bims-microg 2026-07-12 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–07–12
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice.
Plant-derived mitochondria mitigate aging-related neurodegeneration by reprogramming microglial mitochondrial energy metabolism.
Protein kinase CK2α' as a dual modulator of neuroimmune signaling and synaptic dysfunction in tauopathy.
FcγR- and CD9-dependent synapse-engulfing microglia in the thalamus drive cognitive impairment following cortical brain damage in mice.
Fus-depleted oligodendrocytes reduce neuronal damage and Alzheimer's disease progression in the AppNL-G-F mouse.
The Wiskott-Aldrich Syndrome protein (WASp) contribution to microglial phagocytic function and neurodevelopmental support.
Microglial PTP1B promotes synaptic pathology and cognitive deficits in chronic Toxoplasma gondii infection.
Exosomes from bipolar disorder patients induce mania- and depression-like behaviors in mice via shared and distinct neuroimmune signatures.
Sex-associated neuroinflammatory and astrocytic responses in amyotrophic lateral sclerosis: evidence from clinical cohorts and a TDP-43 N390D mouse model.
Calcium signaling in human and mouse microglia exhibit differential susceptibility to phytocannabinoids.
Matrix metalloprotease-9 modulates microglial/macrophage responses in murine brain demyelination.
CSF1R inhibition following antibody mediated demyelination has limited impact on remyelination.
Endothelial TGFβ signaling modulates choroidal neovascularization severity via myeloid-endothelial cell interaction.
Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING.
From DNA-encoded library (DEL) screening to in vivo validation: LILRB4 (ILT3)-targeted small molecules reprograms myeloid immune suppression.
Microglial P2ry12 in the Basolateral Amygdala Underlies Neuropathic Pain-Induced Anxiety.
Unveiling the Functional Role of KIF21B in Microglia Inflammatory Response.
Microglia derived from human induced pluripotent stem cells are regulated by osteopontin, an endogenous extracellular matrix protein maintaining immune homeostasis.
Microglia suppress Müller cell FGF1 and contribute to retinal ganglion cell degeneration in glaucoma.
YAP Regulates the Nrf2 Signaling Axis to Attenuate Oxidative Stress and Neuroinflammation in Retinal Ganglion Cell Degeneration.

Nat Neurosci. 2026 Jul 08.

Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice.

Anne-Claire Compagnion, Andranik Ivanov, Anil Rana, Felipe Espinoza, Thomas Sandmann, Fanny S Martineau, Katia Monsorno, Roberta Facchinetti, Alessandro Matera, Lionel Rougé, Fernando González Ibáñez, Clarissa Catale, Matteo Bizzotto, Sonia Garel, Michela Matteoli, Yutaro Kashiwagi, Ryuta Koyama, Christian Haass, Marie-Eve Tremblay, Dieter Beule, Ileana Jelescu, Valerio Zerbi, Gilbert Di Paolo, Rosa C Paolicelli.

TDP-43 proteinopathy is a hallmark of neurodegenerative disorders such as amyotrophic lateral sclerosis and frontotemporal dementia where mislocalization of TDP-43 has been observed in neurons and glial cells. However, the role of TDP-43 in microglia and the consequences of its loss of function remain unexplored. Combining magnetic resonance imaging, and confocal, and electron microscopy, we uncovered structural changes and myelin abnormalities in the early postnatal brain of mice lacking microglial TDP-43. Spatial transcriptomics further revealed an enriched interferon-responsive signature associated with oligodendrocyte dysfunction. Early depletion of microglial TDP-43 led to motor deficits in adult mice. Mechanistically, knocking out TDP-43 impaired microglial ability to engulf and degrade myelin. It also led to cryptic exon inclusion in the Tyrobp mRNA, resulting in truncated DAP12 protein, thus causing defective TREM2 signaling. Our findings reveal a role for TDP-43 in regulating the TREM2-DAP12 axis in mice, highlighting a previously unrecognized mechanism through which TDP-43 controls microglial function.

DOI: https://doi.org/10.1038/s41593-026-02348-3
Transl Neurodegener. 2026 Jul 08. pii: 30. [Epub ahead of print]15(1):

Plant-derived mitochondria mitigate aging-related neurodegeneration by reprogramming microglial mitochondrial energy metabolism.

Yun Teng, Chao Luo, Qingbo Xu, Jingyao Mu, Lucy Teng, Hongjia Qian, Yinan Huang, Minmin Liu, Lifeng Zhang, Juw Won Park, Jae Yeon Hwang, Maiying Kong, Jun Yan, Michael L Merchant, Huang-Ge Zhang.

   BACKGROUND: Intercellular mitochondrial transfer is pivotal in both healthy and pathological states. Supplementing healthy mitochondria is emerging as a promising therapeutic approach for various diseases. Non-immunogenic edible plants, which contain mitochondria, offer a novel avenue for such therapies.
METHODS: Mitochondria were isolated from several commonly consumed edible plants (P-Mit) using differential centrifugation followed by sucrose gradient ultracentrifugation. The distribution of P-Mit, particularly in the brain, was examined with a mitochondrial membrane-potential dye and an imaging system. As a proof of concept, the molecular interactions underlying turmeric-derived mitochondria (T-Mit) uptake by microglia were elucidated through affinity precipitation coupled with mass spectrometry. By labeling with gold-nanoparticles in a distinct triangular or spherical shape followed by electron microscopy and energy dispersive spectroscopy analysis, we demonstrated the physical fusion of T-Mit and animal mitochondria in microglia. Mitochondrial functions such as superoxide levels, ATP-linked mitochondrial respiration, glycolysis and electron transport chain activity were assessed to determine the impact of T-Mit on aging-related microglial dysfunction. Next-generation small RNA sequencing revealed the underlying mechanism by which T-Mit-derived small RNAs modulate the expression of NADH dehydrogenase (ND) genes in microglia.
RESULTS: Orally administered T-Mit travelled from the gut to the brain in aged male mice, where they fused with microglial mitochondria (M-Mit), reprogramming M-Mit energy metabolism and reversing aging-related cognitive dysfunction. Specifically, T-Mit was taken up by microglia via the phagocytic receptor TREM2. Subsequently, T-Mit fused with M-Mit in a mitofusin 1-dependent manner. The T-Mit microRNAs Tae-miR319 and Osa-miR166a-3p then integrated into M-Mit, inhibiting the expression of complex I subunits ND4 and ND5. This inhibition alleviated reverse electron transport (RET) at complex I, reducing reactive oxygen species (ROS) production and facilitating ATP production, ultimately rescuing aging-related cognitive decline. Data from elderly human subjects also showed overactivation of the RET process and overproduction of ROS, accompanied by low ATP levels in microglia.
CONCLUSIONS: Our findings fundamentally alter our understanding of the regulation of mammalian mitochondrial biology by P-Mit and may lead to P-Mit-based transfer therapy for preventing or treating human mitochondrial disorder-related diseases.

