bims-microg 2025-06-22 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–06–22
thirty-two papers selected by
Marcus Karlstetter, Universität zu Köln

Myelin-axon interface vulnerability in Alzheimer's disease revealed by subcellular proteomics and imaging of human and mouse brain.
Microglial pruning of glycinergic synapses disinhibits spinal PKCγ interneurons to drive pain hypersensitivity in mice.
TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation.
Microglia matters: visualizing the immune battle in Parkinson's disease.
IL-6 trans-signalling is elevated in ALS models and drives TDP-43 induced inflammatory responses in microglia.
Adult human subventricular zone microglia promote a pro-neurogenic niche for neuronal progenitors in Parkinson's disease.
KLK8/HGF/Met signaling pathway mediates diabetes-associated hippocampal neuroinflammation in male mice.
Cell autonomous microglia defects in a stem cell model of frontotemporal dementia tau.
Targeting glial fibrillary acidic protein in glaucoma: a monoclonal antibody approach to modulate glial reactivity and neuroinflammation for neuroprotection.
KChIP3 fosters neuroinflammation and synaptic dysfunction in the 5XFAD mouse model of Alzheimer's disease.
Targeting neuroinflammation: 3-monothiopomalidomide a new drug candidate to mitigate traumatic brain injury and neurodegeneration.
Microglia are required for developmental specification of AgRP innervation in the hypothalamus of offspring exposed to maternal high-fat diet during lactation.
Synaptic pruning genes networks in Alzheimer's disease: correlations with neuropathology and cognitive decline.
Delphinidin attenuates cognitive deficits and pathology of Alzheimer's disease by preventing microglial senescence via AMPK/SIRT1 pathway.
High mobility group box 1, a novel serotonin receptor-7 negative modulator, contributes to M2 microglial ferroptosis and neuroinflammation in post-stroke depression.
Identification of the microglia-associated signature in experimental autoimmune encephalomyelitis.
Microglial Clearance of Alzheimer's Amyloid-Beta Obstructed by Nanoplastics.
Microglia-specific NF-κB signaling is a critical regulator of prion-induced glial inflammation and neuronal loss.
APOE4 impacts cortical neurodevelopment and alters network formation in human brain organoids.
The engineered probiotic strain Lactococcus lactis MG1363-pMG36e-GLP-1 regulates microglial polarization and gut dysbiosis in a transgenic mouse model of Parkinson's disease.
Telmisartan is neuroprotective in a hiPSC-derived spinal microtissue model for C9orf72 ALS via inhibition of neuroinflammation.
Blood serum from individuals with Alzheimer's disease alters microglial phagocytosis in vitro.
Melatonin alleviates neuroinflammation in ischemic stroke by regulating cGAS-mediated microglial pyroptosis signaling.
Integrating explainable machine learning and transcriptomics data reveals cell-type specific immune signatures underlying macular degeneration.
Nicotine exposure in adolescence triggers the activation and subsequent damage of microglia in the dentate gyrus and promotes depression later in life.
Role of MS4A7 in Regulating Microglial Polarization and Neuroinflammation in Spinal Cord Injury via the cGAS-STING-NLRP3 Axis.
VISTA Alleviates Microglia-Mediated Neuroinflammation After Cerebral Ischemia-Reperfusion Injury via Regulating ACOD1/Itaconic Acid Metabolism.
HIF-1α-induced astrocytic D-dopachrome tautomerase activates microglial inflammatory response following spinal cord injury.
Microglia energy metabolism: A new perspective on Alzheimer's disease treatment.
Forged Without FIRE: Normal Brain Development in the Absence of Microglia.
Protocol for sex-specific isolation of microglia, oligodendrocyte precursor cells, and astrocytes from neonatal rats using shake-off technique.
Mitochondrial Preparation from Microglia for Glycan Analysis.

Nat Neurosci. 2025 Jun 13.

Myelin-axon interface vulnerability in Alzheimer's disease revealed by subcellular proteomics and imaging of human and mouse brain.

Yifei Cai, Iguaracy Pinheiro-de-Sousa, Mykhaylo Slobodyanyuk, Fuyi Chen, Tram Huynh, Jean Kanyo, Peiyang Tang, Lukas A Fuentes, Amber Braker, Rachel Welch, Anita Huttner, Lei Tong, Peng Yuan, TuKiet T Lam, Evangelia Petsalaki, Jüri Reimand, Angus C Nairn, Jaime Grutzendler.

Myelin ensheathment is essential for rapid axonal conduction, metabolic support and neuronal plasticity. In Alzheimer's disease (AD), disruptions in myelin and axonal structures occur, although the underlying mechanisms remain unclear. We implemented proximity labeling subcellular proteomics of the myelin-axon interface in postmortem human brains from AD donors and 15-month-old male and female 5XFAD mice. We uncovered multiple dysregulated signaling pathways and ligand-receptor interactions, including those linked to amyloid-β processing, axonal outgrowth and lipid metabolism. Expansion microscopy confirmed the subcellular localization of top proteomic hits and revealed amyloid-β aggregation within the internodal periaxonal space and paranodal/juxtaparanodal channels. Although overall myelin coverage is preserved, we found reduced paranode density, aberrant myelination and altered paranode positioning around amyloid-plaque-associated dystrophic axons. These findings suggest that the myelin-axon interface is a critical site of protein aggregation and disrupted neuro-glial signaling in AD.

DOI: https://doi.org/10.1038/s41593-025-01973-8
Sci Transl Med. 2025 Jun 18. 17(803): eadk8096

Microglial pruning of glycinergic synapses disinhibits spinal PKCγ interneurons to drive pain hypersensitivity in mice.

Yidan Zou, Idy Hiu Ting Ho, Yanjun Jiang, Zhongqi Li, Qingtian Luo, Lhotse Hei Lui Ng, Tingting Jin, Qian Li, Fenfen Qin, Likai Tan, Tony Gin, Ho Ko, Lin Zhang, Huarong Chen, Matthew Tak Vai Chan, Changyu Jiang, William Ka Kei Wu, Xiaodong Liu.

Microglial activation is linked to neuroinflammation in neuropathic pain. Recently, microglia-mediated synaptic pruning has received mounting attention. However, the exact role of spinal microglia in modulating neuropathic pain-associated neural circuits remains unclear. To investigate this question, we used pharmacological, optogenetic, and genetic manipulations combined with behavioral tests, confocal imaging, and patch-clamp studies in a murine spared nerve injury (SNI) model of neuropathic pain. We demonstrate that spinal microglia pruned inhibitory presynaptic terminals in SNI mice, contributing to the disinhibition of spinal protein kinase C γ (PKCγ) interneurons and facilitating neurotransmission from low-threshold Aβ fibers. Single-cell RNA sequencing revealed that SNI-associated microglial subpopulations exhibited high expression of liver X receptor, apolipoprotein E (Apoe), and complement C1q. Global knockout of Apoe, microglia-specific knockdown of Apoe, or treatment with anti-C1q monoclonal antibody reversed SNI-induced pruning of spinal inhibitory synapses, prevented the disinhibition of PKCγ interneurons, and reduced pain hypersensitivity. Our study suggests that destabilization of neural networks through microglia-mediated pruning of inhibitory synapses in the spinal cord contributes to the development of neuropathic pain in mice.

DOI: https://doi.org/10.1126/scitranslmed.adk8096
Nat Commun. 2025 Jun 19. 16(1): 5344

TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation.

