bims-microg 2025-02-23 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–02–23
24 papers selected by
Marcus Karlstetter, Universität zu Köln

Stressed microglia turn to the dark side in Alzheimer's disease.
Microglial depletion decreases Müller cell maturation and inner retinal vascular density.
Human breast milk-derived exosomes attenuate lipopolysaccharide-induced activation in microglia.
Sugar utilization by microglia in Alzheimer's disease.
Impaired peroxisomal beta-oxidation in microglia triggers oxidative stress and impacts neurons and oligodendrocytes.
Single-cell analysis identifies Ifi27l2a as a gene regulator of microglial inflammation in the context of aging and stroke in mice.
Acute liver damage generates age independent microglia morphology changes in mice.
NFAT1 Signaling Contributes to Bone Cancer Pain by Regulating IL-18 Expression in Spinal Microglia.
IDO1 modulates pain sensitivity and comorbid anxiety in chronic migraine through microglial activation and synaptic pruning.
Benefits of equilibrium between microbiota- and host-derived ligands of the aryl hydrocarbon receptor after stroke in aged male mice.
Benzoylacetonitrile as a novel anti-inflammatory compound on attenuating microglia and encephalitogenic T cell activation in experimental autoimmune encephalomyelitis.
Digestive exophagy as a novel mechanism of amyloid-β degradation by microglial lysosomes.
PARP14 inhibits microglial activation via NNT to alleviate depressive-like behaviors in mice.
Partial microglial depletion through inhibition of colony-stimulating factor 1 receptor improves synaptic plasticity and cognitive performance in aged mice.
Microglia aggregates define distinct immune and neurodegenerative niches in Alzheimer's disease hippocampus.
G protein-coupled estrogen receptor deficiency exacerbates demyelination through microglial ferroptosis.
Morphological and functional differences between hippocampal and cortical microglia and its impact on neuronal over-excitation in a germline Pten mutant mouse model.
Deer antler polypeptides inhibit microglial activation via TREM2 to improve behavior and neuroinflammation in CUMS mice.
Critical role of Oas1g and STAT1 pathways in neuroinflammation: insights for Alzheimer's disease therapeutics.
An efficient, non-viral arrayed CRISPR screening platform for iPSC-derived myeloid and microglia models.
Dapagliflozin Improves High-Fat Diet-Induced Cognitive Impairment in Female Mice.
Growth differentiation factor 15 aggravates sepsis-induced cognitive and memory impairments by promoting microglial inflammatory responses and phagocytosis.
Traditional pediatric massage exerted an antidepressant effect and activated IGF-1/Nrf2 pathway in CUMS-exposed adolescent rats.
Cerebral microvascular density, blood-brain barrier permeability, and support for neuroinflammation indicate early aging in a Marfan syndrome mouse model.

Neuron. 2025 Feb 19. pii: S0896-6273(25)00036-4. [Epub ahead of print]113(4): 501-503

Stressed microglia turn to the dark side in Alzheimer's disease.

Gilbert Di Paolo, Joseph W Lewcock.

A microglia subpopulation termed "dark microglia" has been associated with aging and neurodegeneration, although its role has remained elusive. New research from Flury et al. in this issue of Neuron shows that dark microglia drive neurodegeneration via secretion of toxic lipids.1.

DOI: https://doi.org/10.1016/j.neuron.2025.01.010
Cell Commun Signal. 2025 Feb 17. 23(1): 90

Microglial depletion decreases Müller cell maturation and inner retinal vascular density.

Nathaniel Rowthorn-Apel, Naveen Vridhachalam, Kip M Connor, Gracia M Bonilla, Ruslan Sadreyev, Charandeep Singh, Gopalan Gnanaguru.

   BACKGROUND: The neuroretinal vascular system is comprised of three interconnected layers. The initial superficial vascular plexus formation is guided by astrocytes around birth in mice. The formation of the deep and intermediate vascular plexuses occurs in the second postnatal week and is driven by Müller-cell-derived angiogenic signaling. Previously, we reported that microglia play an important role in regulating astrocyte density during superficial vascular plexus formation. Here, we investigated the role of microglia in regulating Müller-cell-dependent inner retinal vascular development.
METHODOLOGY: In this study, we depleted microglia during retinal development using Csf1R antagonist (PLX5622). We characterized the developmental progression of inner retinal vascular growth, effect of microglial depletion on inner retinal vascular growth and Müller cell marker expressions by immunostaining. Differential expressions of genes in the control and microglia depleted groups were analyzed by mRNA-seq and qPCR. Unpaired t-test was performed to determine the statistical differences between groups.
RESULTS: This study show that microglia interact with Müller cells and the growing inner retinal vasculature. Depletion of microglia resulted in reduced inner retinal vascular layers densities and decreased Vegfa isoforms transcript levels. RNA-seq analysis further revealed that microglial depletion significantly reduced specific Müller cell maturation markers including glutamine synthetase, responsible for glutamine biosynthesis, necessary for angiogenesis.
CONCLUSIONS: Our study reveals an important role for microglia in facilitating inner retinal angiogenesis and Müller cell maturation.

Keywords:  Angiogenesis; Aquaporins; Endothelial cells; Glutamine metabolism; Microglia; Müller cells; Potassium channels

DOI:  https://doi.org/10.1186/s12964-025-02083-5
J Neuroinflammation. 2025 Feb 15. 22(1): 41

Human breast milk-derived exosomes attenuate lipopolysaccharide-induced activation in microglia.

Oluwatomi Akinduro, Sanjay Kumar, Yuechuan Chen, Barbara Thomas, Quamarul Hassan, Brian Sims.