Keywords:  Aging-related neurodegeneration; Cardiolipin; Cross-kingdom mitochondrial fusion; Microglia mitochondrial metabolism; Mitochondria transfer therapy; NADH dehydrogenase (Complex I); Plant mitochondrial microRNAs; Plant mitochondria; Reactive oxygen species (ROS); Reverse electron transport (RET)

DOI:  https://doi.org/10.1186/s40035-026-00565-1
Transl Neurodegener. 2026 Jul 09. pii: 31. [Epub ahead of print]15(1):

Protein kinase CK2α' as a dual modulator of neuroimmune signaling and synaptic dysfunction in tauopathy.

Angel White, Peter Gavrilyuk, Persephone Gu, Rafael Falcon-Moya, Reid Thurston, Amal Fickak, Nicholas B Rozema, Prarthana Keshavaram, Scott Vermilyea, Riley Schlichte, Joyce Meints, Ying Zhang, Alfonso Araque, Michael K Lee, Rocio Gomez-Pastor.

   BACKGROUND: Tauopathies are a group of neurodegenerative diseases characterized by tau accumulation, neuroinflammation, and synaptic dysfunction, yet effective treatments remain elusive. Protein kinase CK2 is a holoenzyme composed of two regulatory (CK2β) and two catalytic subunits (CK2α and CK2α') and has been linked to multiple aspects of tau pathology. However, genetic evidence defining the specific contributions of CK2 subunits to tau phosphorylation and tauopathy remains lacking. Elucidating subunit-specific roles is critical for the rational development of CK2-targeted therapies.
METHODS: To investigate the impact of CK2 in tauopathy, Neuro-2a and primary cell cultures expressing mutant tau were treated with siRNAs targeting the two catalytic subunits of CK2, CK2α and CK2α'. In addition, the PS19 mouse model of tauopathy was bred to be haploinsufficient for the catalytic subunit CK2α'. Changes in pathology and symptomatology were analyzed via immunohistochemistry, immunoblotting, RNA-sequencing, in situ hybridization, electrophysiology, and Barnes Maze.
RESULTS: We found that the expression of the catalytic subunit CK2α', but not catalytic CK2α or regulatory CK2β subunits, was elevated in postmortem brains of dementia patients and in the hippocampus of PS19 tauopathy mice, especially in neurons and microglia. Using a haploinsufficient model of CK2α' in PS19 mice, we demonstrated that the PS19:CK2α'(+/-) mice had significantly decreased phosphorylated tau and total tau burden in the hippocampus and cortex. CK2α' depletion also attenuated microglial activation, pro-inflammatory cytokine production and microglia synaptic engulfment, and enhanced synaptic gene expression, synaptic density, and long-term potentiation. Importantly, CK2α' haploinsufficiency rescued cognitive deficits assessed in the Barnes maze.
CONCLUSIONS: Here, we show CK2α', one of the two catalytic subunits of CK2, as a novel regulator of tau-mediated neurodegeneration. These effects appear to be mediated through both neuronal and glial functions and may involve CK2α'-dependent modulation of tau phosphorylation as well as neuroinflammatory and immune signaling pathways. These findings identify CK2α' as a mechanistically defined and potentially druggable target for therapeutic strategies aimed at modifying tau-driven neurodegeneration.

Keywords:  CK2; CK2α′; Microglia; Phagocytosis; Synaptic function; Tauopathy

DOI:  https://doi.org/10.1186/s40035-026-00563-3
Nat Commun. 2026 Jul 09.

FcγR- and CD9-dependent synapse-engulfing microglia in the thalamus drive cognitive impairment following cortical brain damage in mice.

Ken Matoba, Takahiro Kochi, Oluwaseun Fatoba, Md Sorwer Alam Parvez, Inssaf Berkiks, Yassin R Mreyoud, Harrison Strong, Jana H Badrani, Hency Patel, Yoshiko Nagaoka-Kamata, Masakazu Kamata, Hiroshi Tsujioka, Toshihide Yamashita, David K Crossman, Minae Niwa, Shin-Ichi Kano.

Chronic neuroinflammation gives rise to diverse microglial states across the brain, yet how region-specific microglial remodeling contributes to cognitive dysfunction remains unclear. Here we report that synapse-engulfing microglia in the thalamus drive cognitive impairment after cortical brain damage in mice, primarily studied in females. Region-specific manipulations of microglia during the chronic phase show that reactive microglial changes in the thalamus, but not in the hippocampus, impair recognition memory. Single-cell RNA sequencing reveals an enrichment of synapse-engulfing CD9hi microglia in the thalamus. Antibody-based CD9 blockade in the thalamus, as well as microglia-selective CD9 disruption, rescues thalamic synaptic loss, restores neuronal activity, and improves recognition memory. Further analysis shows that the blood-brain barrier disruption and subsequent γ-immunoglobulin (IgG) extravasation facilitate the generation of CD9hi microglia in an Fcγ receptor III-dependent manner. These findings demonstrate that the induction of synapse-engulfing CD9hi microglia in the thalamus by IgG/FcγRIII signaling drives recognition memory deficits following cortical damage.

DOI: https://doi.org/10.1038/s41467-026-74904-1
Brain. 2026 Jul 06. pii: awag234. [Epub ahead of print]

Fus-depleted oligodendrocytes reduce neuronal damage and Alzheimer's disease progression in the AppNL-G-F mouse.