Lena Lößlein, Mathias Linnerbauer, Finnja Zuber, Thanos Tsaktanis, Oliver Vandrey, Anne Peter, Franziska Panier, Julia Zissler, Vivienne Riekher, Tobias Bäuerle, Jannis Hanspach, Frederik B Laun, Lisa Nagel, Lisa Mészáros, Friederike Zunke, Jürgen Winkler, Ulrike J Naumann, Nora Schwingen, Emely Neumaier, Arthur Liesz, Francisco Quintana, Veit Rothhammer.

After acute lesions in the central nervous system (CNS), the interaction of microglia, astrocytes, and infiltrating immune cells decides over their resolution or chronification. However, this CNS-intrinsic cross-talk is poorly characterized. Analyzing cerebrospinal fluid (CSF) samples of Multiple Sclerosis (MS) patients as well as CNS samples of female mice with experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we identify microglia-derived TGFα as key factor driving recovery. Through mechanistic in vitro studies, in vivo treatment paradigms, scRNA sequencing, CRISPR-Cas9 genetic perturbation models and MRI in the EAE model, we show that together with other glial and non-glial cells, microglia secrete TGFα in a highly regulated temporospatial manner in EAE. Here, TGFα contributes to recovery by decreasing infiltrating T cells, pro-inflammatory myeloid cells, oligodendrocyte loss, demyelination, axonal damage and neuron loss even at late disease stages. In a therapeutic approach in EAE, blood-brain barrier penetrating intranasal application of TGFα attenuates pro-inflammatory signaling in astrocytes and CNS infiltrating immune cells while promoting neuronal survival and lesion resolution. Together, microglia-derived TGFα is an important mediator of glial-immune crosstalk, highlighting its therapeutic potential in resolving acute CNS inflammation.

DOI: https://doi.org/10.1038/s41467-025-60363-7
J Clin Invest. 2025 Jun 16. pii: e192919. [Epub ahead of print]135(12):

Microglia matters: visualizing the immune battle in Parkinson's disease.

So Jeong Lee, Changning Wang, Jacob Hooker.

Microglia play critical roles in immune defense within the central nervous system (CNS), and microglia-mediated immune changes in the brain are observed in various neurodegenerative diseases, including Parkinson's disease (PD). While PET imaging with a range of radiolabeled ligands has been invaluable for visualizing and quantifying neuroimmune changes in the brains of patients with PD, no PET ligands currently exist that are specific to microglia. In this issue of the JCI, Mills et al. used the PET radioligand [¹¹C]CPPC to image colony stimulating factor 1 receptor (CSF1R), revealing a connection between increased CSF1R expression and microglia-mediated brain immune changes in patients with PD. The study demonstrated that elevated CSF1R expression colocalized with a microglial-specific marker in brain regions vulnerable to PD. Moreover, quantifying CSF1R density with [¹¹C]CPPC-PET imaging in living brains may provide an indicator of motor and cognitive impairments in the early stages of PD. These findings underscore the potential of CSF1R-PET imaging as a microglial-sensitive biomarker of brain immune function in PD.

DOI: https://doi.org/10.1172/JCI192919
Brain Behav Immun. 2025 Jun 14. pii: S0889-1591(25)00238-7. [Epub ahead of print]129 296-304

IL-6 trans-signalling is elevated in ALS models and drives TDP-43 induced inflammatory responses in microglia.

Grace Risby-Jones, Jianina Marallag, Cyril Jones Jagaraj, Julie D Atkin, Adam K Walker, Trent M Woodruff, John D Lee, Jenny N Fung.

  Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by chronic inflammation in both the central nervous system (CNS) and peripheral tissues. Interleukin-6 (IL-6) has been implicated in ALS pathology; however, IL-6 exhibits both anti-inflammatory and pro-inflammatory functions. Notably, IL-6 trans-signalling possesses pro-inflammatory properties and is emerging as a key contributor to neuroinflammation during neurodegeneration. In this study, we aimed to characterize the expression of the IL-6 trans-signalling pathway in ALS mouse models and investigate its role in ALS protein aggregate-mediated inflammation in microglia and peripheral immune cells. Our results revealed that the protein expression level of a key IL-6 trans-signalling component, soluble IL-6 receptor (sIL-6R), was significantly increased in the spinal cord and tibialis anterior (TA) muscles of both SOD1G93A and rNLS8 TDP-43 transgenic mice. Additionally, using mouse primary microglia, human monocyte-derived microglia-like cells (MDMi), and blood peripheral immune cells, we demonstrated that recombinant TDP-43 protein elicits robust pro-inflammatory cytokine responses, including IL-6, TNF-α, IL-23, and MCP-1. These responses were attenuated when treated with a specific IL-6 trans-signalling inhibitor, sgp130Fc. Our findings suggest that the TDP-43-induced inflammatory response is, in part, IL-6 trans-signalling-dependent and highlight the role of IL-6 trans-signalling as a potential driver of chronic inflammation contributing to ALS pathology. These results support IL-6 trans-signalling as a promising therapeutic target for mitigating inflammation and slowing disease progression. Future research should explore the broader implications of modulating IL-6 trans-signalling in ALS.

Keywords:  IL-6 trans-signalling; Microglia; Neuroinflammation; TDP-43 protein aggregates; sgp130Fc

DOI:  https://doi.org/10.1016/j.bbi.2025.06.021
Brain Behav Immun. 2025 Jun 12. pii: S0889-1591(25)00230-2. [Epub ahead of print]

Adult human subventricular zone microglia promote a pro-neurogenic niche for neuronal progenitors in Parkinson's disease.

Sara Pecoraro, Marloes Verkerke, Jacqueline A Sluijs, Bert van Het Hof, Susanne M A van der Pol, Miriam E van Strien, Rik van der Kant, Carlie de Vries, Helga E de Vries, Wilma D J van de Berg, Elly M Hol, Vanessa Donega.

  Neural stem cells (NSCs) in the subventricular zone (SVZ) of the mammalian brain become increasingly quiescent with aging, which correlates to increased inflammatory signals in the SVZ. Targeting cells that secrete inflammatory signals, such as microglia, could potentially re-activate NSCs. In this study, we characterized CD11b-positive microglia isolated from post-mortem SVZ from non-demented control (Aged), Alzheimer's disease (AD), and Parkinson's disease (PD) by single-cell and bulk RNA sequencing. Our transcriptome data revealed changes in gene signature in SVZ microglia from PD and AD, highlighting a disease-dependent response. Culture of iPSC-derived NSCs with supernatant from Aged, PD, and AD SVZ microglia showed an increase in proliferation and neuronal differentiation in the PD condition. Furthermore, we identified NR4A2, a transcription factor that promotes an anti-inflammatory microglia state, as a potential molecular mechanism that promotes a pro-neurogenic microglia phenotype. Altogether, our work identified a pro-neurogenic subpopulation of SVZ microglia that could be a novel target to promote repair in neurodegenerative diseases.

Keywords:  (single-cell) RNA sequencing; Alzheimer’s disease; Human subventricular zone; Microglia; NR4A2; Neurogenesis; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.bbi.2025.06.017
Theranostics. 2025 ;15(13): 6290-6312

KLK8/HGF/Met signaling pathway mediates diabetes-associated hippocampal neuroinflammation in male mice.

