bims-microg 2025-03-23 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–03–23
twenty-one papers selected by
Marcus Karlstetter, Universität zu Köln

Endothelial TDP-43 depletion disrupts core blood-brain barrier pathways in neurodegeneration.
StainAI: quantitative mapping of stained microglia and insights into brain-wide neuroinflammation and therapeutic effects in cardiac arrest.
Therapeutic potential of AAV2-shmTOR gene therapy in reducing retinal inflammation and preserving endothelial Integrity in age-related macular degeneration.
SARM1: The Checkpoint of Axonal Degeneration in the Nervous System Disorders.
Differential Roles of Macrophages and Microglia in Subretinal Fibrosis Secondary to Neovascular Age-Related Macular Degeneration.
Chronic intermittent hypoxia disrupts protective microgliosis in ischemic proliferative retinopathy.
IRF1 regulates autophagy and microglia polarization in retinal ischemia-reperfusion through NCOA1/Wnt/β-catenin signalling pathway.
MITD1 is a brain-specific interferon-inducible factor that inhibits flavivirus replication.
Targeting HIF-2α in glioblastoma reshapes the immune infiltrate and enhances response to immune checkpoint blockade.
Metabolic stress and age drive inflammation and cognitive decline in mice and humans.
The role of n-3-derived specialised pro-resolving mediators (SPMs) in microglial mitochondrial respiration and inflammation resolution in Alzheimer's disease.
Identifying microglia-derived NFKBIA as a potential contributor to the pathogenesis of Alzheimer's disease and age-related macular degeneration.
The associations of cerebrospinal fluid ApoE and C1q with Alzheimer's disease biomarkers.
Resolvin D1 accelerates resolution of neuroinflammation by inhibiting microglia activation through the BDNF/TrkB signaling pathway.
MAIT cell deficiency exacerbates neuroinflammation in P301S human tau transgenic mice.
Microglia-derived CXCL2 induced neuronal ferroptosis via CXCR2/Jun axis in sepsis-associated encephalopathy.
Microglial depletion increases aggrecan and hyaluronan levels in the diffuse and aggregated extracellular matrix of the mouse brain.
Asrij/OCIAD1 depletion reduces inflammatory microglial activation and ameliorates Aβ pathology in an Alzheimer's disease mouse model.
Decoding microglial functions in Alzheimer's disease: insights from human models.
Functional genomics in age-related macular degeneration: From genetic associations to understanding disease mechanisms.
SIRPα modulates microglial efferocytosis and neuroinflammation following experimental subarachnoid hemorrhage via the SHP1/STAT6 axis.

Nat Neurosci. 2025 Mar 14.

Endothelial TDP-43 depletion disrupts core blood-brain barrier pathways in neurodegeneration.

Omar M F Omar, Amy L Kimble, Ashok Cheemala, Jordan D Tyburski, Swati Pandey, Qian Wu, Bo Reese, Evan R Jellison, Bing Hao, Yunfeng Li, Riqiang Yan, Patrick A Murphy.

Endothelial cells (ECs) help maintain the blood-brain barrier but deteriorate in many neurodegenerative disorders. Here we show, using a specialized method to isolate EC and microglial nuclei from postmortem human cortex (92 donors, 50 male and 42 female, aged 20-98 years), that intranuclear cellular indexing of transcriptomes and epitopes enables simultaneous profiling of nuclear proteins and RNA transcripts at a single-nucleus resolution. We identify a disease-associated subset of capillary ECs in Alzheimer's disease, amyotrophic lateral sclerosis and frontotemporal degeneration. These capillaries exhibit reduced nuclear β-catenin and β-catenin-downstream genes, along with elevated TNF/NF-κB markers. Notably, these transcriptional changes correlate with the loss of nuclear TDP-43, an RNA-binding protein also depleted in neuronal nuclei. TDP-43 disruption in human and mouse ECs replicates these alterations, suggesting that TDP-43 deficiency in ECs is an important factor contributing to blood-brain barrier breakdown in neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41593-025-01914-5
Commun Biol. 2025 Mar 20. 8(1): 462

StainAI: quantitative mapping of stained microglia and insights into brain-wide neuroinflammation and therapeutic effects in cardiac arrest.

Chao-Hsiung Hsu, Yi-Yu Hsu, Be-Ming Chang, Katherine Raffensperger, Micah Kadden, Hoai T Ton, Essiet-Adidiong Ette, Stephen Lin, Janiya Brooks, Mark W Burke, Yih-Jing Lee, Paul C Wang, Michael Shoykhet, Tsang-Wei Tu.

Microglia, the brain's resident macrophages, participate in development and influence neuroinflammation, which is characteristic of multiple brain pathologies. Diverse insults cause microglia to alter their morphology from "resting" to "activated" shapes, which vary with stimulus type, brain location, and microenvironment. This morphologic diversity commonly restricts microglial analyses to specific regions and manual methods. We introduce StainAI, a deep learning tool that leverages 20x whole-slide immunohistochemistry images for rapid, high-throughput analysis of microglial morphology. StainAI maps microglia to a brain atlas, classifies their morphology, quantifies morphometric features, and computes an activation score for any region of interest. As a proof of principle, StainAI was applied to a rat model of pediatric asphyxial cardiac arrest, accurately classifying millions of microglia across multiple slices, surpassing current methods by orders of magnitude, and identifying both known and novel activation patterns. Extending its application to a non-human primate model of simian immunodeficiency virus infection further demonstrated its generalizability beyond rodent datasets, providing new insights into microglial responses across species. StainAI offers a scalable, high-throughput solution for microglial analysis from routine immunohistochemistry images, accelerating research in microglial biology and neuroinflammation.