Te-Hsuan Tung, Sudhagar Babu, Xiangting Tang, Alec L Sciutto, Micah Romer, Prathima Racha, Rong Xu, Victoria Fiesler, Adrita Saha, Teresa Thai, Takashi Saito, Takaomi C Saido, Yongxin Zhao, Judith B Grinspan, Hansruedi Mathys, Takashi D Y Kozai, Franca Cambi.

  Alzheimer's Disease (AD) is an age-dependent neurodegenerative disorder and represents the most common type of dementia, increasing in incidence at an alarming rate in the aging population. The hallmarks of the disease are amyloid plaque accumulation, microglia and astrocyte activation, and loss of presynaptic structure leading to cognitive decline. Recently, oligodendrocyte (OL) and myelin abnormalities have emerged as important contributors to the pathogenesis of AD. In normal brain homeostatic conditions, OL maintain neuronal health through myelin axon interactions and by supplying neurotrophic and metabolic support. How strengthening OL function may support neuronal health in AD neurodegeneration remains to be fully characterized and represents a gap in knowledge and a missed therapeutic opportunity. This study sought to examine how myelin and OL may improve neuronal deficits associated with AD. We have generated a novel mouse model (AD/cKO) by crossing the AppNL-G-F mouse, an established AD model, which carries three human AD mutations in the mouse App gene, with the FusOLcKO whose OL depleted of Fus (Fused in Sarcoma) produce thicker myelin associated with greater cholesterol biosynthesis. We evaluated spatial memory function with standardized cognitive testing. We evaluated microglia density and state, astrocytic activation and toxic phenotype, myelin density, cholesterol content, amyloid plaque burden, presynaptic structures, and neuronal hypoxic and oxidative damage in the hippocampus and cortex. We characterized the transcriptome of AD/cKO hippocampal OL compared to AD by using single-cell transcriptomic studies. Spatial working memory was fully preserved in the aged AD/cKO mouse relative to the AD mouse. This outcome was associated with reduced neuronal oxidative damage, preserved presynaptic structures at the amyloid plaque niches, and a shift in microglia state at the niches in both hippocampus and cortex. In contrast, amyloid plaque burden and microglia density were decreased in the hippocampus but not in cortex, uncoupling the neuronal and microglia effects from the amyloid burden. Fus dependent myelin increase was present in both hippocampus and cortex. Single-cell transcriptomics of AD/cKO hippocampal OL revealed upregulation of energy metabolism and antioxidant genes, suggesting a role of OL enhanced energy metabolism in mediating protection of neurons and affecting microglia state in AD pathology. This work provides new insight into how oligodendrocytes may protect neurons in AD, communicate with other glial cellular players, and point to potential targets for disease intervention aimed at slowing AD progression.

Keywords:  lipid metabolism; microglia; mitochondria; neuroinflammation; neuroprotection; transcriptomics

DOI:  https://doi.org/10.1093/brain/awag234
J Neuroinflammation. 2026 Jul 07.

The Wiskott-Aldrich Syndrome protein (WASp) contribution to microglial phagocytic function and neurodevelopmental support.

Serena Seminara, Aurora Bianchi, Davide Comolli, Marco Spreafico, Wenjie Liao, Hemanta Sarmah, Grazia Iannello, Barbara Corneo, Gianluigi Forloni, Elisa R Zanier, Massimiliano De Paola, Alessandro Fantin, Stefano Fumagalli.

  Myeloid progenitor cells colonize the brain during embryogenesis and differentiate in microglia. Microglia shape neuronal wiring during development and maintain brain homeostasis in adulthood, both actions requiring intact cytoskeletal functionality. The Wiskott-Aldrich syndrome protein (WASp) mediates cytoskeletal dynamics of peripheral myeloid cells, suggesting a similar role in microglia. To investigate WASp's role in microglia, we impaired WASp function in human induced pluripotent stem cells-derived microglia (iMicro) and zebrafish embryos.WASp colocalized with the actin cytoskeleton at membrane ruffles in phagocytic iMicro and appeared required for their phagocytic function. When co-cultured with neuronal cells, the support of iMicro with defective WASp function to neuronal wiring was impaired. Similarly, zebrafish embryos exposed to WASp inhibition showed brain accumulation of uncleared apoptotic bodies, reduced brain colonization of myeloid cells, and impaired sensorimotor response to mechanical stimuli.These findings identify WASp as a regulator of microglial phagocytosis and cytoskeletal dynamics, with implication in neuronal wiring during neurodevelopment.

Keywords:  Microglia; Neurodevelopment; Primary immunodeficiency; Wiskott-Aldrich Syndrome protein (WASp)

DOI:  https://doi.org/10.1186/s12974-026-03948-3
Brain Behav Immun. 2026 Jul 06. pii: S0889-1591(26)00642-2. [Epub ahead of print]138 106894

Microglial PTP1B promotes synaptic pathology and cognitive deficits in chronic Toxoplasma gondii infection.

Daxiang Xu, Cheng He, Huiling Lv, Jensen G Weedor, Yihui Xing, Zhicheng He, Pengxue Jing, Wenjing Cui, Xiaoying Yang, Guihua Zhao, Kun Yin, Kuiyang Zheng, Jianping Cao, Yinghua Yu, Wei Pan.

  Chronic infection with the neurotropic pathogen Toxoplasma gondii has been epidemiologically associated with a risk of neurodegeneration; however, the mechanisms driving infection-associated cognitive decline remain unclear. We investigated the role of microglial protein-tyrosine phosphatase 1B (PTP1B) as a potential driver of neuropathology in chronic toxoplasmosis. Using a murine model, we demonstrate that PTP1B expression is elevated in the hippocampus following infection. Global genetic ablation or pharmacological inhibition of PTP1B rescued infection-induced cognitive deficits and mitigated neuroinflammation. Crucially, microglia-specific deletion of Ptp1b prevented synaptic loss and cognitive impairment. Mechanistically, we show that microglial PTP1B potentiates the nuclear factor-kappa B (NF-κB) pathway, promoting complement component 1q (C1q)-mediated synaptic tagging and subsequent neuronal structural damage. Validating the clinical relevance of these findings, we observed significantly elevated PTP1B levels in peripheral blood mononuclear cells from T. gondii-seropositive individuals, which correlated with inflammatory markers. Overall, our findings identify microglial PTP1B as a pivotal mediator of T. gondii-associated neurodegeneration.