  Microglia mediate the immune response in the central nervous system to many insults, including lipopolysaccharide (LPS), a bacterial endotoxin that initiates neuroinflammation in the neonatal population, especially preterm infants. The synthesis of the proinflammatory proteins CD40 and NLRP3 depends on the canonical NF-κB cascade as the genes encoding CD40 and NLRP3 are transcribed by the phosphorylated NF-κB p50/p65 heterodimer in LPS-induced microglia. Exosomes, which are nanosized vesicles (40-150 nm) involved in intercellular communication, are implicated in many pathophysiological processes. Human breast milk, which is rich in exosomes, plays a vital role in neonatal immune system maturation and adaptation. Activated microglia may cause brain-associated injuries or disorders; therefore, we hypothesize that human breast milk-derived exosomes (HBME) attenuate LPS-induced activation of CD40 and NLRP3 by decreasing p38 MAPK and NF-κB p50/p65 activation/phosphorylation downstream of TLR4 in murine microglia (BV2). Human microglia (HMC3) showed a significant decrease in p65 phosphorylation. We isolated purified HBME and characterized them using nanoparticle tracking analysis, transmission electron microscopy, fluorescence-activated cell sorting, and western blots. Analysis of microglia exposed to LPS and HBME indicated that HBME modulated the expression of signaling molecules in the canonical NF-κB pathway, including MyD88, IκBα, p38 MAPK, NF-κB p65, and their products CD40, NLRP3, and cytokines IL-1β and IL-10. Thus, HBMEs have great potential for attenuating the microglial response to LPS.

Keywords:  BV2; Breast milk; CD40; Exosomes; HMC3; IL-10; IL-1β; Lipopolysaccharide; Microglia; NFκB; NLRP3; Neonatal neuroinflammation

DOI:  https://doi.org/10.1186/s12974-025-03345-2
J Neuroimmunol. 2025 Feb 14. pii: S0165-5728(25)00032-3. [Epub ahead of print]401 578552

Sugar utilization by microglia in Alzheimer's disease.

Kaitlyn M Marino, Daniel C Shippy, Tyler K Ulland.

  Diabetes is a major risk factor for Alzheimer's disease (AD), yet the effect of specific carbohydrate sources in the diet on AD pathology remains unclear. The primary neuroimmune cell, microglia, undergo a metabolic shift during neuroinflammation associated with AD pathology. We utilized existing gene expression data and identified changes in sugar transporters (increased Slc2a1 (glucose) and decreased Slc2a5 (fructose) expression). To examine gene expression with respect to primary sugar source, N9 cells, a mouse microglia cell line, were cultured in glucose or fructose supplemented media and stimulated with lipopolysaccharide (LPS). RNA-sequencing analyses indicated significant changes between control and sugar supplemented media and several differentially expressed genes between glucose and fructose media. Concurrently, 5XFAD mice received equicaloric diets with specific carbohydrate sources: dextrose or fructose. Regardless of diet, sex, or genotype, all mice developed high blood sugar levels; confocal microscopy analyses indicated similar amyloid plaque burden and microglial response relative to the control diet, but there was a change in the microglial response between dextrose and fructose fed mice. Overall, these data indicate microglia preferentially express sugar transporters and sugar source may influence microglial reactivity in response to plaque pathology.

Keywords:  Alzheimer's disease; Fructose; Glucose; Microglia; Sugar metabolism

DOI:  https://doi.org/10.1016/j.jneuroim.2025.578552
Front Mol Neurosci. 2025 ;18 1542938

Impaired peroxisomal beta-oxidation in microglia triggers oxidative stress and impacts neurons and oligodendrocytes.

Ali Tawbeh, Catherine Gondcaille, Fatima-Ezzahra Saih, Quentin Raas, Damien Loichot, Yannick Hamon, Céline Keime, Alexandre Benani, Francesca Di Cara, Mustapha Cherkaoui-Malki, Pierre Andreoletti, Stéphane Savary.

  Microglia, the immune cells of the central nervous system, activate neuroinflammatory pathways in response to homeostatic disturbances, a process implicated in the pathogenesis of various neurodegenerative diseases. Emerging evidence identifies abnormal microglial activation as a causal factor at the onset of peroxisomal leukodystrophies, including X-linked adrenoleukodystrophy (X-ALD). This study investigates how primary peroxisomal deficiencies influence oxidative properties of microglia and examines the subsequent impact on neurons and oligodendrocytes. Using BV-2 microglial cells lacking ABCD1, ABCD2, or ACOX1, peroxisomal proteins that play key roles in the very-long-chain fatty acid beta-oxidation, we analyzed their response under basal condition and after stimulation by lipopolysaccharide (LPS). Transcriptomic analysis of the mutant microglial cells revealed numerous differentially expressed genes, particularly in redox-related pathways following LPS exposure. These changes are consistent with the increased production of reactive oxygen species (ROS) and nitric oxide (NO). Conditioned media (CM) from the mutant cells were then applied to cultures of neuron and oligodendrocyte cell lines. Exposure to CM from LPS-stimulated mutant microglial cells significantly increased apoptosis in both cell types. Furthermore, treated neurons exhibited a reduction in cell complexity and an increased ability to secrete neuropeptides. These findings demonstrate that peroxisomal impairments in microglia exacerbate inflammatory response and ROS/NO production, affecting the survival of neurons and oligodendrocytes, as well as neuronal morphology and function. This dysfunction might contribute to the early neurodegenerative events in X-ALD by triggering and sustaining neuroinflammatory cascades. Therapeutic strategies that target microglial activation and secretion profiles could hold promise in managing peroxisomal disorders such as X-ALD.

Keywords:  X-linked adrenoleukodystrophy; microglia; neuroinflammation; nitric oxide; oxidative stress; peroxisome; reactive oxygen species

DOI:  https://doi.org/10.3389/fnmol.2025.1542938
Nat Commun. 2025 Feb 14. 16(1): 1639

Single-cell analysis identifies Ifi27l2a as a gene regulator of microglial inflammation in the context of aging and stroke in mice.

Gab Seok Kim, Elisabeth Harmon, Manuel C Gutierrez, Sodam Kim, Lauren Vance, Haven Burrous, Jessica M Stephenson, Anjali Chauhan, Anik Banerjee, Zachary Wise, Andrea Doan, John Ahn, Ting Wu, Jesus Bautista-Garrido, Juneyoung Lee, Chunfeng Tan, Joo Eun Jung, Louise D McCullough, Joshua D Wythe, Sean P Marrelli.

