bims-micgli 2026-07-26 papers

bims-micgli

Biomed News

on Microglia

Issue of 2026–07–26
38 papers selected by
Matheus Garcia Fragas, Universidade de São Paulo

Focal astrocyte loss reveals nuclear translocation during lesion repopulation.
Loss of microglial ATM drives synaptic pruning and cognitive impairment in epilepsy.
Disease-associated microglia adopt stage-specific phenotypes that regulate T cell fate and immunity in glioma.
Microglia and its P2RY12 receptors regulate seizure severity.
Microglial states revisited: from homeostasis to disease.
Spatial multi-omics identifies early synaptic pruning and context-specific dopaminergic vulnerability in synucleinopathies.
Autoimmune signatures in neurodegenerative dementias: from peripheral immune activation to CNS pathology.
Acute rapamycin treatment reveals distinct mechanisms of dysfunction in a maternal inflammation mouse model.
CSF1R-related leukoencephalopathy: experimental models and potential for treatment.
Microglia heterogeneity in vascular dementia pathology.
Distribution of Big Tau Isoforms in the Human Central and Peripheral Nervous System.
Nicolás Achúcarro: A forgotten architect of glial biology and neuroprotection.
Monomethyl Fumarate Modulates Iron Metabolism and Mitochondrial Function in Microglia with Implications for Multiple Sclerosis Progression.
A single mild closed-head injury disrupts synaptic strength and promotes hippocampal hyperexcitability in mice.
Decoding lactate signals in Alzheimer's disease: redox control, receptor pharmacology, lactylation chemistry, and neuroglial vulnerability.
iPLA2β-dependent phospholipid remodeling drives ZIKV-induced neuroinflammation and neurological injury.
Distinct thymic pDC populations promote tumor immune tolerance through complementary mechanisms.
Quantifying Heteromer Partitioning Reveals Inflammation-Dependent Redistribution of Microglial Adenosine A2A and Cannabinoid CB2 Receptors.
DNA Sensing and Neuroinflammation: Mechanistic Insights into cGAS-STING Biology and Therapeutic Translation in Age-Related Neurodegenerative Diseases.
Cellular signaling within aged skeletal muscle reveals a dysregulated stress-induced remodeling response following volumetric muscle loss in female mice.
APP/Aβ Signaling Orchestrates Reactive Astrocyte Networks in Alzheimer's Disease.
VAMP7-dependent mitochondria-lysosome contacts contribute to glial mitochondrial dynamics and dopaminergic neuron survival.
Cell death analysis of inducible, titratable neurodegenerative disease models in zebrafish and human stem cell-derived retinal organoids.
Simultaneous activation of border-associated immune cells and glial cells at the CNS-meningeal interface after subarachnoid haemorrhage in rats.
Photobiomodulation of immune crosstalk rescues neuroinflammation in Alzheimer's disease models.
Elevation of JAML Promotes Diabetic Kidney Disease by Modulating Podocyte Lipid Metabolism.
Cdk7 Regulates Myelin Sheath Morphology and Lipid Homeostasis in Schwann Cells.
Cone photoreceptor ablation in microglia-deficient larval zebrafish retina elicits a regenerative response alongside a compensatory immune cell response.
Seipin modulates Alzheimer's disease pathogenesis by regulating ferroptosis through a glycine-mediated metabolic pathway.
AQP4-dependent enhancement of glymphatic function attenuates tau pathology and neurodegeneration in PS19 mice.
Synaptic vesicles that store monoamines and glutamate differ in protein composition.
Senescent cell heterogeneity in brain aging and neurodegenerative disease.
Absent pleocytosis in infant viral central nervous system infections reflects lymphocyte depletion and cytokine activation.
SREBP1c modulates Treg immunobiology through a phospholipid-dependent adenosine pathway.
Central microglia-adenosine-related signaling impairs bone-tendon interface repair via sympathetic ADRB2 activation.
Complement dysregulation during the early phases of synucleinopathy.
Mitochondrial-derived vesicles drive budding-type fission of damaged lysosomes.
Deletion of Astrocytic TNFR1 Attenuates Hyperexcitability and Initiation of Epileptogenesis.

Nat Neurosci. 2026 Jul 23.

Focal astrocyte loss reveals nuclear translocation during lesion repopulation.

Marina Herwerth, Matthias T Wyss, Nicola B Schmid, Anna Lasne, Jacqueline Condrau, Luca Ravotto, José María Mateos Melero, Andres Kaech, Gustav Bredell, Carolina Thomas, Rachel Kim, Petra Kukanja, Vladyslav L Korobeynyk, Christine Stadelmann, Thomas Misgeld, Jeffrey L Bennett, Sebastian Jessberger, Aiman S Saab, Shane A Liddelow, Bruno Weber.

Astrocyte loss occurs in various neurological conditions and can disrupt local tissue homeostasis. While astrocytes surrounding border-forming lesions adopt reactive states without restoring astrocyte networks, how astrocytes respond to spatially confined astrocyte loss remains poorly understood. Here we used longitudinal in vivo two-photon microscopy, combined with spatiotemporal transcriptional profiling, to examine astrocyte responses following focal aquaporin-4 antibody-mediated ablation in the somatosensory cortex of adult mouse brain, a model of astrocytopathy relevant to neuromyelitis optica spectrum disorder. Here we show that perilesional astrocytes undergo pronounced structural remodeling during lesion repopulation, characterized by cell proliferation, prolonged multinucleated astrocyte states, polarized process extension into the depleted area and gradual displacement of nuclei into previously unoccupied astrocyte territories. Spatial transcriptomics reveal an injury-associated molecular response that resolves as the astrocyte network is restored. Together, our findings delineate the spatiotemporal dynamics of astrocyte regeneration after astrocyte loss, extending current understanding of astroglial plasticity in the adult brain.

DOI: https://doi.org/10.1038/s41593-026-02354-5
Free Radic Biol Med. 2026 Jul 18. pii: S0891-5849(26)00948-2. [Epub ahead of print]255 221-235

Loss of microglial ATM drives synaptic pruning and cognitive impairment in epilepsy.

Yang Hu, Jinyu Zhao, Youli Wang, Mingjuan Tan, Lei Wang, Honggang Qi, Jiurong Yang, Xinjian Zhu.

  Microglia are the resident immune cells of the central nervous system, highly sensitive to oxidative stress and essential for maintaining synaptic homeostasis. While epilepsy induces profound redox imbalance, how oxidative stress reshapes microglial function and disrupts synaptic integrity remains unclear. Here we show that epileptic seizures drive early loss of ataxia-telangiectasia mutated (ATM) protein in microglia, independent of canonical DNA damage responses. ATM deficiency shifts microglia into a hyperphagocytic state, with morphological activation and aberrant synaptic engulfment. Single-nucleus transcriptomic analysis of human temporal lobe epilepsy samples reveals that microglial subpopulations with reduced ATM expression display transcriptional signatures of activation, enhanced lysosomal processing, and synapse remodeling, accompanied by extensive rewiring of ligand-receptor interactions with neurons. Restoring ATM in microglia attenuates aberrant phagocytic activity and rescues synaptic integrity and cognitive function. Mechanistically, ATM sustains CREB phosphorylation to maintain G6PD-dependent NADPH production and antioxidant capacity, the disruption of which precipitates mitochondrial oxidative injury and excessive microglial synaptic pruning. Together, our findings reveal a DNA damage-independent ATM-CREB-G6PD axis that limits oxidative stress and maladaptive microglial phagocytosis, highlighting ATM loss as a key driver of synaptic pathology in epilepsy.

Keywords:  ATM; Cognitive impairment; Epilepsy; G6PD; Microglia

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.07.021
Immunity. 2026 Jul 24. pii: S1074-7613(26)00275-X. [Epub ahead of print]

Disease-associated microglia adopt stage-specific phenotypes that regulate T cell fate and immunity in glioma.

Jiawen Qian, Chen Wang, Yi Zhang, Congwen Li, Yingying Zeng, Shuangyan Zhang, Fei Gao, Yiwen Zhu, Peiliang Cai, Zhongyuan Zhang, Yanan Hu, Xiaotong Yu, Benoit Kloeckner, Marco Moreira, Yuedi Wang, Bo Wang, Chujun Julia Zhao, Dan Zhang, Xi Chen, Shang Liu, Auriane Coutansais, Huangmijia Zhuang, Ronghua Liu, Feifei Luo, Liang Wu, Claudia Pasqualini, Yihua Chen, Xinyan Li, Mingfang Lu, Ziyi Li, Wei Guo, Svetoslav Chakarov, Zhaoyuan Liu, Bing Su, Rui Zhao, Yiwei Chu, Florent Ginhoux.

  Malignant gliomas are lethal brain tumors characterized by profound local immunosuppression and a radically remodeled myeloid landscape. Although these tumors mobilize resident microglia and infiltrating monocyte-derived macrophages, the mechanisms governing their phenotypic convergence and diversification remain elusive. Here, we integrated single-cell profiling and spatial transcriptomics of glioma-associated microglia in the GL261 model. We identified distinct microglial states that aligned with tumor architecture, most notably Cst7-expressing disease-associated microglia (DAMs) that aggregated at the tumor invasive margin and exhibited a conserved transcriptional signature shared across various central nervous system pathologies. Interferon-γ and toll-like receptor signaling sequentially tuned stage-specific DAM features, including transient MHC-II expression and sustained PD-L1 upregulation, thereby recalibrating the local immune equilibrium by reshaping bidirectional DAM-T cell interactions during glioma progression. Our findings highlight microglial state transitions as a stage-specific layer of immune regulation in glioma that shapes T cell fate and support targeting microglial plasticity to rebalance anti-tumor immunity.