DOI: https://doi.org/10.1038/s42003-025-07926-y
Sci Rep. 2025 Mar 19. 15(1): 9517

Therapeutic potential of AAV2-shmTOR gene therapy in reducing retinal inflammation and preserving endothelial Integrity in age-related macular degeneration.

Jin Kim, Seo Yun Moon, Ho Geun Kang, Hee Jong Kim, Jun Sub Choi, Steven Hyun Seung Lee, Keerang Park, So-Yoon Won.

  Age-related macular degeneration (AMD) is a prevalent retinal disorder that leads to central vision loss, mainly due to chronic inflammation. Tumor necrosis factor-alpha (TNF-α) is a critical mediator of inflammatory responses within the retinal environment. This study has investigated TNF-α's influence on inflammatory cytokine production and endothelial barrier integrity in human microglial (HMC3) and endothelial (HUVEC) cells. We found that TNF-α significantly elevated the expression and secretion of interleukin-6 (IL-6) and interleukin-1β (IL-1β) in HMC3 cells and disrupted endothelial tight junctions in HUVECs, as evidenced by weakened ZO-1 staining and compromised barrier function. To mitigate these effects and further investigate the in vitro mechanism of actions in CRG-01's in vivo therapeutic efficacy of anti-inflammation, we employed AAV2-shmTOR, CRG-01, as the candidate for therapeutic vector targeting the mammalian target of the rapamycin (mTOR) pathway. TNF-α-induced IL-6, IL-1β, and NF-κB signaling in HMC3 cells were significantly reduced by AAV2-shmTOR treatment, which may present a promising avenue for the fight against AMD. It also effectively preserved endothelial tight junction integrity in TNF-α-treated HUVECs, providing reassurance about its effectiveness. Furthermore, the supernatant medium collected from AAV2-shmTOR-treated HMC3 cells decreased oxidative stress, protein oxidation, and cytotoxicity in ARPE retinal pigment epithelial cells. These results strongly suggested that CRG-01, the candidate therapeutic vector of AAV2-shmTOR, may have a therapeutic potential to treat AMD-related retinal inflammation.

Keywords:  (Vascular endothelial growth factor (VEGF); Adeno-associated virus (AAV); Age-related macular degeneration (AMD); Gene therapy; Retinal inflammation; ShmTOR

DOI:  https://doi.org/10.1038/s41598-025-93993-4
Mol Neurobiol. 2025 Mar 17.

SARM1: The Checkpoint of Axonal Degeneration in the Nervous System Disorders.

Aaditi Karnik, Abhijeet Joshi.

  Axons are metabolically active neuronal segments with well-controlled axonal degeneration and regeneration. External stress or injury displaces this equilibrium toward degeneration leading to axonal dysfunction observed in the pathology of several diseases. The demand and supply matrix of energy at the synapses are maintained by the axonal transport. Nicotinamide adenine dinucleotide (NAD+) is a major energy-driving coenzyme of cells that controls mitochondrial, cytoplasmic, and other organellar energy cycles generating high amounts of adenosine triphosphate (ATP). NAD+ participates in various cellular cycles and is consumed by several enzymes. One of the key enzymes targeting NAD+ is Sterile alpha and TIR motif-containing protein 1 (SARM1) which gets activated in response to external noxious stimuli. SARM1 is an octamer consisting of multiple domains of which the TIR domain governs NAD+ hydrolysis which eventually leads to axonal deficits. Besides its localization in neurons, SARM1 is also present in astrocytes, microglia, and macrophages in which it regulates inflammatory responses associated with disease pathology. SARM1 localization in the outer mitochondrial membrane is responsible for its association with mitochondrial dynamics. SARM1-mediated mitochondrial dysfunction further drives the axonal degeneration associated with peripheral and central nervous system disorders. Several genetic and pharmacological studies highlight the role of SARM1 in axonal degeneration. SARM1 is thus becoming a popular target for preventing axonal degeneration. Several small molecules consisting of isoquinoline, isothiazole, pyridine, and tryptoline acrylamide moieties have been tested for their activity against SARM1 with a promising foundation for drug discovery in targeting SARM1. In our review, we highlight the role of SARM1 in axonal degeneration associated with several disease pathologies focusing on genetic and pharmacological evaluation.

Keywords:  ATP; Axonal degeneration; Cytoskeleton; Mitochondria; Mutations; NAD+ ; SARM1; Wallerian degeneration

DOI:  https://doi.org/10.1007/s12035-025-04835-3
Invest Ophthalmol Vis Sci. 2025 Mar 03. 66(3): 41

Differential Roles of Macrophages and Microglia in Subretinal Fibrosis Secondary to Neovascular Age-Related Macular Degeneration.

Manon Szczepan, María Llorián-Salvador, Caijiao Yi, David Hughes, Matthias Mack, Mei Chen, Heping Xu.