Inflammation is a significant driver of ischemic stroke pathology in the brain. To identify potential regulators of inflammation, we performed single-cell RNA sequencing (scRNA-seq) of young and aged mouse brains following stroke and found that interferon alpha-inducible protein 27 like 2 A (Ifi27l2a) was significantly up-regulated, particularly in microglia of aged brain. Ifi27l2a is induced by interferons for viral host defense and has been linked with pro-inflammatory cellular mechanisms. However, its potential role in neurodegeneration is unknown. Using a combination of cell culture, experimental stroke models in mice, and human autopsy brain samples, we demonstrated that induction of Ifi27l2a occurs in microglia in response to aging, ischemic stroke, and pro-inflammatory molecules. We further showed that induction of Ifi27l2a in microglia was sufficient to stimulate mitochondrial ROS production and promote a pro-inflammatory phenotype. Lastly, using an ischemic stroke model, we demonstrated that hemizygous deletion of Ifi27l2a (Ifi27l2a+/- mice) reduced gliosis (microgliosis and astrogliosis), acute and chronic brain injury, and motor function deficits. Together, these findings identify Ifi27l2a as a critical neuroinflammatory mediator in ischemic stroke and provide support for the therapeutic strategy of disrupting Ifi27l2a to attenuate inflammation in the post-stroke brain.

DOI: https://doi.org/10.1038/s41467-025-56847-1
Rom J Morphol Embryol. 2024 Oct-Dec;65(4):65(4): 679-685

Acute liver damage generates age independent microglia morphology changes in mice.

Gabriel Nedelea, Mădălina Iuliana Muşat, Smaranda Ioana Mitran, Mihai Călin Ciorbagiu, Bogdan Cătălin.

  Non-alcoholic fatty liver disease (NAFLD) has emerged as a silent global epidemic, frequently contributing to systemic inflammation. As the primary immune cells of the central nervous system (CNS), microglia undergo morphological changes that serve as critical indicators of CNS health. In this study, we aimed to quantify alterations in microglial morphology within the cortex of young and aged mice with liver damage. Our results demonstrated that hepatic dysfunction leads to a significant increase in total branch length in both young (285.79±68.23 μm) and aged animals (268.67±69.06 μm), compared to their respective controls (164.07±33.05 μm and 140.96±27.18 μm) (p<0.0001). Additionally, aged animals with liver damage exhibited a mean branch length of 5.84±0.66 μm, higher than 2.63±0.19 μm observed in those without liver injury. The number of primary branches in aged mice with liver damage decreased from 6.6±1.2 branches to 3.1±1.5 (p<0.0001). In addition, we have shown a decrease in the number of secondary branches in aged animals with liver damage. This suggests that microglia not only respond to CNS-specific injuries but also to chronic systemic pathologies like NAFLD. These findings highlight the importance of better understanding the liver-brain axis in order to better understand the neuroimmune consequences of systemic diseases.

Keywords:  NAFLD; cortex; microglia; morphology

DOI:  https://doi.org/10.47162/RJME.65.4.15
CNS Neurosci Ther. 2025 Feb;31(2): e70222

NFAT1 Signaling Contributes to Bone Cancer Pain by Regulating IL-18 Expression in Spinal Microglia.

Xuetai Chen, Ying Zeng, Zizhu Wang, Jixiang Zhu, Fengyun Liu, Mingxuan Zhu, Jiayi Zheng, Qingdaiyao Chen, Dongxu Zhai, Yangyang Chen, Jiayao Niu, Zhouya Xue, Guan Sun, Feng Li, Zhiqiang Pan.

   AIMS: This study aimed to test the hypothesis that nuclear factor of activated T cells 1 (NFAT1) signaling contributes to bone cancer pain by regulating interleukin (IL)-18 expression in spinal microglia.
METHODS: This study was performed on male mice using a Lewis lung carcinoma-induced bone cancer pain model. Nociceptive behaviors were evaluated by measuring mechanical allodynia, thermal hyperalgesia, and spontaneous pain. Expression levels were measured via real-time quantitative polymerase chain reaction, western blotting, and immunofluorescence analysis. The effect of pharmacologic intervention of spinal NFAT1/IL-18 signaling on bone cancer pain was the primary outcome.
RESULTS: NFAT1 expression was upregulated in the spinal microglia after tumor inoculation. Pharmacological inhibition of NFAT1 upregulation prevented and reversed bone cancer-related pain behaviors. In spinal microglia, NFAT1 inhibition decreased p38 MAPK phosphorylation and IL-18 production. Blocking NFAT1 signaling suppressed tumor-induced neuronal sensitization and microglial activation as well as activation of the N-methyl-D-aspartate receptor and the subsequent Ca2+-dependent signaling.
CONCLUSION: Microglia NFAT1-p38 signaling contributes to bone cancer pain through IL-18-mediated central sensitization in spinal microglia. NFAT1 could be a potential target for therapeutic intervention to prevent bone cancer pain.

Keywords:  bone cancer pain; interleukin‐18; microglia; nuclear factor of activated T cells 1; p38 MAPK

DOI:  https://doi.org/10.1111/cns.70222
J Neuroinflammation. 2025 Feb 18. 22(1): 42

IDO1 modulates pain sensitivity and comorbid anxiety in chronic migraine through microglial activation and synaptic pruning.

Jiao Hu, Wen-Juan Ji, Gui-Yu Liu, Xiao-Hong Su, Jun-Ming Zhu, Yu Hong, Yi-Fan Xiong, Yun-Yan Zhao, Wei-Peng Li, Wei Xie.

   BACKGROUND: Chronic migraine is a prevalent and potentially debilitating neurological disorder that is often comorbid with mental health conditions (such as anxiety and depression), but the underlying mechanisms linking these conditions remain poorly understood. Indoleamine 2,3-dioxygenase 1 (IDO1) has been implicated in inflammatory processes, including neuroinflammation and pain. However, its role as a link between neuroinflammation and pain sensitization in chronic migraine is not well defined.
METHODS: Male mice were used to establish a model of chronic migraine by recurrent intraperitoneal injections of nitroglycerin (NTG, 10 mg/kg). Using pharmacological approaches, transgenic strategies and adeno-associated virus (AAV) intervention, we investigated the role of IDO1 in pain sensitization and migraine-related mood disorders in an NTG-induced chronic migraine mouse model. We employed a combination of immunoblotting, immunohistochemistry, three-dimensional reconstruction, RNA sequencing, electrophysiology, in vivo fiber photometry, and behavioral assays to elucidate the underlying mechanisms involved.
RESULTS: Our findings demonstrated that pharmacological inhibition and genetic knockout of IDO1 significantly alleviated pain sensitivity in a chronic migraine model. Neuronal activity in the anterior cingulate cortex (ACC) was evaluated with in vitro c-Fos immunostaining as well as in vivo fiber photometry, and a shift in the excitation/inhibition (E/I) balance toward excitation was observed through whole-cell patch clamp recording. Notably, IDO1 expression was increased in the ACC, and AAV-mediated IDO1 knockdown in the ACC rescued pain sensitivity, electrophysiological E/I balance changes, and anxiety-like behavior in chronic migraine model mice. Furthermore, IDO1 regulated microglial activation and pruning of neuronal synapses in the ACC. IDO1's microglial pruning function appears to be mediated through the interferon (IFN) signaling pathway, and the behavioral changes induced by IDO1 knockdown in the ACC could be reversed by activating this pathway.
CONCLUSIONS: Our findings revealed that microglial IDO1 in the ACC drives pain sensitization and anxiety in chronic migraine, highlighting IDO1 as a potential therapeutic target for chronic migraine treatment.

