation; retina

DOI:  https://doi.org/10.1111/acel.70771
Mol Neurobiol. 2026 Oct 15. pii: 967. [Epub ahead of print]63(1):

C/EBPβ Drives Ischemia-Induced Microglial Inflammatory Reprogramming Through Transcriptional Activation of ATF3 and Exacerbates Brain Injury.

Zhongkai Zhang, Feinan Zhuo, Houqian Ouyang, Chuang Chi, Fu Zhang, Yiye Chi, Zhongxiao Lin.

  Microglial activation contributes substantially to secondary brain injury after ischemic stroke, but the transcriptional mechanisms governing this response remain poorly defined. Here, we identified CCAAT/enhancer-binding protein β (C/EBPβ) as a key regulator of ischemia-induced microglial inflammation. RNA sequencing of microglia isolated from mice subjected to transient middle cerebral artery occlusion (tMCAO) revealed extensive transcriptional reprogramming, characterized by activation of inflammatory pathways, including chemokine, TNF, IL-17, and efferocytosis signaling, as well as cell-cycle programs, together with suppression of homeostatic processes involved in synaptic regulation and neuronal support. Network analysis identified Cebpb as a highly connected hub across multiple inflammatory pathways. C/EBPβ expression was markedly increased in peri-infarct microglia after tMCAO and in primary microglia exposed to oxygen-glucose deprivation/reoxygenation. Microglia-selective Cebpb knockdown reduced TNF-α, IL-1β, CCL2, and CD16 expression, increased IL-4, IL-13, and ARG1 expression, and attenuated ischemia-induced morphological remodeling. Consistent effects were observed in primary microglia and BV2 cells, supporting a central role for C/EBPβ in microglial pro-inflammatory activation under ischemic conditions. Mechanistically, C/EBPβ directly bound the Atf3 promoter and activated its transcription, while ATF3 partially mediated C/EBPβ-dependent Il1b induction. In vivo, microglial Cebpb knockdown reduced acute ischemic lesion volume, neuronal apoptosis in the striatum and cortex, and long-term cerebral atrophy. These histopathological improvements were accompanied by sustained recovery of neurological function, somatosensory performance, motor coordination, recognition memory, and spatial learning and memory. Collectively, these findings establish the C/EBPβ-ATF3 axis as a transcriptional pathway that promotes microglial inflammation and secondary neuronal injury after cerebral ischemia. Targeting microglial C/EBPβ may therefore limit ischemic brain damage and improve long-term neurological recovery after stroke.

Keywords:  ATF3; C/EBPβ; Inflammatory reprogramming; Ischemic stroke; Microglia

DOI:  https://doi.org/10.1007/s12035-026-06256-2
Int Immunopharmacol. 2026 Oct 13. pii: S1567-5769(26)01365-2. [Epub ahead of print]190 117517

UBA6 confers neuroprotection against sepsis-associated encephalopathy through facilitating LCN2 ubiquitin-dependent degradation.

Wei Yang, Xihan Che, Rui Ding, Lina Shang, Yujun Yuan, Ning Li, Yu Li.

  Sepsis-associated encephalopathy (SAE) is a common secondary complication of sepsis, accompanied by neuroinflammation and neuronal apoptosis. As an E1 ubiquitin-activating enzyme, ubiquitin-like modifier-activating enzyme 6 (UBA6) deficiency aggravates inflammation. Herein, we first confirmed that UBA6 is decreased in brain tissues of cecal ligation and puncture (CLP)-induced SAE mice. Lentivirus was bilaterally injected into the hippocampus to establish in vivo UBA6 overexpression. Lentivirus-mediated overexpression of UBA6 effectively inhibited microglial activation, downregulated the levels of pro-inflammatory mediators, and reduced inflammatory cytokine release. Furthermore, UBA6 upregulation mitigated neuronal apoptosis and improved spatial learning and memory functions in SAE model mice. For in vitro validation, BV-2 microglial cells were stimulated with 100 ng/mL LPS for 24 h. Consistent with in vivo observations, exogenous UBA6 decreased the proportion of CD86-positive pro-inflammatory microglia. After culturing HT-22 neuronal cells with BV-2 cell conditioned medium, UBA6 overexpression elevated neuronal viability and restrained caspase-3-mediated neuronal apoptosis. Quantitative proteomics was applied to screen and identify lipocalin 2 (LCN2) as a downstream interacting partner of UBA6. Mechanistically, UBA6 binds LCN2 at residue 147 to accelerate K48 ubiquitination and degradation of LCN2, which attenuates neuronal apoptosis induced by LCN2 paracrine. Rescue assays revealed that ectopic LCN2 expression reversed the protective effects of UBA6 against neuroinflammation and neuronal apoptosis. In summary, UBA6 ameliorates SAE-induced cerebral damage, neuroinflammation and cognitive dysfunction via accelerating LCN2 ubiquitination and degradation. These findings advance the mechanistic understanding of SAE progression and establish UBA6/LCN2 as a prospective therapeutic target for SAE intervention.