Keywords:  Cognitive impairment; Microglia; Neuroinflammation; PTP1B; Synapticpruning; Toxoplasma gondii

DOI:  https://doi.org/10.1016/j.bbi.2026.106894
Brain Behav Immun. 2026 Jul 06. pii: S0889-1591(26)00638-0. [Epub ahead of print]138 106890

Exosomes from bipolar disorder patients induce mania- and depression-like behaviors in mice via shared and distinct neuroimmune signatures.

Tongtong Yao, Liguo Li, Ya Su, Wanying Shao, Fangcheng Fan, Rui Qiu, Jinghang Liu, Shibin Xi, Yong Cheng, Qiang Fu.

  Bipolar disorder (BD) is a recurrent illness characterized by alternating episodes of mania and depression, yet the biological mechanisms underlying these oscillating states remain poorly understood. Exosomes, nanosized extracellular vesicles that mediate peripheral-central communication through transfer of molecular cargo, have emerged as important regulators of brain function and disease. To test whether patient-derived exosome preparations encode phase-specific signals, we isolated serum exosomes from BD patients experiencing manic or depressive episodes and infused them stereotaxically into the medial prefrontal cortex of mice. Behavioral assessments revealed strikingly divergent effects: mania-derived exosomes produced hyperlocomotion, reduced immobility, and heightened sociability, whereas depression-derived exosomes induced hypoactivity, anhedonia, and social withdrawal. Healthy control exosomes produced no changes, underscoring disease specificity. Despite these behavioral contrasts, both mania- and depression-derived exosomes convergently disrupted neural homeostasis, as indicated by oxidative and inflammatory imbalance, glial activation, synaptic impairments, and broad transcriptomic changes in pathways related to immune signaling, oxidative stress, and neuroplasticity. Importantly, phase-dependent patterns also emerged: mania-derived exosomes biased microglia toward a pro-inflammatory profile, whereas depression-derived exosomes favored an alternative polarization state with enrichment of metabolic and neurotrophic signaling. Pharmacological suppression of microglial activation attenuated the mania-exosome phenotype, supporting the functional involvement of M1-associated microglial activation in the mania condition. Integrative exosomal miRNA and transcriptomic analyses further identified miR-629-5p as a candidate mania-enriched cargo, and in vivo inhibition of miR-629-5p attenuated the associated behavioral and molecular abnormalities. Together, these findings show that serum-derived exosome preparations from BD patients are sufficient to induce mood-state-relevant behavioral and neurobiological changes under the experimental conditions tested, while the endogenous relevance of exosome-mediated signaling in spontaneous mood transitions remains to be established.

Keywords:  Bipolar disorder; Exosomes; Microglial polarization; Neuroinflammation; Synaptic dysfunction

DOI:  https://doi.org/10.1016/j.bbi.2026.106890
Brain Behav Immun. 2026 Jul 09. pii: S0889-1591(26)00632-X. [Epub ahead of print] 106884

Sex-associated neuroinflammatory and astrocytic responses in amyotrophic lateral sclerosis: evidence from clinical cohorts and a TDP-43 N390D mouse model.

Wenfei Yu, Bing Zhao, Mingjie Ma, Ninglu Gao, Yan Yun, Xiaohan Sun, Kai Shao, Pengfei Lin, Wei Li, Yuying Zhao, Dexin Yu, Cuiping Zhao, Fuchen Liu, Chuanzhu Yan, Shuangwu Liu.

   BACKGROUND: Sex differences are increasingly recognized as important modifiers of neuroimmune processes in neurodegenerative disorders. However, the sex-associated clinical phenotypes and underlying neuroinflammatory mechanisms in amyotrophic lateral sclerosis (ALS) remain poorly understood. This study integrated multimodal clinical assessments, cerebrospinal fluid (CSF) neuroimmune biomarkers, neuroimaging-based glymphatic metrics, and complementary animal analyses to characterize shared and sex-associated alterations in male and female ALS patients.
METHODS: Two independent cohorts including 158 newly diagnosed ALS patients and 112 healthy controls (HCs) underwent evaluations of motor function, cognition, sleep disturbances, and emotional symptoms. Glymphatic function was assessed using choroid plexus volume (CPV), diffusion-derived analysis along the perivascular space (ALPS) index, and white-matter free-water (FW) fraction. In the original cohort, 12 CSF biomarkers spanning astrocytic activation, neuroinflammation, TDP-43 pathology, synaptic dysfunction, and axonal injury were quantified, and glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), and interleukin-18 (IL-18) were further examined in an independent verification cohort. Complementary neuroimmune alterations were further examined in TDP-43 N390D knock-in mice using ELISA and immunofluorescence.
RESULTS: Male ALS patients showed markedly elevated CSF GFAP, IL-6, and IL-18 compared with female ALS patients and HCs after false discovery rate correction (q < 0.05). Female ALS patients exhibited increased CSF IL-6 versus HCs, whereas GFAP and IL-18 levels were unchanged. Female ALS patients also demonstrated more severe depressive symptoms and post-traumatic stress disorder than male ALS patients and HCs (p < 0.05). Both sexes displayed glymphatic impairment characterized by increased CPV and FW and reduced ALPS index, as well as pronounced sleep disturbances relative to HCs (all p < 0.05), with no clear sex-related differences. Complementary animal data showed that, at a fixed chronological age, male TDP-43 N390D mice exhibited more severe motor impairment accompanied by higher brain levels of GFAP, IL-6, and IL-18 and more prominent astrocyte-associated IL-6 and IL-18 signals than female mutant mice. Although microglial activation was also observed in TDP-43 N390D mice, no clear sex-related difference was detected at the sampled age.
CONCLUSIONS: This multimodal clinical-translational study reveals sex-associated neuroinflammatory heterogeneity in ALS. Male patients exhibit a more pronounced GFAP-, IL-6-, and IL-18-related inflammatory profile, whereas female patients display more prominent affective disturbances. Glymphatic dysfunction and sleep impairment emerge as common pathological pathways across sexes. These findings highlight sex as a crucial biological variable shaping ALS heterogeneity and underscore the importance of incorporating sex-stratified analyses in future ALS neuroimmune research and clinical trials.