Purpose: To investigate the differential role of infiltrating CCR2+ macrophages and CX3CR1+ microglia in neovascular AMD (nAMD)-mediated subretinal fibrosis.
Methods: Subretinal fibrosis was induced using the two-stage laser protocol in C57BL/6J or CX3CR1gfp/+ mice. The fibrotic lesion was detected using collagen-1 staining in retinal pigment epithelial /choroidal flatmounts. Infiltrating macrophages and microglial were identified using F4/80, CCR2, and CX3CR1 markers at one, three, six, and 10 days after the second laser. Circulating CCR2+ monocytes were depleted using the MC-21 antibody, whereas CX3CR1+ microglia were depleted using PLX5622. BV2 microglia were treated with TGF-β1 for 96 hours, and their profibrotic potential was examined by quantitative PCR and immunocytochemistry.
Results: Subretinal fibrosis lesions developed three days after the second laser, accompanied by persistent CCR2+F4/80+ macrophage and CX3CR1+ cell infiltration. Inflammation in the first three days after the second laser was dominated by filtrating CX3CR1+ cells, and the number increased until day (D) 10 post-second laser. Depletion of CCR2+ monocytes from D5-10 significantly reduced the vascular and fibrotic components of the lesion, while CX3CR1+ cell depletion reduced Isolectin B4+ but not collagen-1+ lesion size. Bone marrow-derived macrophages from D6 and D10 mice expressed significantly higher levels of α-smooth muscle actin (α-SMA) and collagen-1 compared to cells from D1 and D3. TGFβ1 treatment increased TMEM119, CX3CR1, IL1b and iNOS gene expression but did not affect Acta2 and Col1a1 gene expression in BV2 cells.
Conclusions: CCR2+ monocytes, but not CX3CR1+ microglia, critically contribute to the development of subretinal fibrosis in nAMD.

DOI: https://doi.org/10.1167/iovs.66.3.41
J Neuroinflammation. 2025 Mar 14. 22(1): 82

Chronic intermittent hypoxia disrupts protective microgliosis in ischemic proliferative retinopathy.

Tianxiang Yang, Kaitryn E Ronning, Sébastien Augustin, Frédéric Blond, Caroline Nous, Foteini Argyriou, Sara Touhami, Cécile Delarasse, Xavier Guillonneau, Florian Sennlaub.

  Sleep apnea that leads to chronic intermittent hypoxia (CIH) is an independent risk factor for advanced, debilitating ischemic proliferative retinopathies, such as diabetic retinopathy (DR) and retinopathy of prematurity (ROP). The underlying mechanisms are unknown. Here we investigated the consequences of CIH on the ischemic retina of the oxygen-induced retinopathy model. We show that experimental CIH inhibited colony stimulating factor 1 (CSF1) expression, blunting the reactive microgliosis during the ischemic phase of OIR. CIH severely delayed beneficial revascularization of the ischemic retina and increased pathological neovascularization. CIH also induced photoreceptor segment thinning and accentuated OIR-induced inner and outer retinal functional deficits. Mechanistically we demonstrated that local CSF1R inhibition during ischemic retinopathy reduced the number of microglial cells, inhibited revascularization, and exacerbated pathological neovascularization, recapitulating the effects of CIH. Our findings provide a novel mechanism by which sleep apnea and CIH aggravate ischemic retinopathies, underscoring the importance of treating apnea in DR and ROP to help prevent sight threatening severe disease.

Keywords:  Hypoxia; Ischemic retinopathy; Microglia; Sleep apnea

DOI:  https://doi.org/10.1186/s12974-025-03392-9
Cell Signal. 2025 Mar 15. pii: S0898-6568(25)00159-7. [Epub ahead of print]131 111746

IRF1 regulates autophagy and microglia polarization in retinal ischemia-reperfusion through NCOA1/Wnt/β-catenin signalling pathway.

Di Yang, Jian-Shu Kang, Hua Zhong, Hong-Mei Liu, Shen Nian, Kai-Xiong Qing.

   BACKGROUND: Interferon regulatory factor 1 (IRF1) is an important regulatory factor in the development of eyes, and it has been proved to be involved in the regulation of ischemia-reperfusion process. But its role in retinal ischemia-reperfusion (RIR) remains unclear.
METHODS: RIR rat model was induced by increasing intraocular pressure. Hematoxylin and eosin (HE) staining, immunofluorescence (IF) staining, and western blot experiments were used to explore the levels of IRF1, autophagy, and microglia polarization in RIR. Western blot, transmission electron microscope, IF, and ELISA assays were used to explore the effects of IRF1, Nuclear receptor coactivator 1 (NCOA1), and Wnt/β-catenin signalling pathways in OGD/R-induced autophagy and polarization of rat retinal microglia. CHIP and dual-luciferase experiments verify the interaction between IRF1 and NCOA1. CHIP and dual-luciferase experiments were used to verify the interaction between IRF1 and NCOA1. Adeno-associated viruses interfering with IRF1 and NCOA1 were injected into the vitreous of rats to explore the functions of IRF1 and NCOA1 in RIR rats.
RESULTS: IRF1 and M1-type markers of microglia in retina of RIR rats increased, and autophagy level decreased. Knockdown of IRF1 and NCOA1 increased autophagy of OGD/R-induced retinal microglia, inhibited M1-type polarization and inflammatory cytokines, alleviated RIR injury in rats, and inhibited the activation of Wnt/β-catenin signalling pathway. The Wnt/β-catenin signalling pathway activator HLY78 partially reversed the effect of knocking down NCOA1 on retinal microglia. Mechanically, knockdown of IRF1 inhibited the activation of Wnt/β-catenin signalling pathway by inhibiting the transcription of NCOA1.
CONCLUSION: Inhibition of IRF1 has a protective effect on RIR damage by regulating NCOA1/Wnt/β-catenin signalling pathway.

Keywords:  Autophagy; IRF1; Microglia; Polarization; Retinal ischemia-reperfusion

DOI:  https://doi.org/10.1016/j.cellsig.2025.111746
Proc Natl Acad Sci U S A. 2025 Mar 25. 122(12): e2502064122

MITD1 is a brain-specific interferon-inducible factor that inhibits flavivirus replication.

Jim Zoladek, Marion Cannac, Maël Seite, Emma Davies, Jordan Quellec, Jonathan Barthelemy, Kamila Gorna, Sophie Desgraupes, Ines Bribes, Sara Salinas, Muriel Coulpier, Nathalie J Arhel, Massimo Palmarini, Yannick Simonin, Sam J Wilson, Sébastien Nisole.