Keywords:  Anterior cingulate cortex (ACC); Chronic migraine; Excitation/inhibition balance; Indoleamine 2,3-dioxygenase 1 (IDO1); Microglia; Synapse

DOI:  https://doi.org/10.1186/s12974-025-03367-w
Nat Commun. 2025 Feb 19. 16(1): 1767

Benefits of equilibrium between microbiota- and host-derived ligands of the aryl hydrocarbon receptor after stroke in aged male mice.

Pedram Peesh, Maria P Blasco-Conesa, Ahmad El Hamamy, Romeesa Khan, Gary U Guzman, Parisa Honarpisheh, Eric C Mohan, Grant W Goodman, Justin N Nguyen, Anik Banerjee, Bryce E West, Kyung Ae Ko, Janelle M Korf, Chunfeng Tan, Huihui Fan, Gabriela D Colpo, Hilda Ahnstedt, Lucy Couture, Solji Roh, Julia K Kofler, Jose F Moruno-Manchon, Michael E Maniskas, Jaroslaw Aronowski, Rodney M Ritzel, Juneyoung Lee, Jun Li, Robert M Bryan, Anjali Chauhan, Venugopal Reddy Venna, Louise D McCullough, Bhanu Priya Ganesh.

Recent studies have highlighted the crucial role of microglia (MG) and their interactions with the gut microbiome in post-stroke neuroinflammation. The activation of immunoregulatory pathways, including the aryl hydrocarbon receptor (AHR) pathway, is influenced by a dynamic balance of ligands derived from both the host and microbiota. This study aimed to investigate the association between stroke-induced dysbiosis and the resultant imbalance in AHR ligand sources (loss of microbiota-derived [indole-based] and increase of host-derived [kynurenine-based]) after stroke. Microbiota-derived AHR ligands decreased in human plasma and remained low for days following an ischemic stroke highlighting the translational significance. Transient-middle-cerebral-artery-occlusion was performed in aged wild-type and germ-free male mice. MG-AHR expression and activity increased in both in vivo and ex vivo stroke models. Germ-free mice showed altered neuroinflammation and antigen presentation while aged mice showed reduced infarct volume and neurological deficits following treatment with microbiota-derived AHR ligands after stroke. Restoring a balanced pool of host- and microbiota-derived AHR ligands may be beneficial after stroke and may represent a therapeutic target.

DOI: https://doi.org/10.1038/s41467-025-57014-2
J Neuroimmunol. 2025 Feb 17. pii: S0165-5728(25)00037-2. [Epub ahead of print]401 578557

Benzoylacetonitrile as a novel anti-inflammatory compound on attenuating microglia and encephalitogenic T cell activation in experimental autoimmune encephalomyelitis.

Ping-Chang Kuo, Zixuan Zhao, Barbara A Scofield, Hallel C Paraiso, I-Chen Ivorine Yu, Dennis A Brown, Jui-Hung Jimmy Yen.

  Multiple sclerosis (MS) is an autoimmune disorder and characterized by immune-mediated neuroinflammation and demyelination triggered by the CNS resident immune cells, microglia (MG), and CNS infiltrating pathogenic T cells. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS, and MG activation and pathogenic Th1/Th17 cell infiltration is responsible for EAE development and progression. We previously demonstrated that benzoylacetonitriles exerted neuro-immunomodulatory activity and identified compound 7a (referred to henceforth as BTA) as promising analog. Here, we investigated whether BTA possessed effects on modulating inflammatory responses in EAE and assessed its effects on MG activation and pathogenic Th1/Th17 differentiation and CNS infiltration in EAE. Our results showed BTA ameliorated disease severity in the chronic C57BL/6 EAE model. Further studies demonstrated BTA suppressed MG activation, attenuated CNS Th1/Th17 infiltration, and inhibited peripheral Th1/Th17 differentiation in EAE. Using protein array, we confirmed BTA inhibited MG activation by suppressing inflammatory cytokines/chemokine production. Furthermore, BTA suppressed Th1/Th17 polarization in vitro, indicating a direct suppressive effect of BTA on Th1/Th17 differentiation. Finally, our results showed that BTA prevented disease relapse in the relapsing-remitting SJL EAE model. In conclusion, our study demonstrates BTA possessed protective and therapeutic effects by ameliorating disease severity in the chronic EAE and mitigating relapse in the relapsing-remitting EAE, respectively. Further analysis revealed BTA exerted effects on inhibiting MG activation and Th1/Th17 differentiation, demonstrated by in vivo and in vitro studies. Altogether, our results suggest the benzoylacetonitrile scaffold could be developed as a novel therapeutic agent for MS/EAE treatment.

Keywords:  BTA; Benzoylacetonitrile; MS/EAE; Microglia; Neuroinflammation; Th1/Th17

DOI:  https://doi.org/10.1016/j.jneuroim.2025.578557
Trends Neurosci. 2025 Feb 13. pii: S0166-2236(25)00019-0. [Epub ahead of print]

Digestive exophagy as a novel mechanism of amyloid-β degradation by microglial lysosomes.

Melanie Meyer-Luehmann.