Keywords:  ALS; Astrogliosis; Glymphatic dysfunction; Neuroinflammation; Sex differences

DOI:  https://doi.org/10.1016/j.bbi.2026.106884
Cell Commun Signal. 2026 Jul 09.

Calcium signaling in human and mouse microglia exhibit differential susceptibility to phytocannabinoids.

Ivana Pilchova, Andrea Fleig, Reinhold Penner.

   BACKGROUND: Neurological disorders affect over 40% of the global population and are driven in part by microglia-mediated neuroinflammation that depends on calcium (Ca²⁺) signaling. Cannabis-derived compounds (CBx) modulate microglial activation and cytokine release, however, the impact of understudied CBx on Ca2+ signaling pathways controlling inflammatory responses remains largely unknown.
METHODS: Here, we systematically examined the effects of over 22 CBx on key microglial Ca2+ signaling pathways. Using pharmacological modulators, live-cell Ca2+ imaging, immunofluorescence, and cytokine and nitric oxide assays, we characterized store-operated Ca2+ entry (SOCE) and purinergic signaling dynamics, inflammatory responses, and CBx effects in human (HMC3) and mouse (BV2) microglia under resting and activated conditions.
RESULTS: We found that microglial SOCE in both mouse and human cell line models were potently inhibited by the same three, minor, acidic CBx - CBGA, CBGVA, CBDVA. In BV2, at least seven CBx (CBD, CBG, CBDVA, CBDA, CBGA, CBDV, CBNM) inhibited LPS-induced proinflammatory secretion of nitric oxide (NO) and TNF-α. Despite the profound SOCE inhibition in HMC3, CBx failed to inhibit downstream proinflammatory cytokine release in TNF-α - or IL-1β-activated cells. We found major differences in Ca2+ signaling between the models, including purinergic pathways, where HMC3 cells appear to express a more limited purinome with more subdued signaling responses. Purinergic Ca2+ responses to ATP in BV2, especially the delayed phase, was suppressed by at least eight CBx, and most prominently by CBDVA, CBGVA and CBGA. We observed partial, indirect involvement of P2X4, P2 X7, and P2Y13 purinoceptors and propose additional Ca2+ signaling targets mediating the anti-inflammatory properties of CBx. Additionally, we documented the pro-inflammatory potential of CBCA and CBNA that is likely facilitated by their ability to mobilize intracellular Ca2+ levels in both, human and mouse microglia.
CONCLUSIONS: These findings provide a comprehensive qualitative and quantitative assessment of how individual CBx influence main Ca2+ signaling pathways in microglia and identify novel anti-inflammatory candidates with therapeutic potential for targeting microglial activation.

Keywords:  Calcium signaling; Cannabinoids; Microglia; Neuroinflammation; Purinergic receptors; Store-operated calcium entry

DOI:  https://doi.org/10.1186/s12964-026-03031-7
Acta Neuropathol Commun. 2026 Jul 10.

Matrix metalloprotease-9 modulates microglial/macrophage responses in murine brain demyelination.

Eline Bernaerts, Amber De Visscher, Sam Vanherle, Marie Rutten, Fran Prenen, Nele Berghmans, Jana Van Broeckhoven, Hanne Meers, Mirre De Bondt, Febe Boudry, Sofie Knoops, Tania Mitera, Lien De Somer, Jeroen Bogie, Patrick Matthys, Jennifer Vandooren.

  Multiple sclerosis (MS) is a chronic autoimmune disorder, in which the immune system targets the protective myelin sheath surrounding axons in the brain, spinal cord and optic nerve, leading to demyelination and ultimately neurodegeneration. Promoting remyelination to delay or halt disease progression remains a major therapeutic challenge in MS research. Matrix metalloproteases (MMPs) have been implicated in the pathogenesis of MS. Elevated levels of MMP-9 have been detected in cerebrospinal fluid (CSF), serum and demyelinating lesions of MS patients, where MMP-9 contributes to myelin breakdown, epitope generation, and leukocyte infiltration. In the in vivo experimental autoimmune encephalomyelitis and lysophosphatidylcholine (LPC) murine MS models, Mmp9-/- mice exhibited delayed resolution of disease symptoms, suggesting a role for MMP-9 in remyelination. In this study, we investigated the role of MMP-9 in demyelination and remyelination, using two complementary models: LPC-induced demyelination in ex vivo brain slices and cuprizone (CPZ)-induced demyelination in vivo. In LPC-treated slices, MMP-9 deficiency impaired remyelination via microglia/macrophage-mediated mechanisms. Consistently, Mmp9-/- mice displayed increased numbers of activated microglia/macrophages in the corpus callosum following CPZ intoxication, with modest persistence during remyelination compared to WT mice. Naïve Mmp9-/- microglia/macrophages also showed enhanced myelin debris phagocytosis compared to WT cells. However, MMP-9 deficiency had minimal impact on demyelination or remyelination in the CPZ model. Proteomic analysis of CSF revealed differential expression of inflammatory mediators, including decreased levels of CCL2 and CXCL9, whereas CCL20 was increased in Mmp9-/- CPZ-treated mice. Collectively, these findings indicate that MMP-9 does not directly regulate demyelination and remyelination in the CPZ-induced demyelination model, but increases microglial abundance, highlighting its indirect role in CNS demyelination.

Keywords:  Cuprizone-induced demyelination model; Inflammation; Lysophosphatidylcholine model; MMP-9; Microglia; Proteolysis; Resolution

DOI:  https://doi.org/10.1186/s40478-026-02371-2
Acta Neuropathol Commun. 2026 Jul 09.

CSF1R inhibition following antibody mediated demyelination has limited impact on remyelination.

Lisa C Golden, Graham C Peet, Rebecca E Rodriguez, Nicholas J Jahahn, Gregory P Owens, Jeffrey L Bennett, Wendy B Macklin.

  Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease of the central nervous system. B cell depleting treatments are effective MS therapies, and while antibodies may serve as a biomarker, little is known about how they participate in MS pathology. Using a proteolipid protein 1 complex-specific (PLP1c) recombinant antibody cloned from cerebrospinal fluid plasmablasts of MS patients, we studied the development and resolution of antibody-mediated demyelinating lesions in vivo in mice. Demyelination was complement-dependent and resolved over four weeks. Because of the previously described impact of microglia on remyelination, we targeted microglia depletion with CSF1R inhibition to test their role in this model. Despite a significant reduction in total microglia following CSF1R inhibition, microglia or macrophage density was high in recovering lesions. Premyelinating oligodendrocyte populations were altered without impacting gross lesion recovery. Future work will determine if PLP1c-binding antibodies are representative of other MS-derived antibodies, and how pathogenic MS autoantibodies may contribute to the variability of MS lesion remyelination.

Keywords:  Complement; Demyelination; Immunoglobulin; Microglia; Multiple sclerosis; PLP1; Remyelination

DOI:  https://doi.org/10.1186/s40478-026-02370-3
Front Immunol. 2026 ;17 1813788

Endothelial TGFβ signaling modulates choroidal neovascularization severity via myeloid-endothelial cell interaction.

Anja Schlecht, Lisa Müllerbauer, Katja Fitz, Bianka Brunne, Nico Hofmann, Christian Müller, Jost Hillenkamp, Süleyman Ergün, Andreas Neueder, Barbara M Braunger.

   Introduction: The blood-retinal barrier (BRB) is essential for maintaining retinal homeostasis, consequently its disruption contributes to pathological angiogenesis in diseases such as neovascular age-related macular degeneration (nAMD). Choroidal neovascularization (CNV) is considered as a hallmark of nAMD. These newly formed vessels break through the BRB leading to rapid and severe vision loss. Here, we investigated how endothelial TGFβ signaling interacts with mononuclear phagocytes (MP), such as microglia to regulate choroidal neovascularization (CNV).
Methods: In this study, we used a laser-induced CNV model in mice with endothelial-specific Tgfbr2 deletion and concomitant MP depletion via PLX5622.
Results: We demonstrate that loss of endothelial TGFβ signaling significantly exacerbates CNV. Strikingly, this effect is fully rescued by MP depletion. Transcriptome and RNA localization of CNV lesions identified fibrinogen alpha chain (Fga) as a MP-derived factor that is exclusively upregulated in mice without endothelial TGFβ signaling.
Discussion: These findings suggest a novel TGFβ-dependent interaction between endothelial cells and MP that promotes angiogenesis through microglia derived Fga expression.

Keywords:  TGFβ signaling; age-related macular degeneration; blood retinal barrier; choroidal neovascularization; endothelial cells; microglia; mononuclear phagocytes

DOI:  https://doi.org/10.3389/fimmu.2026.1813788
Neurosci Bull. 2026 Jul 07.

Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING.

Guanqin Ma, Erlin Wang, Xiaoxu Yan, Xiang-Xiong Xu, Xiaohong Li, Xueling Ma, Wan-Hua Yang, Jianxiong Zeng, Xiaochun Xie.

  Mitochondrial dysfunction induces metabolic dysregulation in immune cells that is etiologically associated with age-related brain disorders. However, how dysfunctional mitochondria in microglia-the brain-resident immune cells-initially affect neurological function remains incompletely understood. Here, we demonstrate that dysfunctional mitochondria in microglia, induced by the conditional knockout of mitochondrial transcription factor A, act as triggers of metabolic dysregulation, cognitive aging, and neurodegeneration in adult mice. Notably, this metabolic disturbance induces a microglial transition to states associated with neuroinflammatory activation and neurodegenerative disease, thereby triggering multiple layers of pathological cascade reactions among other brain cell types and shaping a neuroinflammaging state at single-cell resolution. Mechanistically, mitochondrial dysfunction activates the innate immune cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which mediates immune sensing of cytosolic DNA in microglia and contributes to inflammaging. We further present evidence that combined treatment aimed at restoring metabolic homeostasis and inhibiting neuroinflammatory cGAS-STING partially rescues age-related neurological dysfunction in mice. Collectively, our findings reveal a link between mitochondrial dysfunction in microglia and cognitive aging, underscoring the significance of tightly regulated metabolism in age-associated neurological diseases.

Keywords:  Microglia; Mitochondrial dysregulation; Neurodegeneration; Neuroinflammaging; cGAS–STING

DOI:  https://doi.org/10.1007/s12264-026-01657-8
Biomed Pharmacother. 2026 Jul 06. pii: S0753-3322(26)00776-6. [Epub ahead of print]201 119740

From DNA-encoded library (DEL) screening to in vivo validation: LILRB4 (ILT3)-targeted small molecules reprograms myeloid immune suppression.

Somaya A Abdel-Rahman, Moustafa T Gabr.

  Alzheimer's disease (AD) remains a major unmet clinical challenge, with limited therapeutic strategies capable of effectively modulating neuroimmune dysfunction. Leukocyte immunoglobulin-like receptor B4 (LILRB4/ILT3) has recently emerged as an inhibitory microglial immune checkpoint implicated in ApoE-mediated suppression of amyloid-β (Aβ) clearance and inflammatory signaling, supporting its potential as a therapeutic target in AD. Here, we applied DNA-encoded library (DEL) screening of approximately 3.6 billion compounds to identify small molecule binders of LILRB4. Biophysical validation identified APX1 as a direct LILRB4 ligand with submicromolar affinity, which was further confirmed by cellular thermal shift assay (CETSA). Docking-guided mutagenesis studies defined a discrete ligand-binding interface involving key hotspot residues required for stable target engagement. Functionally, APX1 disrupted the LILRB4-ApoE interaction in orthogonal ELISA and biolayer interferometry assays. In human iPSC-derived microglia, APX1 suppressed SHP1/2 phosphorylation, attenuated NF-κB activation and IL-1β secretion, and restored Aβ42 uptake under ApoE-driven inflammatory conditions. APX1 further demonstrated favorable in vitro developability, metabolic stability, and CNS exposure properties. In the 5xFAD mouse model of AD, oral administration of APX1 improved cognitive performance, reduced cortical and hippocampal Aβ42 burden, suppressed neuroinflammatory cytokines, and decreased activated microglial populations. Collectively, these findings establish APX1 as a promising small molecule modulator of the LILRB4-ApoE signaling axis and support pharmacological targeting of neuroimmune checkpoints as a therapeutic strategy for AD.