  West Nile virus (WNV) and Usutu virus (USUV) are closely related mosquito-borne neurotropic flaviviruses that share common transmission cycle and can infect humans. However, while human infections by WNV are widespread, infections by USUV are comparatively less frequent, less severe, and currently limited to Africa and Europe. To identify human host factors that contribute to the pathogenic signatures of these two flaviviruses, we carried out an arrayed expression screen of over 1,300 interferon-stimulated genes (ISGs). Several ISGs known to target flaviviruses, including IFI6, SHFL, and RTP4 were among the strongest hits. Interestingly, we also found MITD1, an ISG with no previously reported antiviral activity, among the strongest hits. We demonstrated that the antiviral activity of MITD1 was not limited to USUV and WNV, since it also inhibited Zika and dengue virus replication. We found MITD1 to interfere with viral RNA replication by sequestering specific endosomal sorting complexes required for transport-III (ESCRT-III) proteins involved in the formation of viral replication factories. MITD1 expression was not increased by type I interferon (IFN-I) in most human cells and mouse tissues that we examined, although WNV and USUV replication was strongly inhibited by IFN-I. Strikingly, MITD1 was induced in the brain of USUV-infected mice and importantly, in human monocyte-derived microglia. Using human microglial-like cells, we confirmed that MITD1 is an essential mediator of the anti-flavivirus activity of IFN-I in these cells. We conclude that MITD1 plays a key role in the cellular defenses against neurotropic flaviviruses.

Keywords:  flavivirus; innate immune response; interferon-stimulated genes; microglial cells

DOI:  https://doi.org/10.1073/pnas.2502064122
Cell Mol Life Sci. 2025 Mar 17. 82(1): 119

Targeting HIF-2α in glioblastoma reshapes the immune infiltrate and enhances response to immune checkpoint blockade.

Felipe I Espinoza, Stoyan Tankov, Sylvie Chliate, Joana Pereira Couto, Eliana Marinari, Thibaud Vermeil, Marc Lecoultre, Nadia El Harane, Valérie Dutoit, Denis Migliorini, Paul R Walker.

  Glioblastoma (GBM) is an aggressive primary brain tumor with dismal clinical prognosis and resistance to current therapies. GBM progression is facilitated by the tumor microenvironment (TME), with an immune infiltrate dominated by tumor-associated microglia/macrophages (TAMs) and regulatory T cells (Tregs). The TME is also characterized by hypoxia and the expression of hypoxia-inducible factors (HIFs), with HIF-2α emerging as a potential regulator of tumor progression. However, its role in GBM immunosuppression remains unknown. Here, we investigate HIF-2α and the use of the HIF-2α inhibitor PT2385 to modulate the TME in the immunocompetent GL261 mouse GBM model. PT2385 administration in vivo decreased tumor volume and prolonged survival of tumor-bearing mice, without affecting GL261 viability in vitro. Notably, HIF-2α inhibition alleviated the immunosuppressive TME and synergized with immune checkpoint blockade (ICB) using αPD-1 and αTIM-3 antibodies to promote long-term survival. Comprehensive analysis of the immune infiltrate through single-cell RNA sequencing and flow cytometry revealed that combining PT2385 with ICB reduced numbers of pro-tumoral macrophages and Tregs while increasing numbers of microglia, with a corresponding transcriptional modulation towards an anti-tumoral profile of these TAMs. In vitro, deletion of HIF-2α in microglia impeded their polarization towards a pro-tumoral M2-like profile, and its inhibition impaired Treg migration. Our results show that targeting HIF-2α can switch an immunosuppressive TME towards one that favors a robust and sustained response to ICB based immunotherapy. These findings establish that clinically relevant HIF-2α inhibitors should be explored not only in malignancies with defects in the HIF-2α axis, but also in those exhibiting an immunosuppressive TME that limits immunotherapy responsiveness.

Keywords:  Brain tumors; Glioma; HIF-2; Hypoxia inducible factor; Immune checkpoint inhibitors; Immunotherapy; Microglia; Treg; Tumor microenvironment; Tumor-associated macrophage

DOI:  https://doi.org/10.1007/s00018-025-05642-8
Alzheimers Dement. 2025 Mar;21(3): e70060

Metabolic stress and age drive inflammation and cognitive decline in mice and humans.

Sarah E Elzinga, Kai Guo, Ali Turfah, Rosemary E Henn, Ian F Webber-Davis, John M Hayes, Crystal M Pacut, Samuel J Teener, Andrew D Carter, Diana M Rigan, Adam M Allouch, Dae-Gyu Jang, Rachel Parent, Emily Glass, Geoffrey G Murphy, Stephen I Lentz, Kevin S Chen, Lili Zhao, Junguk Hur, Eva L Feldman.

   INTRODUCTION: Metabolic stressors (obesity, metabolic syndrome, prediabetes, and type 2 diabetes [T2D]) increase the risk of cognitive impairment (CI), including Alzheimer's disease (AD). Immune system dysregulation and inflammation, particularly microglial mediated, may underlie this risk, but mechanisms remain unclear.
METHODS: Using a high-fat diet-fed (HFD) model, we assessed longitudinal metabolism and cognition, and terminal inflammation and brain spatial transcriptomics. Additionally, we performed hippocampal spatial transcriptomics and single-cell RNA sequencing of post mortem tissue from AD and T2D human subjects versus controls.
RESULTS: HFD induced progressive metabolic and CI with terminal inflammatory changes, and dysmetabolic, neurodegenerative, and inflammatory gene expression profiles, particularly in microglia. AD and T2D human subjects had similar gene expression changes, including in secreted phosphoprotein 1 (SPP1), a pro-inflammatory gene associated with AD.
DISCUSSION: These data show that metabolic stressors cause early and progressive CI, with inflammatory changes that promote disease. They also indicate a role for microglia, particularly microglial SPP1, in CI.
HIGHLIGHTS: Metabolic stress causes persistent metabolic and cognitive impairments in mice. Murine and human brain spatial transcriptomics align and indicate a pro-inflammatory milieu. Transcriptomic data indicate a role for microglial-mediated inflammatory mechanisms. Secreted phosphoprotein 1 emerged as a potential target of interest in metabolically driven cognitive impairment.