Dan-Hong Xu, Xiao-Yong Zhang, Shi-Yu Liu, Juan Wei, Jun-Hui Zhan, Jian-Kui Du, Yu-Jian Liu, Xiao-Yan Zhu.

  Rationale: Neuroinflammation plays a critical role in the pathogenesis of diabetes-associated depression. Tissue kallikrein-related peptidase 8 (KLK8), a secreted serine protease, has been implicated in the pathogenesis of depression- and anxiety-related behaviors across various etiologies, however the underlying mechanisms remain largely unexplored. This study elucidates a novel mechanism by which KLK8 upregulation contributes to diabetes-induced microglial activation and neuroinflammation in the hippocampus through modulating the hepatocyte growth factor (HGF)/Met signaling pathway. Methods and Results: Streptozotocin (STZ)-induced diabetic mice exhibited increased KLK8 expression in the hippocampus, an effect that was mitigated in KLK8-deficient or aerobic running-exercised mice. KLK8 deficiency significantly reduced depression-like behaviors, microglial activation, and neuroinflammation in diabetic mice. In BV2 mouse microglial cells, adenovirus-mediated overexpression of KLK8 (Ad-KLK8) was sufficient to induce microglial activation. Co-immunoprecipitation (Co-IP) coupled with mass spectrometry revealed that CD44 might interact with KLK8. KLK8 overexpression decreased CD44 levels in microglial cells. However, the CD44 activator Angstrom6 further exacerbated KLK8-induced microglial activation. Conversely, transcriptional profiling of KLK8-overexpressing microglial cells and subsequent validation demonstrated that the Met/Src/Btk/NF-κB signaling pathway played a central role in mediating the stimulatory effects of KLK8 on microglial activation in both Ad-KLK8-treated BV2 cells and human microglial cell line HMC3 cells stably transfected with KLK8 lentivirus (Lv-KLK8). The Met receptor is activated upon binding to its ligand HGF, which exists as an inactive precursor (pro-HGF). Our findings showed that KLK8 cleaved pro-HGF, promoting HGF release and subsequently activating the Met/Src/Btk/NF-κB signaling pathway in microglial cells. High glucose conditions increased KLK8 expression and enhanced HGF release, thereby stimulating the Met/Src/Btk/NF-κB signaling pathway and microglial activation in a KLK8-dependent manner. Systemic administration of a Met inhibitor inactivated the Met/Src/Btk/NF-κB pathway, reducing depression-like behaviors, microglial activation, and neuroinflammation in STZ-induced diabetic mice. Both Met inhibitor and KLK8 deficiency enhanced hippocampal neuroplasticity in STZ-induced diabetic mice. Finally, we demonstrated that running exercise reversed KLK8 upregulation and inactivated Met/Src/Btk/NF-κB signaling pathways, thereby attenuating neuroinflammation, improving neuroplasticity, and alleviating depression-like behaviors in STZ-induced diabetic mice. Conclusions: This study provides evidence that the KLK8/HGF/Met signaling pathway mediates diabetes-associated hippocampal neuroinflammation and depression-like behaviors, highlighting the therapeutic potential of targeting this pathway in diabetes-associated depression.

Keywords:  aerobic exercise; depression; diabetes; hepatocyte growth factor; microglia activation; neuroinflammation; tissue kallikrein-related peptidase 8

DOI:  https://doi.org/10.7150/thno.109513
Mol Psychiatry. 2025 Jun 17.

Cell autonomous microglia defects in a stem cell model of frontotemporal dementia tau.

Abhirami K Iyer, Lisa Vermunt, Farzaneh S Mirfakhar, Miguel Minaya, Mariana Acquarone, Rama Krishna Koppisetti, Arun Renganathan, Shih-Feng You, Emma P Danhash, Kylie J Schache, Anthony Verbeck, Grant Galasso, Scott M Lee, Guangming Huang, Katherine J Miller, Jacob Marsh, Alissa L Nana, Salvatore Spina, William W Seeley, Lea T Grinberg, Sally Temple, Charlotte E Teunissen, Chihiro Sato, Celeste M Karch.

Neuronal dysfunction has been extensively studied as a central feature of neurodegenerative tauopathies. However, across neurodegenerative diseases, there is strong evidence for active involvement of immune cells like microglia in driving disease pathophysiology. Here, we demonstrate that MAPT mRNA and tau protein are expressed in microglia in human brains and in human induced pluripotent stem cell (iPSC)-derived microglia like cells (iMGLs). Using iMGLs harboring the MAPT IVS10 + 16 mutation and isogenic controls, we demonstrate that a tau mutation is sufficient to alter microglial transcriptional states. We discovered that MAPT IVS10 + 16 microglia exhibit cytoskeletal abnormalities, stalled phagocytosis, disrupted TREM2/TYROBP networks, and altered metabolism. Additionally, we found that secretory factors from MAPT IVS10 + 16 iMGLs impact neuronal health, reducing synaptic density in neurons. Key features observed in vitro were recapitulated in human brain tissue and cerebrospinal fluid from MAPT mutations carriers. Together, our findings that MAPT IVS10 + 16 drives cell-intrinsic dysfunction in microglia that impacts neuronal health has major implications for development of therapeutics for tauopathies.

DOI: https://doi.org/10.1038/s41380-025-03073-2
J Neuroinflammation. 2025 Jun 17. 22(1): 159

Targeting glial fibrillary acidic protein in glaucoma: a monoclonal antibody approach to modulate glial reactivity and neuroinflammation for neuroprotection.

Chaoqiang Guan, Linglin Zhang, Kristian Nzogang Fomo, Jie Yang, Norbert Pfeiffer, Franz H Grus.

   BACKGROUND: Glaucoma is a progressive neurodegenerative disorder that leads to irreversible vision loss, with neuroinflammation recognized as a key factor. Overexpression of glial fibrillary acidic protein (GFAP) is linked to glaucoma pathogenesis and plays a pivotal role in astrocyte-driven neuroinflammation. This study aimed to assess the neuroprotective effects of a monoclonal antibody (mAb) targeting GFAP in glaucoma and to elucidate the underlying mechanisms.
METHODS: An ocular hypertension (OHT) glaucoma model was established in female Sprague Dawley rats using episcleral vein occlusion. Three doses of GFAP mAb (2.5, 25, 50 µg) or vehicle were administered via intravitreal injection. Retinal nerve fiber layer (RNFL) thickness and photopic electroretinogram were monitored longitudinally. Retinal ganglion cell (RGC) survival and glial responses were evaluated with immunostaining. Western blot and microarray analyses were performed to investigate molecular and pathway alterations. Additionally, a cobalt chloride (CoCl2)-induced degenerative R28 cell model was used to validate the protective effects of GFAP mAb in vitro. A bioinformatics re-analysis of a public glaucomatous retina protein dataset was conducted using GSEA, GO, and Cytoscape with GENEMANIA.
RESULTS: OHT resulted in a significant loss of RNFL thickness, PhNR amplitude, and RGC survival, all of which were preserved by GFAP mAb treatment. Retinal astrocyte reactivity was inhibited by GFAPmAb in a dose-dependent manner by suppressing GFAP protein overexpression. Notably, 25 µg GFAP mAb effectively regulated both astrocyte and microglial reactivity, leading to a substantial attenuation of neuroinflammation. Mechanistically, GFAP mAb inhibited the p38 MAPK and NF-κB pathways and the NLRP3/Caspase-1/GSDMD axis. In vitro, GFAP mAb improved R28 cell viability under CoCl2 exposure while reducing cell death via inhibition of pyroptosis. Bioinformatic re-analysis highlighted gliosis as a prominent pathway in the glaucomatous retina and indicated GFAP and Caspase1 as central nodes in the putative mechanism network modulated by GFAP mAb.
CONCLUSIONS: This study demonstrates that GFAP mAb inhibits astrogliosis and glial-glial activation, exerting neuroprotection through the inhibition of inflammation and pyroptosis. The findings suggest that targeting GFAP represents a promising immunotherapeutic strategy for glaucoma treatment.