Keywords:  DAMs; MHC class II; PD-L1; disease-associated microglia; glioma; macrophage; microglia; microglia-T cell interaction; myeloid cells

DOI:  https://doi.org/10.1016/j.immuni.2026.06.024
iScience. 2026 Jul 17. 29(7): 116563

Microglia and its P2RY12 receptors regulate seizure severity.

Leigh Ellen Fremuth, Synphane Gibbs-Shelton, Madison Doceti, Aida Oryza Lopez-Ortiz, Abigayle Duffy, William A Mills, Ronald P Gaykema, Kiran Singh, Audrey Nguyen, Sophia Cheng, Edward Perez-Reyes, Ukpong B Eyo.

  Microglia are possible regulators of seizures but previous employed approaches are insufficiently selective of microglial-specific manipulations. To more definitely determine microglial roles in seizure severity, we used the microglial-deficient Csf1r ΔFIRE/ΔFIRE mouse model where mice lack microglia but retain brain border-associated macrophages. Using two experimental paradigms, we confirm that a microglial deficiency exacerbates seizures and facilitates the likelihood of developing spontaneous recurrent seizures, indicating that microglia constrain seizure activity. To gain insights into microglial molecular regulators of seizure severity, we examined P2RY12 contributions and demonstrate that a loss of P2RY12 increased seizure severity in both global and microglial-specific knockout mice indicating that microglia suppress seizure severity. During seizures, P2RY12-deficient microglia displayed altered process complexity, accompanied by increased neuronal activation and reduced inhibitory tone. These results link impaired microglial responses to heightened seizure susceptibility and network excitability. Together, we establish microglia and P2RY12 signaling as protective regulators of seizure activity.

Keywords:  FIRE mice; P2RY12; border-associated macrophages; excitability; microglia; neuronal activity; seizures

DOI:  https://doi.org/10.1016/j.isci.2026.116563
Nat Rev Neurosci. 2026 Jul 20.

Microglial states revisited: from homeostasis to disease.

Bart J L Eggen, Susanne M Kooistra.

Microglia, the resident macrophages of the CNS parenchyma, are recognized as highly plastic, transcriptionally diverse cells whose phenotypes are moulded by development, region, sex, age, genotype and environment. Advances in single-cell and single-nucleus transcriptomics, chromatin accessibility profiling, and spatial multi-omics have negated binary frameworks of 'resting versus activated' or 'M1 (pro-inflammatory) versus M2 (anti-inflammatory)' and revealed a multidimensional state space that supports brain development, homeostasis and adaptive responses to perturbation. Building on the foundational concepts of the microglial sensome, homeostatic and disease-associated signatures, microglia exhibit transcriptomic state transitions in neurodegeneration, demyelination, infection and systemic inflammation. Moreover, a mechanistic framework for more 'hidden' microglial states has emerged, in which latent programmes that appear homeostatic at baseline are revealed by challenges and are instructed through innate immune training or tolerance. We argue that these covert reprogrammed states, which are shaped by ageing, genotype, sex, location and prior exposures such as sepsis or viral infection, help explain interindividual variability in disease trajectories. We conclude by outlining priorities for unifying state annotation across species and modalities, and for translating state-resolved insights into biomarkers and interventions.

DOI: https://doi.org/10.1038/s41583-026-01066-w
Nat Commun. 2026 Jul 21. pii: 6976. [Epub ahead of print]17(1):

Spatial multi-omics identifies early synaptic pruning and context-specific dopaminergic vulnerability in synucleinopathies.

Svenja-Lotta Rumpf, Felix L Strübing, Karsten Nalbach, Claudia Marina Vargiu, Giacomo Berg, Stefan F Lichtenthaler, Piero Parchi, Pan Gao, Weilin Chen, Matthias Brendel, Johannes S Gnörich, Alexander Bernhardt, Léa Dias Rodrigues, Günter U Höglinger, Jochen Herms, Thomas Koeglsperger.

Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta, but the molecular events preceding neuronal loss remain unclear. Here, we combine spatial transcriptomics, spatial proteomics, and α-synuclein (αSyn) seed amplification assays to profile post-mortem midbrain tissue from controls, incidental Lewy body disease (iLBD), PD, Alzheimer's disease (AD), and AD with Lewy body pathology (AD + LBP). We find that αSyn seeding activity correlates with dopaminergic neuron loss in PD-spectrum cases but not in AD-associated LBP, indicating disease-context dependent relationships between αSyn pathology and neurodegeneration. In iLBD, before overt substantia nigra Lewy pathology or detectable αSyn aggregation, we detect increased expression of the complement component C1QC together with loss of inhibitory synaptic markers. These findings support early complement-associated remodeling of inhibitory synapses as a potential pathogenic event preceding overt αSyn aggregation and neuronal degeneration in PD.

DOI: https://doi.org/10.1038/s41467-026-74961-6
Front Immunol. 2026 ;17 1893167

Autoimmune signatures in neurodegenerative dementias: from peripheral immune activation to CNS pathology.

Xin Zhao, Guifeng Zhang, Zheng Wang, Dazheng Zhang, Zhangyong Xia, Chengju Huo.

  Neurodegenerative dementias, including Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, and related tauopathies, are traditionally defined by protein aggregation, neuronal dysfunction, synaptic loss, and glial-mediated neuroinflammation. However, emerging evidence indicates that adaptive immunity may also contribute to disease heterogeneity and progression. These disorders should not be considered classical autoimmune diseases, but they may display autoimmune-like signatures, including neural antigen-specific T cell responses, clonal expansion of T cells in blood or cerebrospinal fluid, CNS infiltration of adaptive immune cells, and brain-targeting autoantibodies. Recent studies have linked α-synuclein-specific T cell reactivity to early Parkinson's disease, identified clonally expanded CD8+ T cells in Alzheimer's disease cerebrospinal fluid, and provided direct evidence of adaptive immune involvement in Lewy body dementia, including altered peripheral immunophenotypes and CD4+ T cell-associated neurodegenerative mechanisms. Experimental tauopathy models further show that microglia-mediated T cell infiltration can drive neurodegeneration. Humoral autoreactivity and progression-associated immune changes further suggest that adaptive immune profiles may help define biologically distinct dementia subgroups. In this mini review, we summarize evidence connecting peripheral immune activation, intrathecal adaptive immune remodeling, and CNS pathology in neurodegenerative dementias. We also discuss how longitudinal blood-CSF profiling, single-cell/TCR/BCR sequencing, autoantibody profiling, and mechanistic validation may clarify whether these immune signatures are pathogenic, compensatory, or bystander responses.

Keywords:  T cells; adaptive immunity; autoantibodies; autoimmunity; neurodegenerative dementia

DOI:  https://doi.org/10.3389/fimmu.2026.1893167
Nat Commun. 2026 Jul 23. pii: 6386. [Epub ahead of print]17(1):

Acute rapamycin treatment reveals distinct mechanisms of dysfunction in a maternal inflammation mouse model.

J E Le Belle, M C Condro, C Cepeda, K D Oikonomou, K Tessema, L Dudley, J Schoenfield, R Kawaguchi, D Geschwind, A J Silva, Z Zhang, K Shokat, N G Harris, H I Kornblum.

Maternal inflammatory response (MIR) during early mouse gestation induces a cascade of physiological and behavioral changes associated with autism spectrum disorder (ASD). We have shown that mild MIR causes chronic systemic and brain inflammation, mTOR pathway activation, mild brain overgrowth with regionally specific volumetric changes, sensory processing dysregulation, and repetitive behavior abnormalities. Prior rapamycin studies in autism models focused on chronic treatments that alter or prevent physical brain changes. Here, we focus on acute rapamycin effects to uncover novel mTOR pathway-mediated mechanisms of dysfunction. Within 2 hours, rapamycin rescues neuronal hyperexcitability, seizure susceptibility, functional network connectivity, brain community structure, repetitive behaviors, and sensory over-responsivity in adult MIR offspring. These CNS-mediated effects coincide with altered expression of genes associated with ASD, ion channels, and epilepsy. Our findings demonstrate that mTOR dysregulation drives dysfunctional brain development in MIR offspring but the adult brain remains amenable to rapid functional normalization, rescuing core and comorbid ASD-associated brain and behavior phenotypes. Restoring excitatory/inhibitory imbalance and sensory functional network modularity may be important targets for therapeutically addressing multiple ASD phenotypes.

DOI: https://doi.org/10.1038/s41467-026-74958-1
Dis Model Mech. 2026 Jul 01. pii: dmm052957. [Epub ahead of print]19(7):

CSF1R-related leukoencephalopathy: experimental models and potential for treatment.

David A Hume, Katharine M Irvine.