Keywords:  cognitive impairment; hippocampus; human; inflammation; microglia; mouse; obesity; prediabetes; type 2 diabetes

DOI:  https://doi.org/10.1002/alz.70060
Mol Neurodegener. 2025 Mar 21. 20(1): 35

The role of n-3-derived specialised pro-resolving mediators (SPMs) in microglial mitochondrial respiration and inflammation resolution in Alzheimer's disease.

Mary Slayo, Christoph Rummel, Pasindu Hansana Singhaarachchi, Martin Feldotto, Sarah J Spencer.

  Alzheimer's disease (AD) is the most common form of dementia globally and is characterised by reduced mitochondrial respiration and cortical deposition of amyloid-β plaques and neurofibrillary tangles comprised of hyper-phosphorylated tau. Despite its characterisation more than 110 years ago, the mechanisms by which AD develops are still unclear. Dysregulation of microglial phagocytosis of amyloid-β may play a key role. Microglia are the major innate immune cell of the central nervous system and are critical responders to pro-inflammatory states. Typically, microglia react with a short-lived inflammatory response. However, a dysregulation in the resolution of this microglial response results in the chronic release of inflammatory mediators. This prolongs the state of neuroinflammation, likely contributing to the pathogenesis of AD. In addition, the microglial specialised pro-resolving mediator (SPM) contribution to phagocytosis of amyloid-β is dysregulated in AD. SPMs are derivatives of dietary n-3 polyunsaturated fatty acids (PUFAs) and potentially represent a strategic target for protection against AD progression. However, there is little understanding of how mitochondrial respiration in microglia may be sustained long term by n-3-derived SPMs, and how this affects their clearance of amyloid-β. Here, we re-evaluate the current literature on SPMs in AD and propose that SPMs may improve phagocytosis of amyloid-β by microglia as a result of sustained mitochondrial respiration and allowing a pro-resolution response.

Keywords:  Alzheimer’s disease; Beta-oxidation; Fatty acids; Inflammation; Microglia; Mitochondria; N-3; Sex differences; Specialised pro-resolving mediators

DOI:  https://doi.org/10.1186/s13024-025-00824-1
J Alzheimers Dis. 2025 Mar 19. 13872877251326267

Identifying microglia-derived NFKBIA as a potential contributor to the pathogenesis of Alzheimer's disease and age-related macular degeneration.

Shizhen Lei, Yani Liu.

  BackgroundAlzheimer's disease (AD) and age-related macular degeneration (AMD) place considerable health burden on affected individuals and significant economic burden on society.ObjectiveThis study aims to explore the shared cellular and molecular mechanisms underlying the pathogenesis of AD and AMD.MethodsThe investigation in this study is conducted via single-cell and bulk tissue transcriptomic analysis. Transcriptomic datasets of AD and AMD were obtained from the GEO database. The shared differentially expressed genes (DEGs) in control and AD- and AMD-affected samples were identified. Functional enrichment analysis for DEGs was subsequently performed. Then, the protein-protein interaction (PPI) network of these DEGs was established via the STRING database and hub genes of this network were identified by Cytoscape software. Single-cell transcriptomic analysis was performed using Seurat R package to explore their expression in different cell types.ResultsDifferential analysis identified 127 shared DEGs of the two diseases, including 71 upregulated and 56 downregulated genes. Upregulated DEGs were enriched in inflammation, gliogenesis, cell apoptosis, and response to bacterial and viral infection and downregulated DEGs were enriched in mitochondrial function and energy production. PPI network and Cytoscape determined 10 hub genes, of which the NFKBIA gene was associated with the severity of both AD and AMD. Moreover, single-cell transcriptomic analysis showed that NFKBIA was highly expressed in microglia from disease-affected tissues.ConclusionsThe findings indicated that microglia with high NFKBIA expression were important contributors to the progression of both AD and AMD. Microglia-derived NFKBIA might serve as a potential therapeutic target for AD and AMD.

Keywords:  Alzheimer's disease; NFKBIA; age-related macular degeneration; microglia; single-cell RNA sequencing

DOI:  https://doi.org/10.1177/13872877251326267
J Alzheimers Dis. 2025 Mar 17. 13872877251320419

The associations of cerebrospinal fluid ApoE and C1q with Alzheimer's disease biomarkers.

Alzheimer's Disease Neuroimaging Initiative *

  BackgroundThe roles of complement 1q (C1q) and Apolipoprotein E (ApoE) in driving Alzheimer's disease (AD) progression might be explained by their associations with neuroinflammation and AD pathology which were previously reported.ObjectiveWe examined the associations of cerebrospinal fluid (CSF) C1q and ApoE with CSF neuroinflammatory biomarkers and AD core biomarkers, as well as explored whether C1q mediated the associations of CSF ApoE with these biomarkers.MethodsHere, we analyzed CSF proteomics data from Alzheimer's Disease Neuroimaging Initiative (ADNI) using two different ADNI proteomics datasets-SomaScan (n = 579)and multiple reaction monitoring (MRM[n = 207]). Linear regression analyses were conducted to explore the association of CSF ApoE and C1q. The mediation model and structural equation model (SEM) were conducted to explore the associations of ApoE and C1q with AD biomarkers.ResultsMultiple linear regression showed that CSF ApoE was positively associated with CSF C1q in total participants and Alzheimer's continuum participants. Mediation analyses indicated that C1q mediated the associations of CSF ApoE with CSF T-tau, P-tau, sTREM2 and GFAP (mediation proportions range from 15.06 to 44.64%; all the p values < 0.05) but not with CSF amyloid-β and progranulin (PGRN). The SEM yielded similar results.ConclusionsOur findings suggest that C1q is linked to ApoE, and it mediates the associations of ApoE with T-tau, P-tau, sTREM2, GFAP, indicating C1q association with ApoE might be involved in AD progression.