Keywords:  Astrocytes; GFAP; Glaucoma; Microglia; Neuroinflammation; Ocular hypertension; Pyroptosis; RGC

DOI:  https://doi.org/10.1186/s12974-025-03482-8
J Neuroinflammation. 2025 Jun 19. 22(1): 160

KChIP3 fosters neuroinflammation and synaptic dysfunction in the 5XFAD mouse model of Alzheimer's disease.

Bolivar Arcos-Encarnación, Eladio Cortes-Flores, Isabel Barón-Mendoza, Jorge Luis Almazán, David Valle-García, Sol Díaz de León-Guerrero, Ladislav Hovan, Karla F Meza-Sosa, Nohemi Camacho-Concha, Jeovanis Gil, Marieke Lydia Kuijjer, Aliesha González-Arenas, Sergio Encarnación-Guevara, Gustavo Pedraza-Alva, Leonor Pérez-Martínez.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by β-amyloid (βA) accumulation, neuroinflammation, excessive synaptic pruning, and cognitive decline. Despite extensive research, effective treatments remain elusive. Here, we identify potassium channel-interacting protein 3 (KChIP3) as a key driver of AD pathology using the 5XFAD mouse model. KChIP3 levels were significantly elevated in the hippocampus of 5XFAD mice, correlating with βA burden and neuroinflammation. This upregulation was triggered by inflammatory signaling via the NLRP3 inflammasome and Caspase-1 activation. Notably, genetic deletion of KChIP3 (5XFAD/KChIP3-/-) markedly reduced βA plaque deposition, pro-inflammatory cytokines, reactive gliosis, and expression of inflammation-related proteins (APO, CLU, MDK). Transcriptomic and proteomic analyses revealed restored synaptic markers (CD47, CD200, CACNB4, GDA) and a shift of the disease-associated microglial (DAM-1) phenotype. Mechanistically, we propose that KChIP3 amplifies AD pathology through two key mechanisms: (1) sustaining neuroinflammation by upregulating pro-inflammatory genes and (2) impairing synaptic integrity by repressing genes critical for neuronal function. Consistently, KChIP3 deletion enhanced dendritic complexity, synaptic plasticity, and cognitive performance in 5XFAD mice. These findings position KChIP3 as a potential therapeutic target for mitigating neuroinflammation and synaptic dysfunction in AD and highlight its potential as a biomarker for disease progression.

Keywords:  5XFAD mice; Aging; Alzheimer’s disease; KChIP3; LTP; Learning; Memory; Microglia; Neuroinflammation; Synaptic plasticity

DOI:  https://doi.org/10.1186/s12974-025-03426-2
J Biomed Sci. 2025 Jun 16. 32(1): 57

Targeting neuroinflammation: 3-monothiopomalidomide a new drug candidate to mitigate traumatic brain injury and neurodegeneration.

Shih Chang Hsueh, Pathik Parekh, Buyandelger Batsaikhan, Neil Vargesson, David Tweedie, Weiming Luo, Chirag N Patel, Dong Liu, Ross A McDevitt, Abdul Mannan Baig, Yu Kyung Kim, Sun Kim, Inho Hwang, Juwan Kim, Mee Youn Lee, Anna R Carta, Warren R Selman, Barry J Hoffer, Dong Seok Kim, Nigel H Greig.

   BACKGROUND: Traumatic Brain Injury (TBI) is a major risk factor for neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD), with neuroinflammation playing a critical role in the secondary cell death that exacerbates the initial injury. While targeting neuroinflammation holds significant therapeutic promise, clinical trials of available anti-inflammatory agents have fallen short. 3-Mono-thiopomalidomide (3-MP), a novel immunomodulatory imide drug (IMiD), was designed to curb inflammation without the adverse effects of traditional IMiDs and was evaluated across models involving neuroinflammation.
METHODS: 3-MP anti-inflammatory activity was evaluated across cellular (RAW 264.7, IMG cells) and mouse studies following lipopolysaccharide (LPS)-challenge (for pro- and anti-inflammatory cytokines/chemokines), and mice subjected to controlled cortical impact (CCI) moderate traumatic brain injury (TBI). 3-MP human cereblon binding, including neosubstrate and molecular modeling evaluation, as well as chicken teratogenicity, ex vivo mouse and human stability studies, and mouse pharmacokinetics were appraised.
RESULTS: 3-MP binds human cereblon, a key protein in the E3 ubiquitin ligase complex, without triggering downstream cascades leading to thalidomide-like teratogenicity in chicken embryos. 3-MP reduces pro-inflammatory markers in LPS-stimulated mouse macrophage and microglial cell cultures, and lowers pro-inflammatory cytokine/chemokine levels in plasma and brain of mice challenged with systemic LPS without lowering anti-inflammatory IL-10. 3-MP readily enters brain following systemic administration, and achieves a brain/plasma concentration ratio of 0.44-0.47. 3-MP mitigates behavioral impairments and reduces activation of astrocytes and microglia in mice challenged with CCI TBI.
CONCLUSION: 3-MP represents a promising new class of thalidomide-like IMiDs with potent anti-inflammatory effects that offers potential for treating TBI and possibly other neurodegenerative diseases possessing a prominent neuroinflammatory component.

Keywords:  Cereblon; Immunomodulatory imide drugs (IMiDs); Microglia; Neurodegeneration; Neuroinflammation; Pomalidomide; Spalt like transcription factor 4 (SALL4); Teratogenicity; Traumatic brain injury

DOI:  https://doi.org/10.1186/s12929-025-01150-w
Elife. 2025 Jun 16. pii: RP101391. [Epub ahead of print]13

Microglia are required for developmental specification of AgRP innervation in the hypothalamus of offspring exposed to maternal high-fat diet during lactation.

Haley N Mendoza-Romero, Jessica E Biddinger, Michelle N Bedenbaugh, Richard Simerly.

  Agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus respond to multiple metabolic signals and distribute neuroendocrine information to other brain regions such as the paraventricular hypothalamic nucleus (PVH), which plays a central role in metabolic homeostasis. Neural projections from AgRP neurons to the PVH form during the postnatal lactational period in mice and these projections are reduced in offspring of dams that consumed a high-fat diet (HFD) during lactation (MHFD-L). Here, we used immunohistochemistry to visualize microglial morphology in MHFD-L offspring and identified changes that were regionally localized to the PVH and appeared temporally restricted to the period when AgRP neurons innervate this region. In addition, axon labeling experiments revealed that microglia engulf AgRP terminals in the PVH, and that the density of AgRP innervation to the PVH in MHFD-L offspring may be dependent on microglia, because microglial depletion blocked the decrease in PVH AgRP innervation observed in MHFD-L offspring, as well as prevented the increased body weight exhibited at weaning. Together, these findings suggest that microglia are activated by exposure to MHFD-L and interact directly with AgRP axons during postnatal development to permanently alter innervation of the PVH, with implications for developmental programming of metabolic phenotype.