  Dominant and recessive mutations in the human CSF1R gene are associated with microglial deficiency in the brain and severe neurodegenerative disease, known as CSF1R-related leukoencephalopathy (CRL). Dominant and recessive Csf1r mutations have been generated in mice, rats, zebrafish and chicken, providing models of the complete or partial microglial loss seen in patients. The impact of Csf1r mutations in inbred mice depends upon genetic background. For example, Csf1r mutants in the C57BL/6J strain are uniquely susceptible to perinatal mortality and hydrocephalus. Congenital microglial deficiency in a range of animal models does not influence postnatal brain development but is associated with age-dependent neuropathology that resembles CRL, indicating that microglial deficiency contributes to disease. None of the available models fully recapitulates the severe functional motor and cognitive impairments seen in patients, raising questions about species differences and the relative contributions of genetic and environmental modifiers. However, they have provided platforms to test ways to repopulate the brain with functional microglia. Here, we briefly review the genetic basis for CRL and evidence of variable penetrance. We also assess experimental models that can enable the development of therapeutic strategies.

Keywords:  Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; CSF1R; CSF1R-related disorder; CSF1R-related leukoencephalopathy; Congenital microglial deficiency

DOI:  https://doi.org/10.1242/dmm.052957
iScience. 2026 Aug 21. 29(8): 116222

Microglia heterogeneity in vascular dementia pathology.

Zhanfei Tan, Dongchen Xu, Yu Cao, Wenhan Li, Jinye Ma, Hao Li, Wei Wei.

  Microglia exhibit remarkable phenotypic heterogeneity and functional plasticity across brain regions, time, and disease states. In vascular dementia (VaD)-the second most common dementia-cerebrovascular pathology drives distinct microglial activation states. This review synthesizes current understanding of microglial phenotypes in neurological disease, focusing on their contributions to VaD following vascular insults such as chronic cerebral hypoperfusion and stroke. Key VaD-associated phenotypes are described, including spatially segregated subsets in ischemic territories (ICAM and IPAM microglia), TREM1 + -activated microglia in hemorrhagic foci, and cytokine-responsive microglia (CRM) identified in human VaD brain. The molecular drivers of this heterogeneity are discussed, arguing for moving beyond the reductive M1/M2 dichotomy. The broader significance lies in a proposed framework for microglia-targeted therapeutic strategies, encompassing precision immunomodulation, antibody-mediated approaches, and in situ cellular reprogramming as promising avenues for future intervention.

Keywords:  Cell biology; Microbiology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2026.116222
Ann Neurol. 2026 Jul 19.

Distribution of Big Tau Isoforms in the Human Central and Peripheral Nervous System.

Rama Krishna Koppisetti, Nicolas R Barthélemy, Kanta Horie, Cindy V Ly, Kaleigh F Roberts, Srinivas Koutarapu, Richard J Perrin, Erin E Franklin, Chiara Pedicone, Joshua Orrick, Justin Melendez, Timothy M Miller, Chihiro Sato, Nupur Ghoshal, Alison M Goate, Celeste M Karch, Randall J Bateman, Soumya Mukherjee.

OBJECTIVE: Tau is widely studied in neurodegeneration, yet most work has focused on canonical brain tau isoforms. A longer isoform, "big tau," produced by inclusion of exon 4a, is expressed in the peripheral nervous system (PNS) and central nervous system (CNS) regions. We sought to characterize big tau composition, anatomic distribution, and disease relevance.
METHODS: Mass spectrometry (MS) was used to sequence big tau and map its distribution across the human nervous system. Postmortem samples included brain tissue from Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and controls; spinal cord and peripheral nerves. Big and canonical ("small") tau isoforms were also quantified in cerebrospinal fluid (CSF) from controls and participants stratified by amyloid status and cognitive impairment.
RESULTS: Human big tau results from insertion of either 355 or 251 amino acids encoded by exon 4a-long and exon 4a-short, respectively. Alternative splicing of exons 2, 3, and 10 generates multiple big tau isoforms. Total tau levels were approximately 1,000-fold higher in the brain than in the PNS; however, the relative abundance of big tau increased from the CNS to the PNS, comprising 50% of the total tau in the periphery and approximately 1% in the brain, primarily localized to the cerebellum. In CSF, big tau levels were unchanged by amyloid abnormalities or cognitive impairment, whereas canonical tau increased with AD pathology.
INTERPRETATION: Big tau represents a distinct tau population enriched in the PNS and uncoupled from disease-associated changes in brain-derived tau, suggesting that distinguishing big tau from canonical tau may improve interpretation of tau biomarkers and help differentiate CNS neurodegeneration from peripheral nerve pathology. ANN NEUROL 2026.

DOI: https://doi.org/10.1002/ana.78300
Neuroprotection. 2026 Jul 23.

Nicolás Achúcarro: A forgotten architect of glial biology and neuroprotection.

Carlos Matute, Luis Pacheco.



Keywords:  Nicolás Achúcarro; microglia; neurodegeneration; neuroglia; neuroinflammation; neuroprotection; neurovascular coupling; oligodendrocytes

DOI:  https://doi.org/10.1002/nep3.70051
Cell Mol Neurobiol. 2026 Jul 20. pii: 118. [Epub ahead of print]46(1):

Monomethyl Fumarate Modulates Iron Metabolism and Mitochondrial Function in Microglia with Implications for Multiple Sclerosis Progression.

Justus Dann, Katharina Klöster, Ulas Ceylan, Neele Heitmann, Britta Eggers, Svitlana Rozanova, Martin Eisenacher, Katrin Marcus-Alic, Konstanze F Winklhofer, Ralf Gold, Simon Faissner.

  Fumaric acid esters have proven to be effective medications in relapsing-remitting multiple sclerosis with neuroprotective effects. In this study, we investigated the impact of fumaric acid esters on primary murine microglia in vitro compared to DMSO vehicle control. Monomethyl fumarate (MMF) increased MTT reduction in a dose-dependent manner, whereas dimethyl fumarate (DMF) exhibited a biphasic response with low concentrations enhancing MTT reduction and higher concentrations inducing toxicity. Notably, complementary analyses of cell number and cell death did not reveal differences between MMF-treated and control conditions, indicating that the increased MTT reduction reflects enhanced cellular metabolic activity rather than increased viability. Consistent with this interpretation, MMF-treated cells exhibited higher basal and maximal oxygen consumption, spare respiratory capacity, and ATP production in the Seahorse XF Cell Mito Stress Test. Proteomic analysis did not indicate an upregulation of mitochondrial respiratory chain proteins, but instead suggested a qualitative shift in mitochondrial homeostasis, including increased expression of mitophagy-associated proteins. MMF-treated Nrf2-deficient microglia showed a blunted increase in MTT reduction, suggesting an involvement of Nrf2 in mediating MMF-induced metabolic effects. Additionally, MMF modulated the microglial iron metabolism and reduced the uptake of non-transferrin-bound iron and altered the gene expression of iron transport proteins, promoting a shift toward the uptake of less toxic, transferrin-bound iron. MMF mitigated iron-induced toxicity and was associated with upregulation of the ferroptosis suppressor protein, indicating a protective response to iron overload. Together, these findings suggest that MMF enhances microglial metabolic activity and mitochondrial function while reducing iron-mediated toxicity, thereby contributing to its neuroprotective effects.

Keywords:  Microglia; Mitochondria; Neuroinflammation; Neuroprotection; Progressive multiple sclerosis

DOI:  https://doi.org/10.1007/s10571-026-01775-x
Brain Commun. 2026 ;8(4): fcag268

A single mild closed-head injury disrupts synaptic strength and promotes hippocampal hyperexcitability in mice.

Jonathan C Vincent, Matthew J Lanning, Kai Saito, Cate D Cox, Leke Bytyqi, Savannah M Shepard, Blake K Byer, Margaret R Hawkins, Teresa Macheda, Kelly N Roberts, Heather M Hash, Kristen A McLaurin, Josh M Morganti, Christopher M Norris, Adam D Bachstetter.

  Traumatic brain injury can result in persistent cognitive, behavioural, and emotional deficits, with the hippocampus among the most vulnerable circuits after injury. However, how diffuse injury differentially alters hippocampal subregions across time remains incompletely defined. Here, we used a mouse closed-head injury model to characterize early transcriptomics, subacute-to-chronic electrophysiology, dendritic spine morphology, and delayed immunoreactivity for glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (IBA1), and the pan-leukocyte marker CD45. Bulk RNA sequencing at 9, 24, and 72 h post-injury revealed induction of immediate early genes and neuronal excitability transcripts at 9 h alongside inflammatory pathways. These neuronal signatures diminished by 24-72 h while immune-associated programs persisted. Ex vivo field recordings in CA1 and dentate gyrus at 1, 3, and 6 weeks post-injury revealed reductions in synaptic strength in both regions at 1 week. Dentate gyrus deficits persisted at 3 weeks but recovered by 6 weeks, whereas CA1 showed depression at 1 and 6 weeks with relative sparing at 3 weeks. Fibre volley recruitment was preserved across regions and timepoints, arguing against gross presynaptic loss. Population spike thresholds were reduced in both regions, indicating increased neuronal excitability that persisted in CA1 but partially recovered in dentate gyrus. DiOlistic labelling and spine reconstruction revealed stable total spine density, but spine class composition showed sex-dependent injury effects in CA1 with altered mushroom and stubby proportions in males. Immunohistochemistry across 1-8 weeks post-injury revealed cortical gliosis but no injury-related changes in hippocampal GFAP or IBA1, while CD45 immunoreactivity increased in a delayed, sex-dependent manner within hippocampus. Together, these findings show that a single closed-head injury produces sustained hippocampal circuit dysfunction characterized by reduced synaptic strength and increased neuronal excitability, with region-dependent recovery dynamics, preserved presynaptic recruitment, and delayed hippocampal CD45 increases that do not parallel local glial activation.