Keywords:  Alzheimer’s disease; Drug discovery; ILT3; Immunotherapy; LIRB4; Small molecules

DOI:  https://doi.org/10.1016/j.biopha.2026.119740
Glia. 2026 Sep;74(9): e70196

Microglial P2ry12 in the Basolateral Amygdala Underlies Neuropathic Pain-Induced Anxiety.

Xiaohui Yang, Li Chen, Qiuxiao Shi, Hanmin Liu, Yuying Tang.

  Anxiety is a common clinical comorbidity of neuropathic pain. The basolateral amygdala (BLA) is critically involved in both pain and anxiety processing. Microglia have emerged as key regulators of neuronal plasticity, and disruption of homeostatic neuron-microglia crosstalk can precipitate neuropsychiatric disorders. Although microglia are abundant in the BLA, their specific role in modulating neuronal plasticity underlying pain-induced anxiety remains poorly understood. Here, we demonstrate that spared nerve injury (SNI) induces anxiety-like behaviors in mice, accompanied by neuronal hyperexcitability and increased spine density in the BLA. These changes correlated with increased density of hyper-ramified microglia, along with upregulated P2ry12 expression and enhanced microglial BDNF production. Importantly, microglial P2ry12 knockdown significantly attenuated both process hyper-ramification and BDNF overexpression in the BLA. Furthermore, either microglial depletion with clodronate or microglial P2ry12 knockdown in the BLA reversed neuronal hyperexcitability and spine overgrowth, and alleviated pain and anxiety-like behaviors in SNI mice. Meanwhile, clodronate mildly suppressed neuronal excitability and dendritic spine density in the BLA of control mice, whereas P2ry12 knockdown had no detectable impact on these neuronal measures. Together, these findings support a role for microglia in maintaining physiological neuronal excitability and spine density. Highly-ramified microglia and their increased P2ry12 expression underlie the enhanced neuronal excitability and spine density in the BLA, thereby promoting comorbidity of pain and anxiety.

Keywords:  P2ry12; anxiety; excitability; microglia; pain; spine

DOI:  https://doi.org/10.1002/glia.70196
Glia. 2026 Sep;74(9): e70198

Unveiling the Functional Role of KIF21B in Microglia Inflammatory Response.

Danny Ganchala, Alvaro Bautista-Abad, Daniel Pinto-Benito, Julia Simon-Areces, Daniela Grassi, Francesco Paolo Ulloa Severino, Maria-Angeles Arevalo.

  Microglia are brain immune cells that maintain homeostasis and respond to injury, changing cell morphology to drive inflammation, migration, and phagocytosis. This study examined the role of the kinesin KIF21B in microglial activation, demonstrating for the first time its expression in microglial cells in two in vivo neuroinflammatory models: TBI (focal inflammation) and LPS administration (diffuse inflammation). While TBI provoked a significant increase in KIF21B/Iba1 colocalization in the tissue around the lesion exclusively in females, LPS administration did not alter KIF21B expression in either sex. Given the importance of cytoskeleton remodeling for microglial migration and phagocytosis, this work investigates whether KIF21B contributes to these actions. Downregulating KIF21B in primary cultured mouse microglia had sex-specific effects. In females, KIF21B silencing reduced both migratory capacity and phagocytosis of E. coli-coated spheres and neuronal debris. In males, it exacerbated migration and selectively increased neuronal debris phagocytosis, while E. coli-coated sphere uptake remained unaffected. These functional differences were accompanied by sex-dependent morphological alterations, quantified through area, circularity, Feret's diameter, and perimeter: KIF21B silencing blocked the transition to amoeboid morphology in females while inducing hyperpolarized elongation in males. Finally, LPS treatment increased KIF21B colocalization with microtubules and reduced its colocalization with F-actin in females, while neither interaction was significantly altered in males. Overall, the findings suggest that KIF21B regulates microglial function in a sex-dependent manner through its effects on cytoskeletal organization.

Keywords:  KIF21B; microglia; neuroinflammation; phagocytosis; sex differences

DOI:  https://doi.org/10.1002/glia.70198
Front Neurosci. 2026 ;20 1785992

Microglia derived from human induced pluripotent stem cells are regulated by osteopontin, an endogenous extracellular matrix protein maintaining immune homeostasis.

Daniel Navin Olschewski, Anna Maria Koenig, Helena Mira Nerone, Elena Gross, Tomo Šarić, Sabine Ulrike Vay, Michael Schroeter, Gereon R Fink, Maria Adele Rueger.