Keywords:  AgRP; developmental biology; hypothalamus; microglia; mouse; neuroscience

DOI:  https://doi.org/10.7554/eLife.101391
Geroscience. 2025 Jun 14.

Synaptic pruning genes networks in Alzheimer's disease: correlations with neuropathology and cognitive decline.

Cristina Sanfilippo, Paola Castrogiovanni, Rosa Imbesi, Paolo Fagone, Grazia Scuderi, Manlio Vinciguerra, Michelino Di Rosa.

  Synaptic pruning (SP) is a critical process in brain development and maintenance, essential for refining neural circuits by eliminating weak or redundant synapses. Dysregulation of SP has been implicated in neurodegenerative disorders such as Alzheimer's disease (AD). Studying the regulation of SP genes across the lifespan and their variation by sex and age is crucial to understanding the interplay between aging, sex, and AD pathogenesis. This study comprehensively analyzes the expression of SP-related genes, including complement system components (C1QA, C1QB, C1QC, C1S, C1R, C3), microglial regulators (ITGB2, ITGAM), and astrocytic factors (MERTK, MEGF10), as well as synaptic protective signals (CD47, SIRPA) in 2294 non-demented healthy controls (NDHC) and 1555 AD patients, stratified by sex, age, and brain area. Our findings reveal significant upregulation of most SP-related genes in AD brains, except for CD47 and SIRPA. Sex-specific patterns emerged, with males exhibiting stronger associations between complement genes and AD pathology, compared to females. Notably, in NDHC, females displayed higher baseline expression of SP-related genes (except CD47), but these sex differences diminished in AD, indicating disease-driven convergence. Age-related dynamics further highlighted distinct profiles, with males showing progressive upregulation of SP genes in NDHC, whereas females exhibited early senescence-like suppression followed by late-life compensatory changes. In AD, males demonstrated early complement dysregulation, while females displayed a pronounced inflammatory shift in advanced age. Region-specific analyses revealed heterogeneity, with the diencephalon showing the highest gene expression in NDHC males, while AD flattened regional differences in males but amplified variability in females. Correlation analyses linked complement and microglial genes to amyloid and tau pathology, with sex-specific associations. Principal component analysis (PCA) and Gene Ontology (GO) highlighted disrupted coordination between microglia, astrocytes, and neurons in AD. Protein expression analysis using the Human Protein Atlas revealed sex-specific differences in the localization of complement and microglial proteins in the prefrontal cortex. These findings underscore the complex interplay of sex, age, and regional factors in SP regulation, implicating complement overactivation, microglial dysfunction, and astrocytic phagocytosis in AD pathogenesis.

Keywords:  Alzheimer’s disease; Astrocytes; Complement system; Microglia; Synaptic pruning

DOI:  https://doi.org/10.1007/s11357-025-01740-4
Alzheimers Res Ther. 2025 Jun 20. 17(1): 138

Delphinidin attenuates cognitive deficits and pathology of Alzheimer's disease by preventing microglial senescence via AMPK/SIRT1 pathway.

Ying Liu, Ting Hong, Mingxuan Lv, Xiaoyu Guo, Panpan Zhang, Aijuan Yan, Wenshi Wei.

   BACKGROUND: Emerging evidence suggests that senescent microglia play a role in β-amyloid (Aβ) pathology and neuroinflammation in Alzheimer's disease (AD). Targeting senescent cells with naturally derived compounds exhibiting minimal cytotoxicity represents a promising therapeutic strategy.
OBJECTIVES: This study aimed to investigate whether delphinidin, a naturally occurring anthocyanin, can alleviate AD-related pathologies by mitigating microglial senescence and to elucidate the underlying molecular mechanisms.
METHODS: We employed APP/PS1 mice, naturally aged mice, and an in vitro model using Aβ42-induced senescent BV2 microglia. Delphinidin's effects were evaluated through assessments of cognitive function, synaptic integrity (synapse loss), Aβ plaque burden, senescent microglia gene signatures, and cellular senescence markers (including senescence-associated β-galactosidase activity, SASP factor expression, oxidative stress, and cyclin p21/p16 levels). Mechanistic studies involved analyzing the AMPK/SIRT1 signaling pathway, testing direct delphinidin-SIRT1 interaction, and using the AMPK inhibitor Compound C.
RESULTS: Delphinidin treatment significantly alleviated cognitive deficits, synapse loss, Aβ peptides plaques of APP/PS1 mice via downregulated senescent microglia gene signature, prevented cell senescence, including senescence-associated β-galactosidase activity, senescence-associated secretory phenotype (SASP), oxidative stress, cyclin p21 and p16. And delphinidin treatment also prevented microglial senescence in naturally aged mice. In vitro, delphinidin treatment attenuated cell senescence induced by Aβ42 in BV2 microglia cells. Further research indicated that delphinidin treatment enhanced the AMPK/SIRT1 signaling pathway. Additionally, delphinidin was found to directly interact with SIRT1. It's noteworthy that AMPK inhibitor Compound C inversed the protective effect of delphinidin against microglial senescence.
CONCLUSION: Our study reveals for the first time that delphinidin effectively improved cognitive deficits, alleviated synapse loss and Aβ pathology in APP/PS1 mice by mitigating microglial senescence. These findings highlight delphinidin as a promising natural anti-aging agent against the development of aging and age-related diseases.

Keywords:  AMPK; Aging; Alzheimer's disease; Microglial senescence; Neuroinflammation

DOI:  https://doi.org/10.1186/s13195-025-01783-x
Free Radic Biol Med. 2025 Jun 15. pii: S0891-5849(25)00774-9. [Epub ahead of print]

High mobility group box 1, a novel serotonin receptor-7 negative modulator, contributes to M2 microglial ferroptosis and neuroinflammation in post-stroke depression.

Ou Du, Chao Wu, Yu-Xin Yang, Han-Yinan Yang, Yi-Jin Wu, Meng-Yang Li, Si-Cen Liu, Zhen-Hua Shao, Jun-Rong Du.

  Emerging evidence points to a pivotal role of microglial polarization in the neuroinflammatory processes linked to post-stroke depression (PSD), with both high mobility group box 1 (HMGB1) and serotonin receptor-7 (5-HT7R) being implicated in the microglial inflammatory response. However, the underlying mechanisms remain unclear. This study investigated the potential roles of HMGB1 and 5-HT7R in PSD. We first examined the interaction between HMGB1 and 5-HT7R in HEK293 cells using bioluminescence resonance energy transfer (BRET) technology. The expression of 5-HT7R was most significantly increased in microglia in vitro upon HMGB1 stimulation and in a transient middle cerebral artery occlusion (tMCAO) model, although it is also enhanced in astrocytes and neurons to some extent. Subsequently, the interaction between HMGB1 and 5-HT7R in primary microglia was examined using co-immunoprecipitation (Co-IP) and pull-down assays. Meanwhile, we found that HMGB1 upregulated the expression of 5-HT7R and downregulated the accumulation of second messenger cyclic adenosine monophosphate (cAMP) in HEK293 cells and primary microglia. Additionally, employing a 4-week tMCAO mice model, we found that 5-HT7R deletion or HMGB1 inhibition alleviated ischemic brain injury, depressive-like behaviors, M2 microglial ferroptosis, and neuroinflammation, meanwhile upregulating the cAMP/PKA and Nrf2/xCT/GPX4 pathways. Moreover, in vitro, recombinant HMGB1 (rHMGB1) effectively induced M2 microglial ferroptosis and neuroinflammation and suppressed the cAMP/PKA and Nrf2/xCT/GPX4 pathways in primary microglia, which were markedly attenuated by 5-HT7R deletion. Finally, cAMP analog dibutyryl cAMP (db-cAMP) or Nrf2 activator sulforaphane (SFN) attenuates ferroptosis in M2-polarized BV2 microglial cells and neuroinflammation induced by rHMGB1. Altogether, these results suggest that HMGB1 functions as a novel negative regulator of 5-HT7R, contributing to ischemic brain injury and PSD by promoting M2 microglial ferroptosis and neuroinflammation.