Keywords:  Alzheimer's disease; Apolipoprotein E; C1q; cerebrospinal fluid; inflammation; neurodegeneration

DOI:  https://doi.org/10.1177/13872877251320419
Eur J Med Res. 2025 Mar 20. 30(1): 189

Resolvin D1 accelerates resolution of neuroinflammation by inhibiting microglia activation through the BDNF/TrkB signaling pathway.

Cunju Bo, Xiaoming Liu, Yongjian Liu, Lingjun Xu, Qiaodong Huang.

   BACKGROUND: Neuropathic pain is characterized by hyperalgesia, allodynia, and inflammation and it is often resistant to treatment. The formyl peptide receptor 2 (ALX/FPR2), a G-protein-coupled receptor, has been implicated in resolving inflammation, making its agonist, Resolvin D1 (RvD1), a potential therapeutic agent. Previous studies suggest that RvD1 alleviates neuropathic pain via anti-inflammatory effects, but its mechanisms remain unclear, particularly in relation to microglial activation and the brain-derived neurotrophic factor (BDNF)/TrkB signaling pathway.
OBJECTIVE: To investigate the analgesic effects of RvD1 in a spared nerve injury (SNI) model of neuropathic pain and explore its mechanisms through the regulation of neuroinflammation and the BDNF/TrkB signaling pathway.
METHODS: SNI mice received intrathecal RvD1 at varying doses (10-40 ng) to determine its efficacy in reducing mechanical allodynia and thermal sensitivity. The anti-inflammatory effects of RvD1 were assessed using ELISA, immunofluorescence, and western blotting to measure the expression of pro-inflammatory cytokines and BDNF. The involvement of ALX/FPR2 and TrkB receptors was further examined using antagonists Boc2 and K252a.
RESULTS: RvD1 significantly reduced mechanical and thermal allodynia in SNI mice in a dose-dependent manner. RvD1 also decreased microglial activation and expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and BDNF in both in vivo and in vitro models. These effects were reversed by Boc2 and K252a, confirming that the analgesic actions of RvD1 are mediated via the ALX/FPR2 receptor and inhibition of BDNF/TrkB signaling.
CONCLUSION: RvD1 alleviates neuropathic pain by reducing neuroinflammation through the ALX/FPR2 receptor and suppressing BDNF/TrkB signaling. These findings suggest RvD1 as a promising therapeutic agent for neuropathic pain management.

Keywords:  BDNF/TrkB; Microglia activation; Neuropathic pain; Resolvin D1

DOI:  https://doi.org/10.1186/s40001-025-02424-7
J Neuroinflammation. 2025 Mar 20. 22(1): 90

MAIT cell deficiency exacerbates neuroinflammation in P301S human tau transgenic mice.

Yuanyue Zhang, Zhi Yang, Na Jiang, Xiaosheng Tan, Peng Jiang, Gaoyuan Cao, Qi Yang.

BACKGROUND: The role of immune cells in neurodegeneration remains incompletely understood. Accumulation of misfolded tau proteins is a hallmark of neurodegenerative diseases. Our recent study revealed the presence of mucosal-associated invariant T (MAIT) cells in the meninges, where they express antioxidant molecules to maintain meningeal barrier integrity. However, the role of MAIT cells in tau-related neuroinflammation and neurodegeneration remains unknown.
METHODS: Flow cytometry analysis was performed to examine MAIT cells in human Tau P301S transgenic mice. Tau pathology, hippocampus atrophy, meningeal integrity, and microglial gene expression were examined in Mr1-/- P301S mice that lacked MAIT cells and control P301S transgenic mice, as well as Mr1-/- P301S mice with adoptive transfer of MAIT cells.
RESULTS: The meninges of P301S mutant human tau transgenic mice had increased numbers of MAIT cells, which retained their expression of antioxidant molecules. Mr1-/-P301S mice that lacked MAIT cells exhibited increased tau pathology and hippocampus atrophy compared to control Mr1+/+P301S mice. Adoptive transfer of MAIT cells reduced tau pathology and hippocampus atrophy in Mr1-/- P301S mice. Meningeal barrier integrity was compromised in Mr1-/-P301S mice, but not in control Mr1+/+P301S mice. A distinctive microglia subset with a proinflammatory gene expression profile (M-inflammatory) was enriched in the hippocampus of Mr1-/-P301S mice. The transcriptomes of the remaining microglia in these mice also shifted towards a proinflammatory state, with increased expression of inflammatory cytokines, chemokines, and genes related to ribosome biogenesis and immune responses to toxic substances. The transfer of MAIT cells restored meningeal barrier integrity and suppressed microglial inflammation in the Mr1-/- P301S mice.
CONCLUSIONS: Our data indicate an important role for MAIT cells in regulating tau-pathology-related neuroinflammation and neurodegeneration.

DOI: https://doi.org/10.1186/s12974-025-03413-7
Front Immunol. 2024 ;15 1512300

Microglia-derived CXCL2 induced neuronal ferroptosis via CXCR2/Jun axis in sepsis-associated encephalopathy.