Keywords:  diffuse brain injury; field potentials; sex differences; spine morphology; transcriptomics

DOI:  https://doi.org/10.1093/braincomms/fcag268
Biochem Pharmacol. 2026 Jul 20. pii: S0006-2952(26)00614-3. [Epub ahead of print]253(Pt 1): 118275

Decoding lactate signals in Alzheimer's disease: redox control, receptor pharmacology, lactylation chemistry, and neuroglial vulnerability.

Wajid Zaman, Asma Ayaz, Aziz Ullah.

  Alzheimer's disease (AD) develops within a metabolically heterogeneous brain in which lactate functions as an oxidative substrate, a redox-coupled metabolite, a proton-linked transport signal, a receptor ligand, and a precursor of lysine lactylation. These roles are often considered independently, obscuring why lactate supports neuronal function in some settings yet accompanies persistent inflammation and neurodegeneration in others. This review introduces a lactate signal-decoding framework that emphasizes cellular interpretation rather than concentration alone. The framework integrates the lactate/pyruvate ratio, the cytosolic reduced-to-oxidized nicotinamide adenine dinucleotide (NADH/NAD + ) state, lactate dehydrogenase (LDH) isoenzyme context, proton-coupled monocarboxylate transport, extracellular pH, hydroxycarboxylic acid receptor 1 (HCAR1) signaling, and enzymatic or non-enzymatic lactylation. We compare neuronal, astrocytic, microglial, and neurovascular responses and examine how aging, apolipoprotein E ε4 (APOE4), amyloid pathology, hypoperfusion, sleep disruption, and systemic metabolic disease reshape them. Particular attention is given to the chemistry and analytical validation of histone and non-histone lactylation; the proposed interaction of tau lactylation with other post-translational modifications; and links to proteostasis, iron homeostasis, and mitochondrial quality control. As a hypothesis-generating model, AD progression may involve loss of coordination among lactate transport, oxidation, receptor signaling, pH control, and covalent modification. This framework prioritizes restoration of metabolic coordination over indiscriminate lactate suppression and identifies biomarker and experimental requirements for clinical translation.

Keywords:  Alzheimer’s disease; HCAR1; Lactate signaling; Lactylation; Monocarboxylate transporters; Neuroglia; Redox state; Tau

DOI:  https://doi.org/10.1016/j.bcp.2026.118275
J Neuroinflammation. 2026 Jul 20.

iPLA2β-dependent phospholipid remodeling drives ZIKV-induced neuroinflammation and neurological injury.

Li Jiao, Wenxin Shao, Ying Xie, Sirong Li, Jiahong Gao, Jianyu Xu, Rui Tong, Dehong Li, Qiangming Sun.

Zika virus (ZIKV) infection of the developing brain induces neuroinflammatory responses that can restrict viral replication but may also contribute to neurological injury when dysregulated. Although neuronal phospholipid homeostasis is critical for membrane integrity and synaptic function, how ZIKV infection reprograms lipid metabolism to drive neuropathogenesis remains unclear. Here, we identify calcium-independent phospholipase A2β (iPLA2β) as a key mediator of ZIKV-induced neuronal lipid remodeling. iPLA2β is rapidly upregulated in neurons and in the neonatal brain following infection, and its expression is promoted by the viral envelope protein, which interacts with iPLA2β in neurons. Genetic ablation of iPLA2β reduces viral burden in the developing brain and in primary neurons and disrupts ZIKV-induced phospholipid remodeling, characterized by altered arachidonic acid-containing phospholipids and depletion of docosahexaenoic acid-enriched species. Importantly, sustained iPLA2β activity promotes phospholipid remodeling that supports efficient ZIKV replication, thereby increasing viral burden and contributing to a pro-inflammatory lipid environment. This is associated with increased prostaglandin E₂ production, glial activation, and neuronal loss. Both genetic and pharmacological inhibition of iPLA2β partially restores phospholipid homeostasis and reduces viral burden, accompanied by attenuation of neuroinflammatory responses. Functionally, targeting iPLA2β improves survival and neurobehavioral outcomes and mitigates long-term cognitive deficits following neonatal ZIKV infection. Collectively, these findings support iPLA2β-dependent phospholipid remodeling as a host process that facilitates ZIKV replication and links infection to neuroinflammation and neurological injury, highlighting iPLA2β as a potential therapeutic target in ZIKV-associated neuropathogenesis.

DOI: https://doi.org/10.1186/s12974-026-03973-2
Sci Adv. 2026 Jul 24. 12(30): eadx9864

Distinct thymic pDC populations promote tumor immune tolerance through complementary mechanisms.

Yangsong Wang, Ryo Koyama-Nasu, Yukihiro Endo, Ichita Hasegawa, Atsushi Onodera, Mingyu Chen, Kiyoshi Hirahara, Shinichiro Motohashi, Toshinori Nakayama, Motoko Y Kimura.

Thymic central tolerance is crucial for preventing autoimmunity, but its contribution to tumor immune evasion remains poorly understood. Here, we demonstrate that plasmacytoid dendritic cells (pDCs) in the thymus have two distinct subsets, accumulating in the thymus of tumor-bearing mice, contributing to immune tolerance through clonal deletion of tumor-specific T cells and reducing newly generated T cells. Mechanistically, common dendritic cell progenitor-derived pDCs (CDP-pDCs) capture tumor antigens and migrate to the thymus in a CCR9-dependent manner, where they present these antigens to induce clonal deletion of tumor-specific T cells. Concurrently, tumor progression inhibits T cell generation by promoting the accumulation of common lymphoid progenitor-derived pDCs (CLP-pDCs) within the thymus, which further produce type I interferon to alter thymic function. CCR9 deficiency prevents thymic accumulation of both pDCs, enhancing antitumor immunity and reducing tumor growth. Our findings reveal a previously unrecognized mechanism by which tumors hijack the physiological system to establish central tolerance against peripheral antigens, thereby promoting tolerance against themselves.

DOI: https://doi.org/10.1126/sciadv.adx9864
Glia. 2026 09;74(9): e70200

Quantifying Heteromer Partitioning Reveals Inflammation-Dependent Redistribution of Microglial Adenosine A2A and Cannabinoid CB2 Receptors.

Rafael Franco, Jaume Lillo, Christian Griñán-Ferré, Mercè Pallàs, Rafael Rivas-Santisteban.

  G protein-coupled receptor (GPCR) heteromerization represents a key organizational mechanism in cell signaling, but it remains difficult to determine, in native cells, how receptor-associated signals are distributed between non-interacting and heteromer-associated states. Here, we address this limitation by combining proximity ligation assay (PLA) with the newly applied MolBoolean methodology, enabling in situ quantification of the partitioning of adenosine A2A and cannabinoid CB2 receptor-associated signals between non-interacting fractions and A2A-CB2 heteromeric complexes in primary microglia. We show that resting microglia contain detectable A2A-CB2 heteromers together with a substantial non-interacting A2A-associated signal fraction. Selective activation of either receptor promotes redistribution of the detectable receptor-associated signal toward the heteromer-associated fraction. Ligand-induced redistribution also occurred in HEK-293T cells expressing the two receptors. In contrast, pro-inflammatory activation of primary microglia with LPS/IFN-γ markedly changes the basal organization of the receptor system, increasing the proportion of MolBoolean-detectable signal associated with A2A-CB2 complexes, with approximately 70% of the detectable receptor-associated signal corresponding to heteromeric complexes. In this inflammatory context, further agonist-induced repartitioning is strongly limited compared with that observed in resting microglia. These findings identify inflammation-dependent receptor partitioning as a quantitatively measurable feature of microglial A2A and CB2 receptor organization and provide a framework for interpreting how receptor context may influence future studies of A2A-CB2 pharmacology under neuroinflammatory conditions.

Keywords:  GPCR heteromerization; MolBoolean; adenosine A2A receptor; cannabinoid CB2 receptor; in situ proximity ligation; microglial activation; neuroinflammation; precision pharmacology; receptor partitioning

DOI:  https://doi.org/10.1002/glia.70200
Mol Neurobiol. 2026 Jul 18. pii: 779. [Epub ahead of print]63(1):

DNA Sensing and Neuroinflammation: Mechanistic Insights into cGAS-STING Biology and Therapeutic Translation in Age-Related Neurodegenerative Diseases.

Ajmal Ahmad, Mohammad Moshahid Khan.