Keywords:  5-HT7R; HMGB1; ferroptosis; neuroinflammation; post-stroke depression

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.06.025
Front Immunol. 2025 ;16 1581878

Identification of the microglia-associated signature in experimental autoimmune encephalomyelitis.

Yan Wu, Jianhong Wang, Bo Chen, Yuxue Guo, Ping Gan, Yanbing Han.

   Background: Multiple sclerosis (MS) is a chronic neuroinflammatory disorder characterized by demyelination and immune dysregulation, and microglia play a central role in disease progression. Despite this, the specific microglial gene signatures contributing to MS remain inadequately characterized.
Methods: We utilized an experimental autoimmune encephalomyelitis (EAE) mouse model and performed RNA sequencing to identify differentially expressed Messenger RNAs (DEmRNAs), Long Non-Coding RNAs (DElncRNAs), Circular RNAs (DEcircRNAs), and microRNAs (DEmiRNAs) in microglia. A machine learning approach incorporating five distinct algorithms was applied to select a robust multigene signature. The biological functions of the included genes were assessed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses and validated by quantitative reverse transcription PCR (qRT-PCR). Additionally, molecular docking studies were conducted to explore potential interactions with approved MS therapeutics.
Results: Six DEmRNAs were identified as key microglia-associated biomarkers: Neutrophilic Granule Protein (NGP), Histone Cluster 1 H2B Family Member J (HIST1H2BJ), Phenazine Biosynthesis-Like Domain-Containing Protein 1 (PBLD1), Muscleblind-Like Protein 3 (MBNL3), Lymphocyte Antigen 180 (CD180), and Coagulation Factor X (F10). All six genes were found to be upregulated in EAE microglia compared to phosphate-buffered saline (PBS) treated mice. These genes are primarily involved in immune-related pathways, including Toll-like receptor (TLR) signaling, and interact with MS therapeutics such as teriflunomide. Among the identified DEcircRNAs, circGAS2 (mmu-circ-0001569) was significantly upregulated, suggesting its potential regulatory role in microglial function. The expression trends of these biomarkers were validated via quantitative reverse transcription PCR (qRT-PCR) and Western blot analysis.
Conclusions: This study provides a comprehensive microglial gene signature for EAE, highlighting the involvement of TLR pathways and circRNA-mediated regulation in MS pathogenesis. These findings provide a foundation for future research into microglia-targeted therapies and diagnostic tools for MS.

Keywords:  RNA sequencing; experimental autoimmune encephalomyelitis (EAE); machine learning (ML); microglia; multiple sclerosis (MS)

DOI:  https://doi.org/10.3389/fimmu.2025.1581878
Environ Sci Nano. 2025 Jun 01. 12(6): 3247-3260

Microglial Clearance of Alzheimer's Amyloid-Beta Obstructed by Nanoplastics.

Yue Wang, Gangtong Huang, Xiufang Liang, Nicholas Andrikopoulos, Huayuan Tang, Feng Ding, Pu Chun Ke, Yuhuan Li.

  Understanding the neurological impact of nanoplastic exposure has become an area of intensive research recently. This study examined the molecular and cellular mechanisms of how nanoplastics affect amyloid-beta (Aβ) clearance by microglia in the context of Alzheimer's disease (AD). Transmission electron microscopy and molecular dynamics simulations showed that polystyrene nanoplastics accelerated Aβ aggregation by forming a protein corona, promoting peptide fibrillization through hydrogen bonding and π-π interactions. Flow cytometry and endocytosis inhibition assays revealed that polystyrene nanoplastics impaired microglial uptake of Aβ while increasing their own cellular internalization, leading to microglial energy depletion and allowing Aβ aggregates to evade immune clearance. Additionally, proteomic analysis indicated that polystyrene nanoplastics disrupted microglial homeostasis, exacerbated neuroinflammation and metabolic dysregulation, and impaired the signalling pathway of ABC transporters critical for Aβ clearance in the AD brain. These findings suggest that nanoplastics contribute to AD pathology by impeding Aβ clearance and corrupting neuroimmune defense.

Keywords:  Alzheimer’s disease; amyloid beta; microglia; nanoplastics; protein corona; uptake

DOI:  https://doi.org/10.1039/D5EN00291E
PLoS Pathog. 2025 Jun 18. 21(6): e1012582

Microglia-specific NF-κB signaling is a critical regulator of prion-induced glial inflammation and neuronal loss.

Arielle J D Hay, Katriana A Popichak, Genova Mumford, Jifeng Bian, Payton Shirley, Lauren Wolfrath, Michael Eggers, Eric M Nicholson, Ronald B Tjalkens, Mark D Zabel, Julie A Moreno.

Prion diseases are a group of rare and fatal neurodegenerative diseases caused by the cellular prion protein, PrPC, misfolding into the infectious form, PrPSc, which forms aggregates in the brain. This leads to activation of glial cells, neuroinflammation, and irreversible neuronal loss, however, the role of glial cells in prion disease pathogenesis and neurotoxicity is poorly understood. Microglia can phagocytose PrPSc, leading to the release of inflammatory signaling molecules, which subsequently induce astrocyte reactivity. Animal models show highly upregulated inflammatory molecules that are a product of the Nuclear Factor-kappa B (NF-κB) signaling pathway, suggesting that this is a key regulator of inflammation in the prion-infected brain. The activation of the IκB kinase complex (IKK) by cellular stress signals is critical for NF-κB-induced transcription of a variety of genes, including pro-inflammatory cytokines and chemokines, and regulators of protein homeostasis and cell survival. However, the contribution of microglial IKK and NF-κB signaling in the prion-infected brain has not been evaluated. Here, we characterize a primary mixed glial cell model containing wild-type (WT) astrocytes and IKK knock-out (KO) microglia. These cultures show a near ablation of microglia compared to WT mixed glial cultures, highlighting the role of IKK in microglial survival and proliferation. We show that, when exposed to prion-infected brain homogenates, NF-κB-associated genes are significantly downregulated, but prion accumulation is significantly increased, in mixed glial cultures containing minimal microglia. Mice with IKK KO microglia show rapid disease progression when intracranially infected with prions, characterized by an increased density of activated microglia and reactive astrocytes, development of spongiosis, and accelerated loss of hippocampal neurons and associated behavioral deficits. These animals display clinical signs of prion disease early and have a 22% shorter life expectancy compared to infected wild-type mice. Intriguingly, PrPSc accumulation was significantly lower in the brains of terminal animals with IKK KO microglia compared to terminal WT mice, suggesting that accelerated disease is independent of PrPSc accumulation, highlighting a glial-specific pathology. Together, these findings present a critical role for microglial IKK and NF-κB signaling in host protection against prion disease.