Keywords:  Apoptosis; Lipocalin 2; Neuroinflammation; Sepsis-associated encephalopathy; Ubiquitin-like modifier-activating enzyme 6; Ubiquitination

DOI:  https://doi.org/10.1016/j.intimp.2026.117517
J Neurosci. 2026 Oct 14. pii: e0310262026. [Epub ahead of print]

Microglial Presenilin-1 modulates neuronal function and memory-associated behaviors.

Paula da Silva Frost, Carley A Martinez, Alon Millet, Joshua McWhirt, Jia Cheng, Michael Bamkole, Yong Kim, Hernandez M Silva, Juan J Lafaille, Estefania P Azevedo, Beth Stevens, Jose Henrique Ledo.

Microglial cells, the macrophages of the brain parenchyma, are increasingly recognized to play a key role in synaptic plasticity and function. Presenilin 1 (PS1) is an essential protein involved in learning and memory; the loss of neuronal Presenilin function causes cognitive deficits and impaired synapse plasticity in mice. Here we show memory enhancement in male mice lacking PS1 in microglia (PS1ΔMG). Leveraging high-throughput RNA sequencing with single-cell deconvolution-analysis, we estimate that PS1ΔMG increases Cd52-lo microglial population, a proliferative group enriched in AP-1 responsive genes; and increases chemokines Ccl7 and Ccl8 In silico prediction of binding partners showed that microglial CCL7 may act via inhibition of neuronal CCR5, a receptor known to negatively regulate learning and memory. By profiling active neuronal populations via PhosphoTRAP the data showed a non-autonomous cell effect of microglial PS1 by modulating genes involved in neuronal excitability and synaptic plasticity. Ex vivo electrophysiology and in vivo calcium imaging in freely behaving mice confirm these effects with functional changes in CA1 hippocampus as seen by increased NMDA/AMPA ratios and increased amplitude of neuronal Ca2+ transients in freely behaving animals, respectively. Remarkably, PS1ΔMG mice exhibited increased memory retention in contextual fear conditioning and novel object recognition. Together, these data suggest a novel mechanism where microglial PS1 negatively regulates neuronal activity through modulation of NMDAR and memory-associated behaviors.Significance Statement Microglia are increasingly recognized as active regulators of neuronal function, yet the molecular mechanisms that constrain their influence on synaptic activity remain incompletely defined. This study identifies microglial Presenilin-1 (PS1) as a key regulator of neuron-microglia signaling that shapes synaptic transmission and learning. We show that loss of microglial PS1 shifts microglia toward a transcriptional and signaling state that enhances NMDA receptor-dependent synaptic activity and improves memory, demonstrating that microglial molecular programs can directly modulate neuronal excitability. These findings establish microglial PS1 as a physiological brake on circuit plasticity and reveal that altering microglial signaling alone is sufficient to influence cognition. Targeting microglial regulatory pathways may therefore provide new strategies to enhance synaptic resilience and cognitive function in brain disorders.

DOI: https://doi.org/10.1523/JNEUROSCI.0310-26.2026
Cell Calcium. 2026 Oct 13. pii: S0143-4160(26)00097-7. [Epub ahead of print]138 103204

Wakefulness enhances somatic Ca²⁺ activity of microglia and astrocytes in the auditory cortex via distinct neuronal dependencies.

Fusheng Ding, Manli Xu, Yu Chen, Jiyu Sun, Xu Cheng, Conghu Li, Sisi Yang.

  Astrocytes and microglia maintain cortical homeostasis via dynamic intracellular calcium (Ca2+) signaling, but their state-dependent activity and neuronal dependencies in the auditory cortex remain poorly understood. Here, using in vivo two-photon imaging, combined with cell-type-specific viral expression of GCaMP sensors, we monitored somatic Ca2+ transients in awake and anesthetized mice. Wakefulness significantly enhanced the active cell fraction, frequency, and amplitude of somatic Ca2+ events in both glial populations compared to the anesthetized state. Local application of tetrodotoxin (TTX) completely abolished microglial Ca2+ activity, revealing an obligatory dependence on neuronal firing. In contrast, astrocytic Ca2+ events persisted at similar frequencies but exhibited significantly reduced peak amplitudes, indicating partial autonomy coupled with neuronal modulation. Together, our findings demonstrate that wakefulness coordinately boosts glial Ca2+ activity, while microglia and astrocytes rely on fundamentally distinct relationships with local neuronal networks.