  Emerging evidence suggests that some of the earliest events contributing to neurodegeneration may occur upstream of classical proteinopathies, underscoring the urgency of identifying molecular pathways that link age-associated genomic instability to chronic neuroinflammation. Among these, DNA sensing through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis has emerged as an important mechanism by which nuclear and mitochondrial stress may promote innate immune activation. In aging and Alzheimer's disease (AD), oxidative stress, impaired DNA repair, and mitochondrial dysfunction can lead to the accumulation of cytosolic DNA and activation of cGAS-STING, contributing to sustained inflammatory signaling, cellular senescence, and synaptic dysfunction. In this review, we synthesize emerging mechanistic and translational insights linking cGAS-STING to genomic instability and neuroinflammation. We highlight the expanding roles of this pathway beyond classical immunity, including its influence on autophagy, cellular senescence, microglial activation, and neurovascular integrity as well as its interactions with key pathological features of age-related neurodegenerative disorders, particularly AD. Finally, we highlight recent advances in pharmacological and genetic modulation of cGAS-STING that support its potential as a therapeutic target for age-related neurodegenerative diseases. By reframing neurodegeneration through the lens of DNA sensing, this review provides an updated perspective on the potential role of cGAS-STING in age-related neurodegenerative diseases.

Keywords:  Aging; Alzheimer’s disease; DNA damage; Immune response; Neuroinflammation; Senescence; cGAS-STING

DOI:  https://doi.org/10.1007/s12035-026-06061-x
Physiol Rep. 2026 Jul;14(14): e71022

Cellular signaling within aged skeletal muscle reveals a dysregulated stress-induced remodeling response following volumetric muscle loss in female mice.

Krista M Habing, Tyler J Sagendorf, Cynthia A Alcazar-Daleo, James A Sanford, Damon Leach, Joshua C Vanderpool, Chelsea M Hutchinson-Bunch, Marina Gritsenko, Gina M Many, Karina H Nakayama.

  Severe muscle trauma disrupts endogenous repair mechanisms and produces chronic functional deficits that are poorly defined in aging. We investigated inflammatory, molecular, and physiological responses to volumetric muscle loss in young adult and aged female mice. Cytokine profiling revealed elevated baseline inflammation in aged mice and a blunted early injury response; for example, IL-6 increased 4.4-fold in young versus 1.8-fold in aged mice at day 3 post-injury. By day 28, histological analyses revealed comparable reductions in muscle size and increased fibrosis across ages. Despite similar structural pathology, age-dependent differences emerged in functional and molecular adaptations. Both groups exhibited persistent force deficits; however, aged muscles showed significantly altered relaxation kinetics (p < 0.001), suggesting dysregulated excitation-contraction coupling. Aged mice also demonstrated altered post-injury limb loading patterns. Global proteomics identified age-associated enrichment of complement and antigen-processing pathways and signatures of metabolic dysfunction (p < 0.05). Phosphoproteomic analysis revealed reduced basal kinase activity in aged muscle but exaggerated injury-induced phosphorylation of Mapk1-associated sites indicating a dysregulated stress response. Together, these findings indicate that aging muscles operate within a heightened inflammatory and perturbed kinase-signaling environment that may impair coordinated regeneration and functional recovery following traumatic injury.

Keywords:  aging; inflammation; muscle regeneration; phosphoproteomics; stress response; volumetric muscle loss

DOI:  https://doi.org/10.14814/phy2.71022
J Neurochem. 2026 Jul;170(7): e70526

APP/Aβ Signaling Orchestrates Reactive Astrocyte Networks in Alzheimer's Disease.

Gretsen Velezmoro Jauregui, Sophie Coomes, Elizabeth Emmett, Alex Thatcher, Nicole Oyelakin, Maria Čarna, Jana Zelinkova, Jan Sebastian Novotny, Natalie Polakova, Tarun Kuruvilla, Robert Zorec, Alexei Verkhratsky, Vladimir Parpura, David Morgan, Kenneth L Moya, Clara Limback-Stokin, Gorazd Bernard Stokin.

  Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, neurofibrillary pathology, synaptic dysfunction, and chronic neuroinflammation, yet the mechanisms driving early, localized pathology remain elusive. While traditionally viewed through a neuron-centric lens, astrocytes express abundant amyloid precursor protein (APP)-predominantly Kunitz-type protease inhibitor (KPI)-containing isoforms-and possess the complete enzymatic machinery for APP processing and Aβ clearance. Astrocytic APP is a stress-responsive signaling molecule regulated by inflammatory, metabolic, excitotoxic, and mechanical insults. Under local tissue stress, reactive astrocytes upregulate APP and shift toward amyloidogenic processing. The resulting bioactive fragments, including Aβ, promote astrocyte activation, disrupt homeostatic functions, and trigger feed-forward upregulation of endogenous APP. We propose that this reciprocal coupling establishes a self-reinforcing network where APP integrates local stress and diffusible Aβ propagates reactive states across the astroglial syncytium. This framework positions astrocytic APP signaling as an upstream driver of localized amyloid accumulation, neuroinflammation, and sporadic AD progression.

Keywords:  Alzheimer's disease; amyloid precursor protein; amyloid‐β peptides; reactive astrocytes

DOI:  https://doi.org/10.1111/jnc.70526
Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2603069123

VAMP7-dependent mitochondria-lysosome contacts contribute to glial mitochondrial dynamics and dopaminergic neuron survival.

Honglei Wang, Mengxiao Wang, Yu-Ting Tsai, Yi-Hsuan Cheng, Yu-Tung Lin, Chia-Ching Lin, Yi-Hua Lee, Linfang Wang, Shuanglong Yi, Shiping Zhang, Yufeng Pan, Margaret S Ho.

  Although disrupted mitochondrial dynamics in neurons are closely linked to neurodegenerative diseases, far less is known about how mitochondrial dynamics are regulated in glia or whether glial mitochondrial dysfunction contributes to neurodegeneration. Here, we show that the R-SNARE protein VAMP7 regulates the untethering of mitochondria-lysosome contacts (MLCs) in adult fly glia. Glial-specific knockdown of VAMP7 leads to prolonged MLCs and mitochondrial elongation associated with altered fission/fusion dynamics. These VAMP7-deficient mitochondria exhibit hyperpolarized membrane potential, leading to increased reactive oxygen species production, lipid droplet accumulation, and dopaminergic neurodegeneration. Mechanistically, VAMP7 interacts with the GTPase-activating protein TBC1D15-17 to promote Rab7 GTP hydrolysis. Without VAMP7, TBC1D15-17 remains bound to Rab7 but fails to activate its hydrolysis, resulting in elevated GTP-bound Rab7 and impaired MLCs untethering. Consistently, expression of GTP-locked Rab7Q67L or GTPase-activating protein-dead TBC1D15-17ΔGAP phenocopies the mitochondrial defects, while GDP-bound Rab7T22N or wild-type TBC1D15-17 restores the MLC dynamics. Considering that SNARE proteins mediate membrane fusion, our results demonstrate a role for VAMP7 in glial mitochondrial dynamics via organelle contacts, impacting neuron survival in a non-cell-autonomous manner.

Keywords:  VAMP7; glia; mitochondrial dynamics

DOI:  https://doi.org/10.1073/pnas.2603069123
Dis Model Mech. 2026 Jul 01. pii: dmm052747. [Epub ahead of print]19(7):

Cell death analysis of inducible, titratable neurodegenerative disease models in zebrafish and human stem cell-derived retinal organoids.

Anneliese Ceisel, Gianna Graziano, Kevin Emmerich, Xiangqian Shi, Tae-In Kam, Miguel Flores-Bellver, M Natalia Vergara, Silvia Aparicio-Domingo, Boris M Brenerman, Anne Vielle, Elsie M Williams, Abigail V Sharrock, Uche Onuchuwku, Georgina S Martinez, Lydia G Sanders, Uzoamaka Nwagbo, Beichen Wang, Huanhuan Xiao, Grant Kroeschell, Yiqi Gao, Daniel J Choe, Caroline E Clouatre, Diego Alfaro Carcoba, Barak Reibman, Catalina Rodriguez, Kevin Yang, Shreya Banerjee, Frazer Matthews, James H Thierer, Genevieve Stein-O'Brien, Ted M Dawson, Valina L Dawson, David F Ackerley, M Valeria Canto-Soler, Liyun Zhang, Jeff S Mumm.

  Inducible disease models enable large-scale screening by providing control over pathology onset, such as cell death in neurodegenerative disease. The nitroreductase (NTR)/prodrug system of cell ablation has facilitated investigations of cell function and regeneration but has not been widely adopted as a disease modeling platform, perhaps owing to assumptions that the cell death mechanism(s) elicited is artificial in nature. Prior reports suggested that NTR/prodrug-mediated death occurred through apoptosis, necroptosis and/or parthanatos, which have all been implicated in neurodegenerative disease. To clarify this issue, we investigated the cell death pathway(s) elicited by the prodrug metronidazole (MTZ) with improved nitroreductase enzyme variants. We assessed the cell death pathway(s) elicited by NTR 2.0-expressing zebrafish retinal neurons using a transcriptomic analysis, chemical inhibitors and gene-targeting assays. NTR-H, a novel NTR variant, was tested - and found to be effective - in human stem cell-derived retinal organoids. Parthanatos was implicated across all conditions tested, while evidence of apoptosis was variable. As parthanatos is associated with neurodegeneration, our results support the use of the NTR/MTZ system to create inducible neurodegenerative models targeted to specific disease-relevant neuronal cell types.