DOI: https://doi.org/10.1371/journal.ppat.1012582
Stem Cell Reports. 2025 Jun 06. pii: S2213-6711(25)00141-9. [Epub ahead of print] 102537

APOE4 impacts cortical neurodevelopment and alters network formation in human brain organoids.

Karina K Meyer-Acosta, Eva Diaz-Guerra, Parul Varma, Adyasha Aruk, Sara Mirsadeghi, Aranis Muniz-Perez, Yousef Rafati, Ali Hosseini, Vanesa Nieto-Estevez, Michele Giugliano, Christopher Navara, Jenny Hsieh.

  Apolipoprotein E4 (APOE4) is the leading genetic risk factor for Alzheimer's disease. While most studies examine the role of APOE4 in aging, APOE4 causes persistent changes in brain structure as early as infancy and is associated with altered functional connectivity that extends beyond adolescence. Here, we used human induced pluripotent stem cell-derived cortical and ganglionic eminence organoids (COs and GEOs) to examine APOE4's influence during the development of cortical excitatory and inhibitory neurons. We show that APOE4 reduces cortical neurons and increases glia by promoting gliogenic transcriptional programs. In contrast, APOE4 increases proliferation and differentiation of GABAergic progenitors resulting in early and persistent increases in GABAergic neurons. Multi-electrode array recordings in assembloids revealed that APOE4 disrupts neural network function resulting in heightened excitability and synchronicity. Together, our data provide new insights on how APOE4 influences cortical neurodevelopmental processes and the establishment of functional networks.

Keywords:  APOE4; Alzheimer's disease; cortical development; differentiation; disease modeling; gliogenesis; iPSC; network excitability; neurodevelopment; neurogenesis

DOI:  https://doi.org/10.1016/j.stemcr.2025.102537
Neural Regen Res. 2026 Mar 01. 21(3): 1211-1221

The engineered probiotic strain Lactococcus lactis MG1363-pMG36e-GLP-1 regulates microglial polarization and gut dysbiosis in a transgenic mouse model of Parkinson's disease.

Mengyun Yue, Tingtao Chen, Wenjie Chen, Jing Wei, Bin Liao, Jie Zhang, Fangjun Li, Daojun Hong, Xin Fang.

  JOURNAL/nrgr/04.03/01300535-202603000-00044/figure1/v/2025-06-16T082406Z/r/image-tiff Parkinson's disease is characterized by synucleinopathy-associated neurodegeneration. Previous studies have shown that glucagon-like peptide-1 (GLP-1) has beneficial effects in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. However, the effect of GLP-1 on intrinsic synuclein malfunction remains unclear. In this study, we investigated the effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism in SncaA53T transgenic mice and explored the underlying mechanisms. Our data showed that Lactococcus lactis MG1363-pMG36e-GLP-1 inhibited dopaminergic neuronal death, reduced pathological aggregation of α-synuclein, and decreased movement disorders in SncaA53T transgenic mice. Furthermore, Lactococcus lactis MG1363-pMG36e-GLP-1 downregulated lipopolysaccharide-related inflammation, reduced cerebral activation of microglia and astrocytes, and promoted cell survival via the GLP-1 receptor/PI3K/Akt pathway in the substantia nigra. Additionally, Lactococcus lactis MG1363-pMG36e-GLP-1 decreased serum levels of pro-inflammatory molecules including lipopolysaccharide, lipopolysaccharide binding protein, interleukin-1β, and interleukin-6. Gut histopathology and western blotting further revealed that Lactococcus lactis MG1363-pMG36e-GLP-1 increased the expression of gut integrity-related proteins and reduced lipopolysaccharide-related inflammation by reversing gut dysbiosis in SncaA53T transgenic mice. Our findings showed that the beneficial effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism traits in SncaA53T transgenic mice is mediated by microglial polarization and the reversal of dysbiosis. Collectively, our findings suggest that Lactococcus lactis MG1363-pMG36e-GLP-1 is a promising therapeutic agent for the treatment of Parkinson's disease.

Keywords:  ; A53T transgenic mice; Parkinson’s disease; engineered probiotics; glucagon-like peptide-1; gut dysbacteriosis; gut-brain axis; microglial polarization; neurodegenerative disease; neuroinflammation

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-00702
Stem Cell Reports. 2025 Jun 16. pii: S2213-6711(25)00139-0. [Epub ahead of print] 102535

Telmisartan is neuroprotective in a hiPSC-derived spinal microtissue model for C9orf72 ALS via inhibition of neuroinflammation.

Berkiye Sonustun, Björn F Vahsen, Mario Ledesma-Terrón, Zhuoning Li, Laura Tuffery, Nan Xu, Elizabeth L Calder, Johannes Jungverdorben, Leslie Weber, Aaron Zhong, David G Miguez, Mara Monetti, Ting Zhou, Elisa Giacomelli, Lorenz Studer.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron (MN) loss. The most common genetic cause, a hexanucleotide repeat expansion in C9orf72 (C9-ALS), disrupts microglial function, contributing to neuroinflammation, a key disease driver. To investigate this, we developed a three-dimensional spinal microtissue (SM) model incorporating human induced pluripotent stem cell (hiPSC)-derived MNs, astrocytes, and microglia. Screening 190 Food and Drug Administration (FDA)-approved compounds, we identified sartans-angiotensin II receptor I blockers (ARBs)-as potent inhibitors of neuroinflammation. Telmisartan, a highly brain-penetrant ARB, significantly reduced the levels of pro-inflammatory cytokines interleukin (IL)-6 and IL-8 and rescued MN loss in C9-ALS SMs. Our findings suggest that C9-ALS microglia drive MN toxicity and that telmisartan can effectively mitigate inflammation and preserve MN viability. This work lays the groundwork for modeling disease-related neuroinflammation and points to telmisartan as a therapeutic candidate worth further exploration for treating C9-ALS.

Keywords:  3D microtissue; C9orf72; amyotrophic lateral sclerosis; astrocytes; drug screen; microglia; motor neurons; neuroinflammation; sartans; triculture

DOI:  https://doi.org/10.1016/j.stemcr.2025.102535
Neural Regen Res. 2025 Jun 19.

Blood serum from individuals with Alzheimer's disease alters microglial phagocytosis in vitro.

Barbara Altendorfer, Rodolphe Poupardin, Sophie Lefèvre-Arbogast, Claudine Manach, Dorrain Y Low, Mireia Urpi-Sarda, Cristina Andres-Lacueva, Raúl González-Domínguez, Thomas K Felder, Julia Tevini, Marco Zattoni, Andreas Koller, Reinhold Schmidt, Paul J Lucassen, Silvie R Ruigrok, Chiara de Lucia, Andrea Du Preez, Catherine Helmer, Jeanne Neuffer, Cécile Proust-Lima, Aniko Korosi, Cécilia Samieri, Sandrine Thuret, Ludwig Aigner.