  Microglia are known to be involved in the modulation of amyloid-β (Aβ) plaques in Alzheimer's disease (AD). In a recent study, Jacquet et al. describe how microglia degrade larger Aβ aggregates by forming lysosomal synapses, further implicating the microglial release of lysosomal Aβ, amongst other processes, in the growth and spread of fibrillary Aβ.

Keywords:  Alzheimer’s disease; amyloid-β; glia; neurodegeneration; neuroinflammation; plaques

DOI:  https://doi.org/10.1016/j.tins.2025.01.005
Brain Behav Immun. 2025 Feb 18. pii: S0889-1591(25)00057-1. [Epub ahead of print]

PARP14 inhibits microglial activation via NNT to alleviate depressive-like behaviors in mice.

Xiaoyu Yu, Tingting Yang, Di Wu, Chenxue Xu, Zhuoran Li, Ao Sun, Shulei Gao, Heng Li, Zhenyu Fan, Rongrong Huang.

  Microglial inflammation has been implicated in the pathophysiology of major depressive disorder; however, the underlying biological mechanisms remain inadequately understood. Consequently, we conducted a screening of the Poly ADP-ribose (PAR) polymerase (PARP) family expression in the hippocampus of chronic unpredictable stress (CUS) mouse models and investigated the specific role of PARP14 in microglial inflammation and its association with depression. Here, this study demonstrated the elevated PARP14 expression in the hippocampus of CUS mice. The knockdown of PARP14 in the hippocampus did not mitigate depressive-like behaviors in mice, whereas overexpression of PARP14 significantly mitigated these behaviors. Furthermore, PARP14 is abundant in microglia, and microglial-targeted PARP14 overexpression significantly alleviated depressive-behaviors in CUS, reduced microglial activation, and inhibited the central inflammatory responses. Mechanistically, PARP14 positively regulated nicotinamide nucleotide transhydrogenase (NNT) expression in microglia, and the inflammatory response of microglia induced by PARP14 knockdown was suppressed through NNT overexpression. Additionally, deficiency in NNT led to an accumulation of reactive oxygen species (ROS) and subsequent microglial inflammation, which was effectively inhibited by the ROS inhibitor N-Acetylcysteine. These findings suggest that PARP14 alleviates depressive-like behaviors in mice by inhibiting microglial activation via NTT-mediated clearance of ROS.

Keywords:  Depression; Inflammation; Microglia; NNT; PARP14

DOI:  https://doi.org/10.1016/j.bbi.2025.02.017
Exp Neurol. 2025 Feb 14. pii: S0014-4886(25)00050-0. [Epub ahead of print]387 115186

Partial microglial depletion through inhibition of colony-stimulating factor 1 receptor improves synaptic plasticity and cognitive performance in aged mice.

Luisa Strackeljan, David Baidoe-Ansah, Hadi Mirzapourdelavar, Shaobo Jia, Rahul Kaushik, Carla Cangalaya, Alexander Dityatev.

  Microglia depletion, followed by repopulation, improves cognitive functions in the aged mouse brain. However, even temporal ablation of microglia puts the brain at a high risk of infection. Hence, in the present work, we studied if the partial reduction of microglia with PLX3397 (pexidartinib), an inhibitor of the colony-stimulating factor 1 receptor (CSF1R), could bring similar benefits as reported for microglia ablation. Aged (two-years-old) mice were treated with PLX3397 for a total of 6 weeks, which reduced microglia numbers in the hippocampus and retrosplenial cortex (RSC) to the levels seen in young mice and resulted in layer-specific ablation in the expression of microglial complement protein C1q mediating synaptic remodeling. This treatment boosted long-term potentiation in the CA1 region and improved performance in the hippocampus-dependent novel object location recognition task. Although PLX3397 treatment did not alter the number or total intensity of Wisteria floribunda agglutinin-positive perineuronal nets (PNNs) in the CA1 region of the hippocampus, it changed the fine structure of PNNs. It also elevated the expression of perisynaptic proteoglycan brevican, presynaptic vGluT1 at excitatory synapses, and vGAT in inhibitory ones in the CA1 stratum radiatum. Thus, targeting the CSF1R may provide a safe and efficient strategy to boost synaptic and cognitive functions in the aged brain.

Keywords:  Aging; Brevican; Extracellular matrix; Glia; Parvalbumin; Perineuronal nets; Perisynaptic ECM; Synapses

DOI:  https://doi.org/10.1016/j.expneurol.2025.115186
Acta Neuropathol. 2025 Feb 15. 149(1): 19

Microglia aggregates define distinct immune and neurodegenerative niches in Alzheimer's disease hippocampus.

Sonja Fixemer, Mónica Miranda de la Maza, Gaël Paul Hammer, Félicia Jeannelle, Sophie Schreiner, Jean-Jacques Gérardy, Susana Boluda, Dominique Mirault, Naguib Mechawar, Michel Mittelbronn, David S Bouvier.

  In Alzheimer's disease (AD), microglia form distinct cellular aggregates that play critical roles in disease progression, including Aβ plaque-associated microglia (PaM) and the newly identified coffin-like microglia (CoM). PaM are closely associated with amyloid-β (Aβ) plaques, while CoM are enriched in the pyramidal layer of the CA2/CA1 hippocampal subfields, where they frequently engulf neurons and associate with tau-positive tangles and phosphorylated α-synuclein. To elucidate the role of these microglial subtypes, we employed high-content neuropathology, integrating Deep Spatial Profiling (DSP), multiplex chromogenic immunohistochemistry and confocal microscopy, to comprehensively map and characterise their morphological and molecular signatures, as well as their neuropathological and astrocytic microenvironments, in AD and control post-mortem samples. PaM and PaM-associated astrocytes exhibited signatures related to complement system pathways, ErbB signalling, and metabolic and neurodegenerative processes. In contrast, CoM displayed markers associated with protein degradation and immune signalling pathways, including STING, TGF-β, and NF-κB. While no direct association between CD8 + T cells and either microglial type was observed, CD163 + perivascular macrophages were frequently incorporated into PaM. These findings provide novel insights into the heterogeneity of microglial responses, in particular their distinct interactions with astrocytes and infiltrating immune cells, and shed light on specific neurodegenerative hotspots and their implications for hippocampal deterioration in AD.