Keywords:  Cell death; Inducible disease model; Neurodegeneration; Nitroreductase; Parthanatos; Retinal organoids

DOI:  https://doi.org/10.1242/dmm.052747
Brain Struct Funct. 2026 Jul 22. pii: 105. [Epub ahead of print]231(7):

Simultaneous activation of border-associated immune cells and glial cells at the CNS-meningeal interface after subarachnoid haemorrhage in rats.

Thannoon Masood, Szandra Lakatos, Melissza Ignácz, Judit Rosta.

  Border-associated macrophages (BAM) and mast cells are resident immune cells at the peripheral CNS borders, strategically located close to the brain surface, potentially influencing the homeostasis of the underlying parenchyma. Subarachnoid haemorrhage (SAH), when blood enters between the meningeal layers that cover the brain, is associated with neuroinflammation, which has been shown to play a critical role in subsequent brain damage; however, the impact of the activation of border-associated immune cells on the pathomechanism of the disease has not been investigated. Our aim was to examine inflammatory reactions that occur simultaneously at the cellular level in various compartments of the CNS: meningeal, subdural space, and parenchyma after experimental SAH in rats. Using immunohistochemistry, we performed the morphological characterisation of the BAM subpopulations in meningeal preparations. Additionally, confocal microscopy and image analysis were used to evaluate the reactive state of microglia cells and the integrity of the glial boundary in the upper fronto-parietal cortex of the rat 72 h after SAH. We demonstrated morphological alterations of BAM populations in the meninges and parallel disintegration of the astrocyte barrier due to haemorrhage. Furthermore, we confirmed the crucial role of mast cells in subsequent glial reactions. Our results suggest that activation of border-associated immune cells, contemporaneously with the early neuroinflammatory reactions that take place in the brain parenchyma, proposes a feasible signalling between these compartments following haemorrhage. Further studies are to be performed to reveal the importance of CNS meningeal border as a communication interface in the pathomechanism of SAH.

Keywords:  Border-associated macrophage; Mast cell; Meningeal immunity; Meninges; Neuroinflammation; Subarachnoid haemorrhage

DOI:  https://doi.org/10.1007/s00429-026-03156-y
Brain. 2026 Jul 23. pii: awag247. [Epub ahead of print]

Photobiomodulation of immune crosstalk rescues neuroinflammation in Alzheimer's disease models.

Qi Shen, Haocai Chang, Junyu Li, Haoyun Guo, Wenbin Shi, Yihua Yan, Wenwen Ouyang, Zhan Zhang, Xiaolei Wu, Da Xing, Sihua Yang.

  Peripheral immune cell infiltration and crosstalk with brain-resident cells critically drive Alzheimer's disease (AD)-associated neuroinflammation, highlighting its therapeutic potential. Here, we found that photobiomodulation (PBM) markedly reduced cerebral CD8+ T cells infiltration in the cortex of AD (APP/PS1 and 3×Tg) mice, thereby improving cognition, and alleviating AD-related pathology by mitigating neuronal damage and gliosis. Immunofluorescence and transcriptomic analyses revealed that PBM inhibited the release of chemokines and pro-inflammatory cytokines from microglia, reducing endothelial adhesion molecules-mediated T cell migration. Concurrently, reduced secretion of tumor necrosis factor-α, interleukin-1α, and complement component 1q by pro-inflammatory microglia further diminished neurotoxic A1 astrocyte induction. Genetic overexpression or pharmacological inhibition further validated that PBM disrupted microglia NOD-like receptor protein 3 inflammasomes activation, attenuating astrocyte reactivity and T cells recruitment. These findings collectively suggest that the PBM-induced modulation of crosstalk between microglia, astrocytes, and CD8+ T cells is closely related to cognitive improvement. Reprogramming central-peripheral immune crosstalk with PBM resolves neuroinflammation and restores cognition in AD models-a translatable strategy for combating neurodegeneration.

Keywords:  Alzheimer’s disease; CD8+ T cells; central-peripheral immune crosstalk; neuroinflammation; photobiomodulation

DOI:  https://doi.org/10.1093/brain/awag247
Cell Metab. 2026 Jul 20. pii: S1550-4131(26)00284-6. [Epub ahead of print]

Elevation of JAML Promotes Diabetic Kidney Disease by Modulating Podocyte Lipid Metabolism.

Yi Fu, Yu Sun, Mei Wang, Yunfeng Hou, Wei Huang, Di Zhou, Ziying Wang, Shuting Yang, Wei Tang, Junhui Zhen, Yujia Li, Xiaojie Wang, Min Liu, Yan Zhang, Baobao Wang, Guangyi Liu, Xiao Yu, Jinpeng Sun, Chun Zhang, Fan Yi.

DOI: https://doi.org/10.1016/j.cmet.2026.07.011
Glia. 2026 Sep;74(9): e70194

Cdk7 Regulates Myelin Sheath Morphology and Lipid Homeostasis in Schwann Cells.

Nathalie Schumacher, Alexandra Pieltain, Pierre Tocquin, Nicolas Thelen, Arnaud Lavergne, Nathalie Masar, Romano Terrasi, Romane Leloup, Giulio Muccioli, Philippe Gailly, Peter Arthur-Farraj, Renaud Vandenbosch, Rachelle Franzen.

  Schwann cells (SC) are responsible for myelination in the peripheral nervous system (PNS). Myelin allows saltatory transmission of action potentials along axons and functionally relies on its unique constitution. We previously reported that Cdk7, a regulator of cell cycle progression and transcription, regulates myelin gene expression in oligodendrocytes and contributes to myelin maintenance in the central nervous system. Using mice with conditional Cdk7 knock-out in SCs, we provide evidence that Cdk7 is dispensable for myelin initiation but needed for the correct myelin thickness of larger caliber fibers in young mice, as well as for myelin elongation and rapid nerve conduction throughout age. We report that Cdk7 loss results in disturbed myelin stoichiometry, with significant dysregulation of lipid-related genes in SCs and a reduction in myelin protein zero. Finally, we demonstrate that Rxrγ, a nuclear receptor involved in lipid metabolism, is significantly downregulated in the absence of Cdk7. However, although Cdk7 regulates myelin segment length, our results indicate that this effect occurs independently of Rxrγ in myelinating dorsal root ganglion explants.

Keywords:  Cdk7; Schwann cells; lipids; myelin

DOI:  https://doi.org/10.1002/glia.70194
PLoS One. 2026 ;21(7): e0344737

Cone photoreceptor ablation in microglia-deficient larval zebrafish retina elicits a regenerative response alongside a compensatory immune cell response.

Jordan E Rumford, Ashley A Farre, Justin Mai, Halle V Weimar, Claire D Shelton, Michael Morales, Diana M Mitchell.

Emerging evidence implicates retinal microglia and inflammation as important components impacting the outcome of retinal regeneration, which is spontaneously achieved in zebrafish retina following acute damage but is limited or blocked in mammals. Here we describe the regenerative response in the larval zebrafish retina following ablation of cone photoreceptors. To investigate the role of microglia in the regenerative response, we used irf8st95 heterozygote (microglia-sufficient) and irf8st95 homozygous mutant (microglia-deficient) zebrafish. We compared multiple aspects of the regenerative response in irf8 + /- and irf8-/- larval retinas, including entry of the Müller glia (MG) into the cell cycle, the amplification of MG-derived progenitor cell (MGPC) proliferation, inflammatory and glial reactivity-associated gene expression, and the regeneration of cones. We found only modest impacts to early and late stages of MGPC proliferation and to inflammatory gene expression in irf8 mutants, with no obvious impacts to the regeneration of cones. Notably, we detected a population of immune cells in irf8 mutants that emerged following cone ablation, which expanded in number then were reduced over time, following a trajectory similar to microglia-sufficient siblings but at markedly reduced abundance. The immune cells detected in irf8 mutants included a subset with L-plastin/4C4 antibody staining patterns different than those in microglia-sufficient siblings, suggesting distinct origins and/or phenotype compared to resident microglia in controls. The presence of immune cells in irf8 mutants following cone ablation limited our ability to make strong conclusions about the role of microglia in regeneration of cones. However, our results are consistent with several reports that indicate a role for microglia in regulating MGPC proliferation in the regenerating retina. Collectively considered with other reports, our results further indicate that compensatory responses, which may include different immune cells and/or signaling from other retinal cell types such as Müller glia, may be elicited in microglia-deficient retinas upon neuronal damage.

DOI: https://doi.org/10.1371/journal.pone.0344737
Metab Brain Dis. 2026 Jul 21. pii: 173. [Epub ahead of print]41(1):

Seipin modulates Alzheimer's disease pathogenesis by regulating ferroptosis through a glycine-mediated metabolic pathway.

Xiaoqiong An, Daoju Wu, Yijia Wang, Zhenkui Ren, Wenfeng Yu.