Yu-Shen Yang, Jin-Wei Liang, Meng-Qin Pei, Yu-Ming Fang, Zhen-Dong Sun, He-Fan He.

   Background: Neuronal ferroptosis is a characteristic pathological change of sepsis-associated encephalopathy (SAE), which can be induced by activated microglia. CXCL2 is mainly secreted by inflammatory cells (neutrophil and microglia) and involved in neuronal damage. However, the specific mechanism behind microglia-neuron crosstalk in SAE remains unclear.
Method: This study is to explore in which way microglia-secreted CXCL2 induced neuronal ferroptosis. For this purpose, the present study used CXCL2 knockdown (KD) mice to generate SAE model and determined effects of CXCL2 on neuronal ferroptosis. Afterward, BV2 and HT22 were used to instead of microglia and neuron respectively and the co-cultured system was used to simulate their interaction in vivo environment. RNA-sequencing technology was applied to investigate the key mechanism and targets of CXCL2-induced neuronal ferroptosis. siRNA was used to evaluate the function of key molecules.
Results: Cecum ligation perforation (CLP) induced an obvious cognitive dysfunction, shorten the survival time and promoted the activation of microglia and neuronal loss. The level of inflammatory cytokines, ferroptosis-related markers and malonaldehyde was obviously lower and the level of glutathione was significantly higher in CXCL2 KD mice when compared with wide-type SAE mice. RNA-seq revealed that Jun is a potential target of CXCL2. The following experiments further demonstrated that microglia-secreted CXCL2 induced the neuronal ferroptosis, but siRNA-Jun in neuron can abolish this effect. In addition, siRNA-CXCL2 of microglia mitigated the neuronal ferroptosis induced by sepsis, while Jun agonist reversed this protective effect.
Conclusion: In conclusion, microglia-derived CXCL2 could induce the occurrence of neuronal ferroptosis by targeting Jun. Thus, regulating the expression and secretion of CXCL2 will probably be a crucially novel strategy for the treatment of SAE.

Keywords:  CXCL2/CXCR2 axis; crosstalk; microglia activation; neuronal ferroptosis; sepsis-associated encephalopathy

DOI:  https://doi.org/10.3389/fimmu.2024.1512300
Sci Rep. 2025 Mar 18. 15(1): 9376

Microglial depletion increases aggrecan and hyaluronan levels in the diffuse and aggregated extracellular matrix of the mouse brain.

Diana Egorova, Aurelien Kerever, Masaki Inada, Yoshifumi Itoh, Eri Arikawa-Hirasawa, Shinji Miyata.

  The extracellular matrix (ECM) in the brain can be divided into aggregated ECM, such as perineuronal nets (PNNs) around neurons, and diffuse ECM, which is present throughout the brain parenchyma. Both aggregated and diffuse ECM restrict synaptic plasticity and stabilize neural circuits in the adult brain. Hyaluronan (HA) acts as a scaffold for the brain ECM, and multiple proteoglycans, such as aggrecan, bind to HA to form a macromolecular complex. Recent evidence suggests that microglia, the resident immune cells of the brain, play a crucial role in ECM homeostasis. However, it remains unclear how microglia influence the molecular composition of the ECM. Using a tissue-clearing technique and histochemical analysis, we found that microglial depletion increased the staining intensity of aggrecan and HA in both PNNs and diffuse ECM. Biochemical analyses further confirmed the accumulation of the aggrecan core protein and HA following microglial depletion. Our findings highlight the essential role of microglia in regulating the ECM composition and provide new insights into the mechanisms by which microglia influence neuronal function.

Keywords:  Aggrecan; Brain extracellular matrix; Chondroitin sulfate; Hyaluronan; Microglia; Perineuronal nets; Proteoglycan

DOI:  https://doi.org/10.1038/s41598-025-94224-6
J Neuroinflammation. 2025 Mar 20. 22(1): 89

Asrij/OCIAD1 depletion reduces inflammatory microglial activation and ameliorates Aβ pathology in an Alzheimer's disease mouse model.

Prathamesh Dongre, Madhu Ramesh, Thimmaiah Govindaraju, Maneesha S Inamdar.

   BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles, neuroinflammation, and glial activation. Asrij/OCIAD1 (Ovarian Carcinoma Immunoreactive Antigen Domain containing protein 1) is an AD-associated factor. Increased Asrij levels in the brains of AD patients and mouse models are linked to the severity of neurodegeneration. However, the contribution of Asrij to AD progression and whether reducing Asrij levels is sufficient to mitigate Aβ pathology in vivo is unclear.
METHODS: To explore the impact of Asrij on AD pathology, we deleted asrij in the APP/PS1 mouse model of AD and analyzed the effects on AD hallmarks. We used the Morris water maze and open field test to assess behavioral performance. Using immunohistochemistry and biochemical analyses, we evaluated Aβ plaque load, neuronal and synaptic damage, and gliosis. Further, we utilized confocal microscopy imaging, flow cytometry, and RNA sequencing analysis to comprehensively investigate changes in microglial responses to Aβ pathology upon Asrij depletion.
RESULTS: Asrij depletion ameliorates cognitive impairments, Aβ deposition, neuronal and synaptic damage, and reactive astrogliosis in the AD mouse. Notably, Asrij-deficient microglia exhibit reduced plaque-associated proliferation and decreased phagocytic activation. Transcriptomic analyses of AD microglia reveal upregulation of energy metabolism pathways and downregulation of innate immunity and inflammatory pathways upon Asrij depletion. Mechanistically, loss of Asrij increases mitochondrial activity and impedes the acquisition of a pro-inflammatory disease-associated microglia (DAM) state. Reduced levels of proinflammatory cytokines and decreased STAT3 and NF-κB activation indicate protective changes in AD microglia. Taken together, our results suggest that increased Asrij levels reported in AD, may suppress microglial metabolic activity and promote inflammatory microglial activation, thereby exacerbating AD pathology.
CONCLUSIONS: In summary, we show that Asrij depletion ameliorates Aβ pathology, neuronal and synaptic damage, gliosis, and improves behavioral performance in APP/PS1 mice. This supports that Asrij exacerbates the AD pathology. Mechanistically, Asrij is critical for the development of DAM and promotes neuroinflammatory signaling activation in microglia, thus restricting neuroprotective microglial responses. Hence, reducing Asrij in this context may help retard AD. Our work positions Asrij as a critical molecular regulator that links microglial dysfunction to AD pathogenesis.