Keywords:  Alzheimer's disease; Glial cells; Hippocampus; Peripheral immune cells; Proteinopathies; Spatial profiling

DOI:  https://doi.org/10.1007/s00401-025-02857-8
J Biol Chem. 2025 Feb 13. pii: S0021-9258(25)00160-7. [Epub ahead of print] 108312

G protein-coupled estrogen receptor deficiency exacerbates demyelination through microglial ferroptosis.

Xiaojuan Mi, Junjie Li, Ziqi Feng, Yanbo Liu, Chun Zhang, Yu Shao, Ting Wang, Zhilun Yang, Haowen Lv, Juan Liu.

  Microglial activation is the initial pathological event that occurs in demyelination, a prevalent feature in various neurological diseases. G protein-coupled estrogen receptor (GPER1), which is highly expressed in microglia, has been reported to reduce myelin damage. However, the precise molecular mechanisms involved remain unclear. In this study, the cuprizone (CPZ) -induced demyelination model was used to investigate the relationship between GPER1 and myelin sheath injury and its mechanism. The results demonstrated that GPER1 deficiency exacerbated cognitive impairment in mice. Along with more severe myelin damage as well as fewer oligodendrocytes. Moreover, GPER1 deficiency not only directly reduced the number of microglia in CPZ mice, but also caused iron ions overload in microglia of myelin debris induced in vitro. Transcriptomic, molecular biological, and morphological analyses revealed that microglial ferroptosis caused by GPER1 deficiency contributes to the reduction of microglia number. In summary, these findings revealed that GPER1 can regulate demyelination through ferroptosis of microglia.

Keywords:  GPER1; demyelination; ferroptosis; microglia; myelin

DOI:  https://doi.org/10.1016/j.jbc.2025.108312
Neuroscience. 2025 Feb 19. pii: S0306-4522(25)00162-9. [Epub ahead of print]

Morphological and functional differences between hippocampal and cortical microglia and its impact on neuronal over-excitation in a germline Pten mutant mouse model.

Zhibing Tan, Parker L Bussies, Nicholas B Sarn, Muhammad Irfan, Tara DeSilva, Charis Eng.

  High-throughput, transcriptomic analyses of the brain have revealed significant differences of microglia between the hippocampus and the cortex. However, it remains unclear whether these regional differences translate into different microglial behaviors and impact disease progression. Here, we show that microglia possess higher morphological complexity and phagocytic capacity in the hippocampus compared to the cortex of wild-type mice. These regional differences are preserved in mice harboring a germline Pten mutation, which have a general increase of microglial ramification and phagocytic capacity. Moreover, we find that Pten-mutant microglia protect neurons from over-excitation through pruning excessive excitatory synapses and forming more microglia-neuron junctions. However, Pten-mutation induced neuronal over-excitation is normalized in the hippocampus but not the cortex which we are attributing to regional differences of microglia in both function and morphology. These Pten-mutant microglia may protect Pten mutant mice from developing spontaneous seizures, but cannot eliminate their heightened risk of provoked seizure. Collectively, our findings have revealed a potential protective role of microglia in an over-excited brain, underscoring the impact of microglial regional heterogeneity in disease development and highlighting their prospect as a therapeutic target for epilepsy.

Keywords:  Microglia; Morphology; Neuronal excitation; Phagocytosis; Pten; Seizure

DOI:  https://doi.org/10.1016/j.neuroscience.2025.02.044
Int Immunopharmacol. 2025 Feb 15. pii: S1567-5769(25)00274-7. [Epub ahead of print]150 114284

Deer antler polypeptides inhibit microglial activation via TREM2 to improve behavior and neuroinflammation in CUMS mice.

Liping Zhai, Heping Shen, Shasha Wu, Li Guo, Yi Yang, Jian Sheng, Chenyang Han.

  To investigate the effects and mechanisms of deer antler total polypeptides (VAP-T) and its active component Y (VAP-Y) in treating depression in CUMS mice.VAP-T improved depression-like behavior in CUMS mice, reduced microglial activation, and tissue inflammation. VAP-Y showed better improvement in depression-like behavior in CUMS mice compared to VAP-T, significantly inhibiting microglial activation and tissue inflammation. Chromatographic analysis of VAP-Y revealed that short peptides had good binding activity with TREM2. VAP-T and VAP-Y have significant improvement effects on depression-like behavior in CUMS mice, which is related to the inhibition of TREM2-mediated microglial activation. VAP-Y has better activity than the total polypeptides and is a polypeptide with potential for treating depression.

Keywords:  Deer antler polypeptides; Depression; Microglia; Neuroinflammation; TREM2

DOI:  https://doi.org/10.1016/j.intimp.2025.114284
J Transl Med. 2025 Feb 14. 23(1): 182

Critical role of Oas1g and STAT1 pathways in neuroinflammation: insights for Alzheimer's disease therapeutics.

Zhixin Xie, Linxi Li, Weizhong Hou, Zhongxi Fan, Lifan Zeng, Limin He, Yunxiang Ji, Jingbai Zhang, Fangran Wang, Zhou Xing, Yezhong Wang, Yongyi Ye.

   BACKGROUND: Alzheimer's disease (AD) has a significant impact on an individual's health and places a heavy burden on society. Studies have emphasized the importance of microglia in the progression and development of AD. Interferon responses and Interferon-stimulated genes (ISGs) significantly function in neuroinflammatory and neurodegenerative diseases involving AD. Therefore, further exploration of the relationship among microglia, ISGs, and neuroinflammation in AD is warranted.
METHODS: Microglia datasets from the GEO database were retrieved, along with additional microglia RNA-seq data from laboratory mice. Weighted Correlation Network Analysis was used on the training dataset to identify gene co-expression networks. Genes from the black module were intersected with interferon-stimulated genes, and differentially expressed genes (DEGs) were identified. Machine learning algorithms were applied to DEGs, and genes selected by both methods were identified as hub genes, with ROC curves used to evaluate their diagnostic accuracy. Gene Set Enrichment Analysis was performed to reveal functional pathways closely relating to hub genes. Microglia cells were transfected with siRNAs targeting Oas1g and STAT1. Total RNA from microglia cells and mouse brain tissues was extracted, reverse-transcribed, and analyzed via qRT-PCR. Proteins were extracted from cells, quantified, separated by SDS-PAGE, transferred to PVDF membranes, and probed with antibodies. Microglia cells were fixed, permeabilized, blocked, and stained with antibodies for STAT1, then visualized and photographed.
RESULTS: Bioinformatics and machine learning algorithms revealed that Oas1g was identified as a hub gene, with an AUC of 0.812. Enrichment Analysis revealed that Oas1g is closely associated with interferon-related pathways. Expression of Oas1g was validated in AD mouse models, where it was significantly upregulated after microglial activation. Knockdown experiments suggested siOas1g attenuated the effect of siSTAT1, and the expressions of STAT1 and p-STAT1 were elevated. siOas1g could reverse the effect of siSTAT1, indicating that Oas1g potentially regulates the ISGs through the STAT1 pathway.
CONCLUSION: We demonstrated that Oas1g was identified as a hub ISG in AD and can downregulate the activation of IFN-β and STAT1, reducing the expression of ISGs in neuroinflammation. Oas1g might potentially be a beneficial candidate for both prevention and treatment of AD.