   Introduction: Microglia are brain-resident immune cells responsible for maintaining homeostasis, coordinating responses to injury and disease, and mediating regeneration. Upon activation, they undergo dynamic changes in morphology, gene expression, and function, reflecting the nature and context of the stimuli encountered. Although pharmacological modulation of microglia holds great promise for treating various neurological disorders, its development is hampered by a major translational roadblock: Human microglial cell lines commonly used in preclinical studies, as well as primary rodent microglia, substantially limit the translatability of results. Here, we aimed to generate microglia from human induced pluripotent stem cells (hiPSCs) and to demonstrate their physiological responsiveness to the brain-endogenous, context-relevant ligand osteopontin (OPN).
Materials and methods: Microglia generated from two healthy hiPSC lines were stimulated with OPN, lipopolysaccharide (LPS), or their combination for 24 h and subsequently analyzed. Microglial identity and the expression of the phagocytic cell marker cluster of differentiation 68 (CD68) were determined by immunocytochemistry. Cell viability was assessed by propidium iodide (PI)/Hoechst staining, morphological activation was evaluated using Sholl analysis, and inflammatory gene expression changes were assessed by RT-qPCR.
Results: hiPSC-derived microglia acquired a native central nervous system (CNS)-specific immunophenotype, expressing the microglia-specific markers ionized calcium-binding adapter molecule 1 (IBA1), transmembrane protein 119 (TMEM119), PU.1, and Spalt-like transcription factor 1 (SALL1), while remaining negative for Myb and membrane-spanning 4-domains, subfamily A, member 7 (MS4A7) at the protein level. Exposure to LPS led hiPSC-derived microglia to adopt a rounded, process-retracted shape and to increase CD68 protein intensity, a surrogate marker of lysosomal and phagocytic activity, while downregulating the anti-inflammatory marker cluster of differentiation 206 (CD206) at the transcriptional level. OPN induced a distinct microglial functional state characterized by intermediate morphology, increased CD68 intensity, and reduced homeostatic gene expression, without eliciting robust inflammatory gene expression. Intriguingly, OPN prevented LPS-induced microglial cell death, and when hiPSC-derived microglia exposed to LPS were additionally treated with OPN, the morphological effects of LPS were reversed.
Conclusion: OPN induced a distinct early response profile in hiPSC-derived microglia, characterized by intermediate morphological remodeling, increased CD68 intensity, and reduced homeostatic gene expression, without overt pro-inflammatory gene expression. These findings support the role of OPN as a physiological priming signal in microglia and highlight hiPSC-derived microglia as a model for studying regulators of microglial modulation.

Keywords:  iPSC (induced pluripotent stem cell); in vitro model culture system; microglia; neuroinflammation; osteopontin

DOI:  https://doi.org/10.3389/fnins.2026.1785992
Exp Eye Res. 2026 Jul 09. pii: S0014-4835(26)00317-9. [Epub ahead of print] 111161

Microglia suppress Müller cell FGF1 and contribute to retinal ganglion cell degeneration in glaucoma.

Yang Sui, Siti Tong, Zhe Qin, Pingxiu Dang, Tianyi Sui, Yabo Ma, Jiabin Wang, Yajing Zhao, Shipeng Wang, Shaojun Wang, Dajiang Wang.

  Glaucoma is a progressive neurodegenerative disease characterized by retinal ganglion cell (RGC) loss, in which glial activation and neuroinflammation contribute importantly to disease progression. However, the mechanisms by which microglia-Müller cell interactions influence retinal neuroinflammation and neurotrophic support during glaucoma remain unclear. Here, we aimed to identify glia-associated regulatory factors involved in microglia-Müller cell communication during glaucoma and to determine their contribution to retinal neurodegeneration. A chronic ocular hypertension (COH) mouse model and a conditioned medium (CM)-based inflammatory system were used to investigate microglia-Müller cell interactions and the role of fibroblast growth factor 1 (FGF1) in retinal neuroinflammation. Sustained intraocular pressure (IOP) elevation induced glial activation and progressive RGC degeneration in COH retinas. Transcriptomic profiling of Müller cells exposed to microglia-conditioned medium identified FGF1 as a significantly downregulated candidate neurotrophic factor, accompanied by enrichment of immune and inflammatory pathways. Functionally, Müller cell FGF1 deficiency exacerbated, whereas exogenous FGF1 attenuated, inflammation-induced RGC apoptosis in vitro. In vivo, intravitreal rFGF1 reduced RGC apoptosis, preserved RGC survival, and maintained retinal structure without affecting IOP. Consistently, reduced FGF1 expression was observed in Müller cell-enriched regions of human glaucomatous retinas. Together, these findings suggest that microglia-driven inflammation suppresses Müller cell FGF1 expression, thereby impairing neurotrophic support and increasing retinal vulnerability during COH. Restoration of FGF1 signaling confers neuroprotection independently of IOP reduction and may represent a promising glia-targeted therapeutic strategy for glaucoma.

Keywords:  FGF1; Müller cell; glaucoma; microglia; neuroinflammation; retinal ganglion cell

DOI:  https://doi.org/10.1016/j.exer.2026.111161
Invest Ophthalmol Vis Sci. 2026 Jul 01. 67(8): 31

YAP Regulates the Nrf2 Signaling Axis to Attenuate Oxidative Stress and Neuroinflammation in Retinal Ganglion Cell Degeneration.

Shirui Zhou, Fumin Yang, Ke Ding, Rui Chen, Mingchang Zhang, Wei Liu.

Purpose: Oxidative stress is a key driver of retinal ganglion cell (RGC) degeneration after optic nerve injury. Yes-associated protein (YAP), a Hippo pathway effector, is known to reprogram stress responses, yet its role in regulating oxidative stress during RGC degeneration is unclear.
Methods: This study investigated the role of YAP in RGC injury using an in vivo optic nerve crush (ONC) model and an in vitro oxidative-stress model with primary RGCs. YAP expression was modulated pharmacologically and genetically. We assessed its effects on nuclear factor erythroid 2-related factor 2 (Nrf2) signaling-related outcomes; on oxidative stress markers, including superoxide dismutase-1/2 (SOD-1/2), NAD(P)H:quinone oxidoreductase 1 (Nqo-1), and reactive oxygen species (ROS); and on neuroinflammation (microglial and astrocytic activation) via quantitative reverse-transcription PCR and immunofluorescence.
Results: YAP activation demonstrated robust neuroprotection in both the in vivo ONC model and in vitro oxidative-stress paradigms, significantly enhancing RGC survival, whereas YAP suppression exacerbated RGC degeneration. Mechanistically, YAP activation was associated with elevated Nrf2 signaling activity, as indicated by upregulation of antioxidant effectors (Nqo-1, SOD-2) and reduced intracellular ROS. YAP activation attenuated neuroinflammation, characterized by decreased microglial reactivity and astrocytic activation, whereas inhibition of YAP reversed these effects.
Conclusions: This study identified YAP as a neuroprotective regulator in both in vivo ONC and primary RGC models. YAP activation attenuated oxidative stress and neuroinflammation, which correlated with the activity of Nrf2-mediated antioxidant pathways, highlighting the potential relevance of YAP and Nrf2 interaction for therapeutic targeting in RGC injury.

DOI: https://doi.org/10.1167/iovs.67.8.31