Keywords:  Alzheimer’s disease; Amyloid beta; Asrij/OCIAD1; Disease-associated microglia (DAM); Inflammatory signaling; Mitochondria; Neuroinflammation

DOI:  https://doi.org/10.1186/s12974-025-03415-5
Trends Immunol. 2025 Mar 19. pii: S1471-4906(25)00054-7. [Epub ahead of print]

Decoding microglial functions in Alzheimer's disease: insights from human models.

Chandrika Rao, Stefan Semrau, Valentina Fossati.

  Microglia, key orchestrators of the brain's immune responses, play a pivotal role in the progression of Alzheimer's disease (AD). Emerging human models, including stem cell-derived microglia and cerebral organoids, are transforming our understanding of microglial contributions to AD pathology. In this review, we highlight how these models have uncovered human-specific microglial responses to amyloid plaques and their regulation of neuroinflammation, which are not recapitulated in animal models. We also illustrate how advanced human models that better mimic brain physiology and AD pathology are providing unprecedented insights into the multifaceted roles of microglia. These innovative approaches, combined with sophisticated technologies for cell editing and analysis, are shaping AD research and opening new avenues for therapeutic interventions targeting microglia.

Keywords:  Alzheimer's disease; human in vitro models; induced pluripotent stem cells (iPSCs); microglia; single-cell technologies

DOI:  https://doi.org/10.1016/j.it.2025.02.011
Exp Eye Res. 2025 Mar 13. pii: S0014-4835(25)00115-0. [Epub ahead of print]254 110344

Functional genomics in age-related macular degeneration: From genetic associations to understanding disease mechanisms.

Rinki Ratnapriya, Felix Grassman, Rui Chen, Alex Hewitt, Jianhai Du, Daniel R Saban, Caroline C W Klaver, John Ash, Dwight Stambolian, Santa J Tumminia, Jiang Qian, Deeba Husain, Sudha K Iyengar, Anneke I den Hollander.

  Genome-wide association studies have been remarkably successful in identifying genetic variants associated with age-related macular degeneration (AMD), demonstrating a strong genetic component largely driven by common variants. However, progress in translating these genetic findings into a deeper understanding of disease mechanisms and new therapies has been slow. Slow progress in this area can be attributed to limited knowledge of the functional impact of AMD-associated non-coding variants on gene function, the molecular mechanisms and cell types underlying disease. This review offers a comprehensive overview of functional genomics approaches to uncover the genetic, epigenetic, cellular and molecular mechanisms underlying AMD and outlines future directions for research.

Keywords:  Cellular models of AMD; Gene prioritization; Gene regulation; Genome-wide association study (GWAS); Microglia; Quantitative trait loci (QTL); Village-in-a-dish

DOI:  https://doi.org/10.1016/j.exer.2025.110344
J Neuroinflammation. 2025 Mar 19. 22(1): 88

SIRPα modulates microglial efferocytosis and neuroinflammation following experimental subarachnoid hemorrhage via the SHP1/STAT6 axis.

Bingtao Zhang, Yan Zou, Qikai Tang, Zixuan Yuan, Kun Jiang, Zhaoxiang Zhang, Shujuan Chen, Qi Wu, Xiaoming Zhou, Xin Zhang.

  Subarachnoid hemorrhage induces extensive neuronal cell death, leading to the release of damage-associated molecular patterns (DAMPs). These DAMPs, along with hemoglobin and cell corpses, trigger localized inflammation. Signal regulatory protein alpha (SIRPα) plays a crucial role in efferocytosis by acting as a "don't eat-me" signal, modulating inflammation and tissue homeostasis. However, the precise function and regulatory mechanisms of SIRPα in efferocytosis remain unclear. Proteomic analysis of cerebrospinal fluid (CSF) reveals that SIRPα levels are significantly elevated in the CSF of SAH patients and correlate with clinical outcomes. In vivo and in vitro studies show that microglial knockdown of SIRPα promotes efferocytosis and attenuates neuroinflammation following SAH. SIRPα inhibits efferocytosis by recruiting and phosphorylating SHP1 and SHP2 through phosphorylation of four tyrosine residues in its cytoplasmic domain, with SHP1 playing a particularly critical role. Mutation of these tyrosine residues to non-phosphorylatable alanine residues enhances efferocytosis and reduces neuroinflammation in vitro. RNA-seq analysis suggests that this mutation upregulates the expression of "eat-me" signals, MerTK and CD36, and identifies STAT6 as a key transcription factor involved in this process. In conclusion, SIRPα plays a central role in regulating microglia efferocytosis and neuroinflammation after SAH via the SHP1/STAT6 axis. Targeting this pathway may provide a promising therapeutic approach for SAH.

Keywords:  Efferocytosis; Neuroinflammation; Signal regulatory protein alpha; Signal transducer and activator of transcription 6; Subarachnoid hemorrhage

DOI:  https://doi.org/10.1186/s12974-025-03414-6