Keywords:  Alzheimer’s disease; Interferon-stimulated genes; Machine learning; Neuroinflammation; Oas1g; WGCNA

DOI:  https://doi.org/10.1186/s12967-025-06112-2
Stem Cell Reports. 2025 Feb 11. pii: S2213-6711(25)00024-4. [Epub ahead of print] 102420

An efficient, non-viral arrayed CRISPR screening platform for iPSC-derived myeloid and microglia models.

Sonja Meier, Anne Sofie Gry Larsen, Florian Wanke, Nicolas Mercado, Arianna Mei, Livia Takacs, Eva Suszanna Mracsko, Ludovic Collin, Martin Kampmann, Filip Roudnicky, Ravi Jagasia.

  Here, we developed a CRISPR-Cas9 arrayed screen to investigate lipid handling pathways in human induced pluripotent stem cell (iPSC)-derived microglia. We established a robust method for the nucleofection of CRISPR-Cas9 ribonucleoprotein complexes into iPSC-derived myeloid cells, enabling genetic perturbations. Using this approach, we performed a targeted screen to identify key regulators of lipid droplet formation dependent on Apolipoprotein E (APOE). We identify the Mammalian Target of Rapamycin Complex 1 (mTORC1) signaling pathway as a critical modulator of lipid storage in both APOE3 and APOE knockout microglia. This study is a proof of concept underscoring the utility of CRISPR-Cas9 technology in elucidating the molecular pathways of lipid dysregulation associated with Alzheimer's disease and neuroinflammation.

Keywords:  APOE; CRISPR-Cas9 gene editing; arrayed genetic screening; iPSC-derived microglia; lipid accumulation; lipid droplet screen; lipid metabolism; lipid regulation; lysosome; mTORC1

DOI:  https://doi.org/10.1016/j.stemcr.2025.102420
Brain Behav. 2025 Feb;15(2): e70361

Dapagliflozin Improves High-Fat Diet-Induced Cognitive Impairment in Female Mice.

Xiaolin Chen, Mingxia Fan, Zhuoni Xiao, Xiaoxing Xiong.

   BACKGROUND: High fat consumption is a known risk factor for the development of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been found to possess anti-inflammatory and neuroprotective properties. However, the cognitive effects and mechanisms of SGLT2is on female mice fed with a high-fat diet remain unknown.
OBJECTIVE: This study aimed to investigate the impacts of dapagliflozin on metabolism, cognition, neuroinflammation, insulin resistance, and microglial activation in female mice fed a HFD.
METHODS: Dapagliflozin (1 mg/kg) was administered to HFD-fed mice for 24 weeks. Body weight, glucose tolerance, and insulin resistance were assessed. Additionally, all mice were subjected to the Morris water maze (MWM) and one-trial Y-maze tests. The levels of metabolic hormones and cytokines were analyzed using ELISA kits. The levels of phosphorylated tau (p-tau) protein in the hippocampus were measured. Microglia, insulin receptors, NLRP3, and IL-1β in the hippocampus of mice were evaluated by immunofluorescence or immunohistochemical staining.
RESULTS: As anticipated, dapagliflozin improved insulin resistance and glucose metabolism and reduced cognitive impairment in female mice fed with a HFD. In the hippocampus, dapagliflozin alleviated microglial activation yet did not reduce the secretion of inflammatory chemokines. Furthermore, it increased the expression of insulin receptor in the hippocampus of HFD-fed mice and decreased the expression of p-tau.
CONCLUSIONS: Our results provide a foundation for the clinical application of SGLT2is as an adjuvant to slow down the progression of central degenerative diseases related to metabolic disorders, such as AD.

Keywords:  cognitive impairment; dapagliflozin; high‐fat diet; hippocampus

DOI:  https://doi.org/10.1002/brb3.70361
J Neuroinflammation. 2025 Feb 21. 22(1): 44

Growth differentiation factor 15 aggravates sepsis-induced cognitive and memory impairments by promoting microglial inflammatory responses and phagocytosis.

Lijiao Chen, Shiyuan Luo, Ting Liu, Zhewei Shuai, Yifan Song, Qianzi Yang, Ying Wang, Hongjun Huang, Yan Luo.

   BACKGROUND: Sepsis-associated encephalopathy (SAE) is a severe neurological condition caused by sepsis, and presents with symptoms ranging from delirium and coma to long-term cognitive dysfunction. SAE is acknowledged as a widespread brain impairment characterized by the activation of microglia. However, the specific pathological mechanisms that drive this activation are still not clearly understood. Growth differentiation factor 15 (GDF15) levels have been noted to be considerably increased in patients with sepsis, where they are linked to disease severity and can independently predict short- and long-term mortality risk. Serum levels of GDF15 have also been negatively associated with gray matter volume and predict cognitive impairment in older individuals. However, the impact of GDF15 on sepsis-induced cognitive and memory impairments, as well as the mechanisms behind these effects, are poorly understood.
METHODS: To examine the role of GDF15 in SAE, a sepsis model was created in adult C57BL/6J mice using intraperitoneal administration of lipopolysaccharide (LPS). GDF15 levels in plasma and cerebrospinal fluid were measured by ELISA. The anti-GDF15 monoclonal antibody ponsegromab was injected intracerebroventricularly before modeling, and cognitive and memory functions of the septic mice were assessed using fear-conditioning and novel object recognition tests. Microglial activation and phagocytosis were evaluated using immunofluorescence and Golgi staining. Additionally, an in vitro investigation of LPS-stimulated microglia was conducted to evaluate the impacts of GDF15 on inflammatory cytokine productions and microglial phagocytic activity. Mechanisms were explored using RNA sequencing, qPCR, western blotting, flow cytometry, and immunofluorescence assays.
RESULTS: In the cerebrospinal fluid of septic mice, levels of GDF15 were notably elevated after intraperitoneal injection of LPS. Lateral ventricular injection of the anti-GDF15 antibody alleviated both cognitive and memory impairment in the septic mice, together with microglial activation and phagocytosis in the hippocampus, thereby protecting against synaptic loss.
CONCLUSION: The levels of GDF15 were elevated in the brains of septic mice. Targeting GDF15 with an anti-GDF15 antibody was found to improve sepsis-induced cognitive and memory impairment by reducing the microglial inflammatory response and phagocytosis. These results indicate that GDF15 could serve as an important therapeutic target for treating SAE.