Keywords:  Astrocytes; Auditory cortex; Brain states; Calcium signaling; In vivo two-photon imaging; Microglia

DOI:  https://doi.org/10.1016/j.ceca.2026.103204
Mol Pain. 2026 Jan-Dec;22:22 17448069261495308

Spinal microglia mediate chronic itch by promoting ferroptosis.

Zhao-Ting Li, Guang-Yi Si, Qi Dai, Min Zhang, Xiao-Na Bu, Ji-Yun Peng, Shun-Qi Wang, Chong Sun, Min Yuan, Bao Xue, Chao-Lin Ma, Hai-Li Pan.

  Chronic itch, affecting 8-10% of the global population, is a debilitating condition linked to dermatoses, systemic diseases, and neurological disorders, with limited therapeutic efficacy due to unclear central mechanisms. Spinal microglia, central nervous system-resident immune cells, regulate neuroinflammation and synaptic plasticity in chronic pain and neurodegeneration, but their role in chronic itch remains unknown. This study investigated the role of spinal microglia in chronic itch. Using an allergic contact dermatitis (ACD) mouse chronic itch model, we found robust microglial activation, accompanied by c-Fos-positive neuronal activation, in the spinal dorsal horn of a chronic itch model. Pharmacological inhibition (minocycline) or genetic ablation of microglia significantly reduced mechanical itch hypersensitivity and spontaneous scratching, alongside decreased microglial/neuronal activation. Morphological and molecular analyses revealed downregulated antioxidants (glutathione peroxidase 4 [GPX4], superoxide dismutase [SOD], glutathione [GSH],) and upregulated lipid peroxidation (malondialdehyde [MDA], acyl-CoA synthetase long-chain family member 4 [ACSL4]) in the spinal cord, indicating ferroptosis. Intrathecal liproxstatin-1 (ferroptosis inhibitor) alleviated itch behaviors and restored GPX4, SOD, GSH and MDA level, without affecting microglial activation. Our findings demonstrate that spinal microglia promote chronic itch by triggering ferroptosis in spinal dorsal horn. These findings provide the first evidence of microglia-ferroptosis crosstalk in chronic itch, providing a mechanistic basis for targeting glial activity or ferroptosis to develop novel therapies.

Keywords:  Chronic itch; ferroptosis; microglia; mouse; spinal cord

DOI:  https://doi.org/10.1177/17448069261495308
Elife. 2026 Oct 16. pii: RP112083. [Epub ahead of print]15

In vivo virus-free lineage tracing and live imaging reveal that NeuroD1 does not reprogram microglia into neurons.

Xiaoyu Li, Yuxin Li, Yue Cao, Niewen Hu, Baozhi Yang, Pei Ouyang, Yuxiao Jin, Shuai Gao, Li Cao, Bo Peng, Yanxia Rao.

  In situ glia-to-neuron conversion induced by a single transcription factor is a promising regenerative strategy for treating central nervous system injuries and neurodegenerative diseases. Previous studies reported that NeuroD1 can induce microglia-to-neuron cross-lineage conversion and improve recovery after brain injury. However, these findings remain controversial. To examine the ability of NeuroD1 in inducing microglia-to-neuron conversion, we employed virus-free genetic lineage-tracing systems in mice to specifically induce NeuroD1 expression in microglia and track the cell fate of NeuroD1-expressing cells at multiple timepoints. Meanwhile, we longitudinally monitored NeuroD1-expressing microglia via two-photon imaging and characterized their transcriptional profile by single-cell RNA sequencing. All observations across these methods revealed that NeuroD1-expressing cells retained their microglia identity and cannot convert into neurons, no matter under physiological and injury conditions. Instead, sustained expression of NeuroD1 facilitated microglia apoptosis in vivo. Collectively, our findings provide strong evidence that NeuroD1 alone is not sufficient to induce microglia-to-neuron conversion. This study further highlights the importance of rigorous lineage-tracing and cell fate-mapping strategies for validating in situ glia-to-neuron conversion.

Keywords:  NeuroD1; lineage tracing; microglia-to-neuron conversion; microglial reprogramming; mouse; neuroscience

DOI:  https://doi.org/10.7554/eLife.112083