  Alzheimer's disease (AD) remains an incurable neurodegenerative disorder with an elusive pathogenesis, where emerging evidence implicates metabolic dysregulation and ferroptosis in neuronal loss. Although the BSCL2 gene, which encodes Seipin, is crucial for lipid metabolism, its specific role in the progression of AD remains undefined. This study employed Mendelian randomization (MR) analysis, in vivo APP/PS1 mouse models, and in vitro BV2 microglial assays to elucidate the mechanistic axis linking BSCL2, metabolites, and ferroptosis in AD. MR analysis demonstrated a causal relationship between genetically predicted elevated BSCL2 expression and an increased risk of AD, partially mediated by glycine. Supporting these genetic findings, stereotactic knockdown of Seipin in the hippocampus of APP/PS1 mice significantly ameliorated cognitive deficits without inducing systemic metabolic toxicity. Mechanistically, Seipin deficiency reduced ferroptosis in both AD mouse brains and Aβ-stimulated microglia, as evidenced by the upregulation of anti-ferroptotic markers (GPX4, Nrf2, HO-1) and the suppression of pro-ferroptotic effectors (ACSL4, NCOA4). Moreover, glycine supplementation partially ameliorated the aggravated ferroptotic phenotype caused by Seipin overexpression, indicating a functional feedback mechanism in which glycine facilitates glutathione synthesis to mitigate Seipin-induced lipid peroxidation. These findings collectively identify Seipin as a novel regulator of ferroptosis in the pathogenesis of AD and underscore the potential of the BSCL2-glycine-ferroptosis axis as a therapeutic target. Future research should aim to elucidate the specific molecular interactions between Seipin and the iron-handling machinery and to validate glycine-based interventions in clinical settings as a means to prevent neurodegeneration.

Keywords:  Alzheimer's disease; EQTL; Ferroptosis; Mendelian randomization (MR); Seipin

DOI:  https://doi.org/10.1007/s11011-026-01941-6
Mol Neurodegener. 2026 Jul 18.

AQP4-dependent enhancement of glymphatic function attenuates tau pathology and neurodegeneration in PS19 mice.

Kaoru Yamada, Kazuhisa Ishida, Asami Sakamoto, Hitoshi Shimada, Masaki Watanabe, Masato Shimojo, Hironaka Igarashi, Takeshi Iwatsubo.

   BACKGROUND: The glymphatic system facilitates cerebrospinal fluid-interstitial fluid exchange and contributes to the clearance of pathogenic proteins from the brain. Glymphatic dysfunction has been associated with Alzheimer's disease and related tauopathies; however, whether impaired glymphatic transport causally drives tau accumulation and neurodegeneration, and whether its enhancement confers therapeutic benefit, remains unclear.
METHODS: Glymphatic water dynamics in PS19 tau transgenic mice were assessed using JJVCPE, a novel MRI-based approach for evaluating brain water exchange. The effect of pharmacological activation of aquaporin-4 (AQP4) with TGN-073 on glymphatic cerebrospinal fluid influx was examined in wild-type mice using dynamic contrast-enhanced MRI. Tau pathology, neurodegeneration, and cerebrospinal fluid tau levels were analyzed in PS19 mice following chronic TGN-073 treatment. AQP4-deficient PS19 mice were examined to determine target specificity.
RESULTS: PS19 mice exhibited significant impairment of glymphatic water exchange at early disease stages, which progressively worsened with ageing. Pharmacological activation of AQP4 with TGN-073 robustly enhanced glymphatic-related tracer influx, reduced tau accumulation, neuronal loss, and gliosis, and was accompanied by increased cerebrospinal fluid tau levels. TGN-073 also restored perivascular AQP4 enrichment without significantly altering overall AQP4 abundance. Importantly, these beneficial effects were abolished in AQP4-deficient PS19 mice, demonstrating that both glymphatic enhancement and suppression of tau pathology and neurodegeneration are AQP4-dependent.
CONCLUSIONS: Our findings support a mechanistic contribution of impaired glymphatic function to tau accumulation and neuronal vulnerability in tauopathy. Pharmacological activation of AQP4 enhances glymphatic function, restores perivascular AQP4 organization, and ameliorates tau pathology, neurodegeneration, and gliosis. These findings identify AQP4-mediated glymphatic modulation as a disease-relevant and therapeutically tractable pathway for tau-related neurodegenerative disorders.

Keywords:  Alzheimer’s disease; Aquaporin-4; Cerebrospinal fluid dynamics; Glymphatic system; Tau pathology

DOI:  https://doi.org/10.1186/s13024-026-00977-7
Sci Adv. 2026 Jul 24. 12(30): eadz6836

Synaptic vesicles that store monoamines and glutamate differ in protein composition.

Hrach Asmerian, Alexia J Diaz, Hongfei Xu, Juan A Oses-Prieto, Jacob Alberts, Barathan Gnanabharathi, Anna M Sanetra, Poulomi Das, Noah Carr, Alma L Burlingame, Robert H Edwards, Kätlin Silm.

Neuromodulators such as monoamines assure essential brain functions, but relatively little is known about their mechanism of release. While recent work has advanced our knowledge of active zone architecture in dopamine axons, release machinery within the synaptic vesicle (SV) remains poorly understood. Here, we address differences between the release of monoamines and synaptic transmitters by comparing the composition of SVs that contain the vesicular monoamine transporter 2 (VMAT2) versus vesicular glutamate transporter 2 (VGLUT2). Previous work revealed that these SVs differ in frequency dependence, recycling kinetics, and biogenesis. We now find differences in the abundance and isoform expression of many SV protein families and validate these differences in primary neurons and brain tissue. Functional analysis after heterologous expression in hippocampal neurons shows that loss of differentially expressed SCAMP5 selectively impairs the recycling of VGLUT2 SVs, sparing vesicles targeted by VMAT2 in the same neuronal population. These findings provide insights into the molecular diversity of SVs and mechanisms of dopamine release.

DOI: https://doi.org/10.1126/sciadv.adz6836
Neuron. 2026 Jul 21. pii: S0896-6273(26)00488-5. [Epub ahead of print]

Senescent cell heterogeneity in brain aging and neurodegenerative disease.

Sara I Graves, Pedro Versuti Del Cioppo Vasques, Darren J Baker.

  Senescent cells in the aging and diseased brain are increasingly recognized as highly heterogeneous catalysts of dysfunction, originating from diverse cell types and characterized by wide-ranging molecular signatures and functional outcomes. Additionally, technological advances in single-cell transcriptomics and mouse modeling have helped reframe senescence from a static fate to a dynamic trajectory that is heavily influenced by evolving environmental cues. In this review, we identify key hubs of heterogeneity in brain cell senescence. We discuss how differences in senescence induction, cell-cycle arrest mechanisms, cell-type biology, and microenvironments contribute to the diverse senescence programs observed in the central nervous system. We also synthesize insights from the recent wave of single-cell transcriptomic studies and discuss how advances in spatial omics technologies could transform our ability to study senescent cells within intact neural circuits. Finally, we argue that integrating multimodal molecular profiling with functional studies in mice will be essential for advancing mechanistic understanding and therapeutic targeting of senescent cells in brain aging and disease.

Keywords:  aging; cellular senescence; mouse models; neurodegeneration

DOI:  https://doi.org/10.1016/j.neuron.2026.06.020
Nat Commun. 2026 Jul 23. pii: 6817. [Epub ahead of print]17(1):

Absent pleocytosis in infant viral central nervous system infections reflects lymphocyte depletion and cytokine activation.

Clare Mills, Holly Drummond, Helen E Groves, Etimbuk Umana, Thomas Waterfield.

Enterovirus and parechovirus infections are common causes of fever in young infants and frequently prompt evaluation for meningitis. A notable feature of these infections is that many infants have detectable viral genetic material in the cerebrospinal fluid but no increase in white blood cells. This absence of pleocytosis has been attributed to early presentation, immature or suppressed immune responses, or incidental virus detection during systemic infection rather than true central nervous system (CNS) infection or meningitis. Here, we clarify the clinical and biological significance of absent pleocytosis in infant viral CNS infections using plasma proteomic profiling and detailed clinical data from a prospective multicentre cohort of febrile infants. We show that infants without pleocytosis display lymphopenia and marked activation of inflammatory and apoptotic pathways in the plasma, implicating lymphocyte depletion in impaired cerebrospinal fluid leucocyte recruitment and supporting true neurological infection.

DOI: https://doi.org/10.1038/s41467-026-75026-4
J Clin Invest. 2026 Jul 21. pii: e201325. [Epub ahead of print]

SREBP1c modulates Treg immunobiology through a phospholipid-dependent adenosine pathway.

Fabrizia Bonacina, Claudio Procaccini, Marta Iaia, Arianna Moretti, Monika Svecla, Silvia Pedretti, Jeroen Fj Bogie, Giovani Battista Vingiani, Annalisa Moregola, Francesca Genova, Claudia Russo, Giusy De Rosa, Claudia La Rocca, Giada Mondanelli, Marco Gargaro, Nico Mitro, Giuseppe Matarese, Giuseppe Danilo Norata.