Keywords:  GDF15; Microglial phagocytosis; Neuroinflammation; Sepsis; Sepsis-associated encephalopathy

DOI:  https://doi.org/10.1186/s12974-025-03369-8
J Neuroimmunol. 2025 Feb 10. pii: S0165-5728(25)00034-7. [Epub ahead of print]400 578554

Traditional pediatric massage exerted an antidepressant effect and activated IGF-1/Nrf2 pathway in CUMS-exposed adolescent rats.

Xingxing Zhang, Que Liu, Siyuan Li, Rong Wu, Ying Xiong, Yuhang Wang, Yun Gu, Zhixiu Song, Jiaxuan Gong, Shaoyun Zhao.

  The activation of insulin-like growth factor-1 (IGF-1)/nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway contributes to enhance anti-inflammatory M2 microglia polarization and inhibit proinflammatory M1 microglia polarization, which is essential to resist neuroinflammation and thus resist depression. The prevalence of depression is high in adolescents, who are hypersensitive to chronic stress. Traditional pediatric massage (TPM) can effectively relieve depression. In this study, we investigated the action mechanism of TPM on preventing depression-like behaviors in adolescent rats exposed to chronic unpredictable mild stress (CUMS). In this investigation, we employed several behavioral tests and detections, including western blotting, immunofluorescence staining and RT-qPCR. The findings of this study demonstrated that TPM had an effectively antidepressant effect, maintained microglia polarization homeostasis and resisted neuroinflammation in the hippocampus in CUMS-exposed adolescent rats. With the treatment of picropodophyllin, the inhibitor of IGF-1 receptor, the antidepressant effect of TPM was blocked, along with inhibited IGF-1/Nrf2 pathway which were closely related with anti-inflammatory and anti-ferroptosis actions. The results suggest that TPM enhanced the resilience of adolescent rats to CUMS and exerted an antidepressant effect partially via activating IGF-1/Nrf2 pathway.

Keywords:  Depression; Insulin-like growth factor-1; Massage; Microglia; Nuclear factor-erythroid 2 related factor 2

DOI:  https://doi.org/10.1016/j.jneuroim.2025.578554
Front Physiol. 2024 ;15 1457034

Cerebral microvascular density, blood-brain barrier permeability, and support for neuroinflammation indicate early aging in a Marfan syndrome mouse model.

Tala Curry-Koski, Liam P Curtin, Mitra Esfandiarei, Theresa Currier Thomas.

   Introduction: Marfan Syndrome (MFS) is a connective tissue disorder due to mutations in fibrillin-1 (Fbn1), where a Fbn1 missense mutation (Fbn1 C1039G/+ ) can result in systemic increases in the bioavailability and signaling of transforming growth factor-β (TGF-β). In a well-established mouse model of MFS (Fbn1 C1041G/+ ), pre-mature aging of the aortic wall and the progression of aortic root aneurysm are observed by 6-month-of-age. TGF-β signaling has been implicated in cerebrovascular dysfunction, loss of blood-brain barrier (BBB) integrity, and age-related neuroinflammation. We have reported that pre-mature vascular aging in MFS mice could extend to cerebrovasculature, where peak blood flow velocity in the posterior cerebral artery (PCA) of 6-month-old (6M) MFS mice was reduced, similarly to 12-month-old (12M) control mice. Case studies of MFS patients have documented neurovascular manifestations, including intracranial aneurysms, stroke, arterial tortuosity, as well as headaches and migraines, with reported incidences of pain and chronic fatigue. Despite these significant clinical observations, investigation into cerebrovascular dysfunction and neuropathology in MFS remains limited.
Methods: Using 6M-control (C57BL/6) and 6M-MFS (Fbn1 C1041G/+ ) and healthy 12M-control male and female mice, we test the hypothesis that abnormal Fbn1 protein expression is associated with altered cerebral microvascular density, BBB permeability, and neuroinflammation in the PCA-perfused hippocampus, all indicative of a pre-mature aging brain phenotype. Glut1 immunostaining was used to quantify microvascular density, IgG staining to assess BBB permeability, and microglial counts to evaluate neuroinflammation.
Results: Using Glut1 staining, 6M-MFS mice and 12M-CTRL similarly present decreased microvascular density in the dentate gyrus (DG), cornu ammonis 1 (CA1), and cornu ammonis 3 (CA3) regions of the hippocampus. 6M-MFS mice exhibit increased BBB permeability in the DG and CA3 as evident by Immunoglobulin G (IgG) staining. No differences were detected between 6M and 12M-CTRL mice. 6M-MFS mice show a higher number of microglia in the hippocampus compared to age-matched control mice, a pattern resembling that of 12M-CTRL mice.
Discussion: This study represents the first known investigation into neuropathology in a mouse model of MFS and indicates that the pathophysiology underlying MFS leads to a systemic pre-mature aging phenotype. This study is crucial for identifying and understanding MFS-associated neurovascular and neurological abnormalities, underscoring the need for research aimed at improving the quality of life and managing pre-mature aging symptoms in MFS and related connective tissue disorders.

Keywords:  Marfan syndrome; blood-brain barrier; microvascular density; neuroinflammation; neuropathology; premature aging

DOI:  https://doi.org/10.3389/fphys.2024.1457034