  Regulatory T cells (Tregs) maintain immune tolerance through mechanisms tightly coupled to cellular metabolism. Whereas glycolysis supports Treg migration, lipid metabolism sustains their suppressive phenotype. Here, we identify the sterol regulatory element-binding protein 1c (SREBP1c) as a central regulator of Treg immunobiology. Tregs from Srebp1c-deficient mice displayed impaired suppressive function, reduced frequencies in circulation and lymphoid tissues, and diminished expression of functional markers. These defects stemmed from intrinsic metabolic rewiring rather than systemic alterations, as both ex vivo Tregs (CD4+CD25hiFoxP3+) and in vitro-derived Tregs lacking Srebp1c were shifted toward glycolysis. Integrated transcriptomic and lipidomic analyses revealed that Srebp1c-deficient Tregs exhibited defective phospholipid remodeling, with an accumulation of lysophosphatidylcholines over phosphatidylcholines, which we attributed to enhanced cytosolic phospholipase A2 (cPLA2α) activity and disruption of the Lands cycle. Altered lipid composition impaired adenosine-mediated immunosuppression by reducing CD73 expression and extracellular adenosine generation. Accordingly, pharmacological inhibition of cPLA2α restored adenosine signaling, CD73 expression, and Treg suppressive capacity. Thus, by preserving phospholipid homeostasis, SREBP1c functions as an immunometabolic checkpoint that links lipid metabolism to adenosine-dependent Treg suppression.

Keywords:  Immunology; Lipidomics; Metabolism; Metabolomics; Tregs

DOI:  https://doi.org/10.1172/JCI201325
J Neuroinflammation. 2026 Jul 21.

Central microglia-adenosine-related signaling impairs bone-tendon interface repair via sympathetic ADRB2 activation.

Tingmo Huang, Liyang Wan, Ruixue Du, Liyue Zeng, Wenjie Li, Feifei Yuan, Hongbin Lu.

  Bone-tendon interface (BTI) injuries pose a major clinical challenge because surgical repair often fails to restore the native enthesis and its structural and mechanical integrity. Although local repair mechanisms have been extensively studied, whether central neuroimmune circuits contribute to BTI healing remains unclear. Here, using a murine rotator cuff injury model, we provide evidence that BTI injury engages a sensory-central-sympathetic regulatory axis that contributes to impaired repair. BTI injury activated sensory afferent signaling and was associated with microglia-mediated neuroinflammation in the hypothalamic paraventricular nucleus (PVN), reduced PVN neuronal activity, and increased central adenosine-related signaling. Chemogenetic activation of PVN microglia suppressed PVN neuronal activity, enhanced sympathetic-associated changes, and impaired BTI healing, whereas microglial inhibition produced the opposite effects. Metabolomic, microdialysis, and pharmacological analyses identified extracellular adenosine as a microglia-associated signaling mediator, likely involving A1R-expressing PVN neurons. Downstream, increased sympathetic signaling at the healing interface was associated with elevated β2-adrenergic receptor (ADRB2) activity and reduced osteogenic and chondrogenic factor expression. Local ADRB2 blockade improved molecular, structural, and histological indices of BTI repair, supporting ADRB2 as a peripheral effector node of this neuroimmune-sympathetic pathway. Together, these findings suggest that central microglia-adenosine-related signaling contributes to BTI repair impairment through sympathetic ADRB2 activation. Targeting central neuroimmune signaling or local ADRB2 activity may provide potential strategies for improving BTI healing.

Keywords:  Adenosine signaling; Bone-tendon interface; Microglia; Neuro-immune-skeletal axis; Paraventricular nucleus

DOI:  https://doi.org/10.1186/s12974-026-03977-y
Acta Neuropathol. 2026 Jul 20. pii: 7. [Epub ahead of print]152(1):

Complement dysregulation during the early phases of synucleinopathy.

Hina Khan, Mary Gifford, Arash Kordbacheh, Asher Bury, Spencer Panoushek, Allyson Cole-Strauss, Christopher J Kemp, Kelvin C Luk, Kathy Steece-Collier, Nathan C Kuhn, Nicholas M Kanaan, Caryl E Sortwell, Joseph R Patterson, Matthew J Benskey.

  Parkinson's disease (PD) is characterized by progressive degeneration of nigrostriatal dopamine neurons and synucleinopathy, which is the accumulation of aggregated α-synuclein (α-syn). Increasing evidence implicates α-syn-associated neuroinflammation as a contributor to PD pathogenesis, yet immune mechanisms linking synucleinopathy to neurodegeneration remain incompletely defined. Activation of the complement cascade occurs in PD and other synucleinopathies, but most studies report complement activation after overt neurodegeneration, making it difficult to conclude if complement is directly activated by pathological α-syn or secondarily following neurodegeneration. We used the rat α-syn preformed fibril (PFF) model, in vitro complement assays and postmortem human PD tissue to investigate whether pathological α-syn directly activates complement prior to overt neurodegeneration. The α-syn PFF model exhibits a protracted pathological time course and distinct temporal separation between peak α-syn aggregation and nigrostriatal degeneration. Thus, we quantified complement expression, activation, and regulation during the aggregation phase. Synucleinopathy caused complement activation prior to nigrostriatal degeneration, including upregulation of components of both the classical (C1qa, C1r, C4b) and alternative (Cfd, Cfb) pathways, the anaphylatoxin (C3aR, C5aR) and phagocytic (CR3) complement receptors, and activation of complement C3. During early synucleinopathy microglia upregulated C3, which significantly correlated with synucleinopathy burden across several brain regions, including the substantia nigra pars compacta (SNc) and cortex. Concurrently, complement regulators, including Cd55, Cd59, neuronal pentraxin-1 (Nptx1), and the neuronal pentraxin receptor were downregulated in the synucleinopathy-affected SNc. Importantly, increased levels of C1q and iC3b along with downregulation of CD55 and NPTX1 protein were also observed in human postmortem PD SNc tissue, supporting the translational relevance of our findings. Mechanistically, we demonstrate that aggregated, but not monomeric, α-syn directly binds C1q and activates the complement cascade in a C1q-dependent manner. These data provide the first in vivo evidence that synucleinopathy triggers complement activation and dysregulation prior to neurodegeneration.

Keywords:  Alpha-synuclein; Complement system; Neurodegeneration; Neuroinflammation; Parkinson’s disease; Synucleinopathy

DOI:  https://doi.org/10.1007/s00401-026-03057-8
Nat Cell Biol. 2026 Jul 20.

Mitochondrial-derived vesicles drive budding-type fission of damaged lysosomes.

Yuanchun Luo, Jianglong Yu, Zhuofan Li, Wanning Li, Le Jiang, Chen Huang, Zhouyi Rong, Long Lin, Yueguang Rong, Chaojun Yan, Zhishui Chen, Jingfeng Tang, He He, Anbing Shi, Zhiyin Song.

Lysosomes are central degradative organelles essential for cellular homeostasis, yet the mechanisms that maintain their integrity and function under stress remain incompletely understood. Here we identify a previously unrecognized lysosomal renewal process, termed budding-type fission (B-fission), which restores lysosomal function during hypoxia-reoxygenation stress. During B-fission, damaged lysosomes generate membrane buds that undergo scission to form small, fully functional lysosomes, independently of autophagic lysosome reformation. Mechanistically, mitochondrial-derived vesicles (MDVs) deliver the fission adaptor MFF to lysosomes, where MFF recruits the dynamin-related GTPase DRP1 to drive membrane scission. MIRO2 promotes the formation of MFF+ MDVs through direct interaction with MFF, while the lysosomal membrane protein ITM2C binds MIRO2 to tether and guide MFF+ MDVs to lysosomes, enabling efficient MFF delivery and subsequent B-fission. Notably, AMPK activation by 991 or metformin promotes MFF-dependent lysosomal B-fission under normoxic conditions, whereas AMPK inhibition by dorsomorphin suppresses B-fission during hypoxia-reoxygenation. This stress-responsive ITM2C-MIRO2-MFF-DRP1 axis co-opts the mitochondrial division machinery to drive lysosomal fission from damaged lysosomes, thereby enabling the undamaged components to reorganize into daughter lysosomes and promote lysosomal renewal. Thus, our findings uncover a fundamental mode of lysosomal renewal and reveal an unexpected role for MDV-mediated mitochondria-lysosome communication in mediating lysosomal quality control during ischaemia-reperfusion and related stresses.

DOI: https://doi.org/10.1038/s41556-026-02010-x
Glia. 2026 09;74(9): e70205

Deletion of Astrocytic TNFR1 Attenuates Hyperexcitability and Initiation of Epileptogenesis.

Lukas Henning, Ioannis Zalachoras, Giovanni Carriero, Gerald Seifert, Peter Bedner, Christian Steinhäuser, Andrea Volterra.

  Temporal lobe epilepsy (TLE), the most common form of adult focal epilepsy, is highly resistant to current medical therapy. Cytokine signaling, including via tumor necrosis factor-alpha (TNFα), has been implicated not only as an accompanying factor but as a key aspect in the initiation of the disease. TNFα, through its type-1 receptor (TNFR1) in astrocytes, controls excitatory circuits in the hippocampus, yet it remains unknown whether this astrocyte pathway specifically contributes to epilepsy. Here, we used a conditional cell-specific knockout mouse line to induce TNFR1 deletion selectively in astrocytes and test its roles in the initiation and progression of TLE. Mice lacking astrocyte TNFR1 showed decreased basal spectral power, longer latency to first seizure following treatment with kainic acid, and a less severe phenotype up to 4 weeks later. Thus, abrogation of astrocyte TNFR1 signaling may be beneficial in TLE and could provide a new therapeutic target for this disease.

Keywords:  astrocyte; cytokine; gap junction channels; hippocampal sclerosis; status epilepticus; temporal lobe epilepsy; tumor necrosis factor alpha

DOI:  https://doi.org/10.1002/glia.70205