   ABSTRACT: In Alzheimer's disease, microglial phagocytosis is engaged in the pathogenesis as it clears abnormal protein accumulations, debris, and apoptotic cells in the early stages of Alzheimer's disease, but fuels neuroinflammation and accelerates disease progression in later stages. In vivo parabiosis experiments in aged animals have demonstrated that blood-born factors modulate synaptic plasticity, neurogenesis, and microglial responses. We hypothesize that peripheral factors can modulate microglial function and thereby possibly influence Alzheimer's disease pathology. The objective of this study is to investigate the effects of Alzheimer's disease serum on microglial phagocytosis. Here, we use an immortalized human microglial cell line in an in vitro parabiosis assay to investigate the impact of the serum from individuals diagnosed with Alzheimer's disease (n = 30) and age-matched controls (n = 30) (PRODEM study) on microglial phagocytosis. Exposure to Alzheimer's disease serum increased microglial phagocytic uptake of pH-sensitive fluorescent particles and downregulated expression of the lysosomal master regulator transcription factor EB (TFEB) and of ATPase H+ transporting lysosomal V1 subunit B2 (ATP6V1B2), a component of the vacuolar ATPase. To identify serum components that may relate to changes in phagocytosis, serum samples of the Three-City Study (3C Study) were used. In the 3C Study, blood samples were collected up to 12 years before the onset of cognitive decline or dementia and their serum metabolome is well-defined. Microglia exposed to the serum of future Alzheimer's disease patients from the 3C Study displayed an increased phagocytic uptake compared with the serum of matched controls, depending on the presence of the apolipoprotein E ε4 allele in the Alzheimer's disease patients. Furthermore, microglial phagocytosis correlated inversely with serum levels of the omega-3 fatty acid eicosapentaenoic acid. We confirmed this inverse correlation between eicosapentaenoic acid and phagocytosis in the serum samples of the PRODEM cohort. In addition, in vitro testing of eicosapentaenoic acid on microglial phagocytosis showed a concentration-dependent decrease in phagocytic uptake. In conclusion, following incubation with Alzheimer's disease blood serum, we observed increased microglial phagocytic uptake and the downregulation of TFEB and ATP6V1B2, possibly indicating lysosomal dysfunction. Furthermore, microglial phagocytosis was inversely correlated with serum eicosapentaenoic acid levels, suggesting an important role for dietary eicosapentaenoic acid in microglial function.

Keywords:  ; Alzheimer’s disease; blood serum; eicosapentaenoic acid; metabolome; microglia; omega-3 fatty acids; phagocytosis

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01287
Neural Regen Res. 2025 Jun 19.

Melatonin alleviates neuroinflammation in ischemic stroke by regulating cGAS-mediated microglial pyroptosis signaling.

Qian Li, Lin Feng, Yu Tian, Erliang Guo, Yiran Li, Jingyan Niu, Haodong Pan, Chun Dang, Yaoheng Lu, Lihua Wang.

   ABSTRACT: Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke. Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis. However, the role and mechanisms by which melatonin regulates microglial pyroptosis and the inflammatory cascade through double-stranded DNA (dsDNA)-sensing cyclic GMP-AMP synthase (cGAS) signaling warrant further study. Using middle cerebral artery occlusion mice, we investigated the effects of melatonin on cGAS-mediated pyroptosis and neuroinflammation. Middle cerebral artery occlusion model mice exhibited significantly increased DNA damage and cytoplasmic dsDNA release, as reflected by γH2AX staining, as well as heightened activation of the cytosolic dsDNA-sensing cGASSTING pathway, both of which were notably suppressed by melatonin treatment. Melatonin also mitigated NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome activation and nuclear factor (NF)-κB/gasdermin D-mediated pyroptosis in microglia following ischemic stroke, while exhibiting the capacity to attenuate the immune response to ischemia in mice. This led to reduced infiltration of peripheral neutrophils and monocytes/macrophages in the ischemic brain. Specifically, melatonin administration resulted in reductions in the numbers of ionized calcium-binding adapter molecule 1-positive cells and production of interleukin-6 and tumor necrosis factor-α by microglia. Regarding neurological outcomes, melatonin significantly reduced cerebral infarct volume and ameliorated neurological deficits in mice. Notably, the neuroprotective effect of melatonin was correlated with the inhibition of cGAS activity. We also developed and tested melatonin co-loaded macrophage membrane-biomimetic reactive oxygen species-responsive nanoparticles (Mϕ-MLT@FNGs), which exhibited therapeutic properties in middle cerebral artery occlusion mice. Our findings suggest that melatonin acts on microglial pyroptosis to inhibit neuroinflammation and reshape the immune microenvironment through regulation of the cGAS-STING-NF-κB signaling pathway. By doing so, melatonin rescues damaged brain tissue and protects neurological function, highlighting its potential as a neuroprotective treatment for ischemic stroke.

Keywords:  STING; cGAS; immune injury; inflammation; ischemic stroke; melatonin; microglia; pyroptosis

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01070
NPJ Genom Med. 2025 Jun 14. 10(1): 48

Integrating explainable machine learning and transcriptomics data reveals cell-type specific immune signatures underlying macular degeneration.

Khang Ma, Hosei Nakajima, Nipa Basak, Arko Barman, Rinki Ratnapriya.

Genome-wide association studies (GWAS) have established key role of immune dysfunction in Age-related Macular Degeneration (AMD), though the precise role of immune cells remains unclear. Here, we develop an explainable machine-learning pipeline (ML) using transcriptome data of 453 donor retinas, identifying 81 genes distinguishing AMD from controls (AUC-ROC of 0.80, CI 0.70-0.92). Most of these genes were enriched in their expression within retinal glial cells, particularly microglia and astrocytes. Their role in AMD was further strengthened by cellular deconvolution, which identified distinct differences in microglia and astrocytes between normal and AMD. We corroborated these findings using independent single-cell data, where several ML genes exhibited differential expression. Finally, the integration of AMD-GWAS data identified a regulatory variant, rs4133124 at PLCG2, as a novel AMD association. Collectively, our study provides molecular insights into the recurring theme of immune dysfunction in AMD and highlights the significance of glial cell differences in AMD progression.

DOI: https://doi.org/10.1038/s41525-025-00507-2
Int Immunopharmacol. 2025 Jun 12. pii: S1567-5769(25)01050-1. [Epub ahead of print]161 115060

Nicotine exposure in adolescence triggers the activation and subsequent damage of microglia in the dentate gyrus and promotes depression later in life.

Yunli Fang, Rongrong Yang, Rongrong Song, Yiming Gu, Xu Lu, Zhuo Chen, Wenfeng Hu, Ziwei Cao, Micona Sun, Hanxiao Wang, Lijuan Tong, Chao Huang.

  Adolescence is a critical period of neuroplasticity during which the brain can be affected by various harmful factors such as nicotine. Nicotine abuse in adolescence can promote depression in adulthood, but the underlying mechanisms are still unknown. The decline of microglia in the hippocampus, triggered by over-activation of microglia, is thought to be an important mechanism for the progression of depression. Since nicotine can also activate microglia, we speculate that the depression-like behavior triggered by nicotine exposure in adolescents may be related to the dynamic changes of microglia in the hippocampus. Our results show that 12 days of nicotine exposure during adolescence, followed by 28 days of nicotine withdrawal, triggered depression-like behavior and impaired neurogenesis in the hippocampus of adult mice, accompanied by a significant decrease of microglia in the dentate gyrus, which might be due to pyroptosis triggered by their early activation and proliferation. Pre-treatment with minocycline before the start of nicotine stimulation, which suppressed the initial activation of microglia, simultaneously prevented the depression-like behavior and the impairment of neurogenesis and microglia in the dentate gyrus. Restoration of microglia function by injection of an innate immune system stimulant, lipopolysaccharide (LPS, 100 μg/kg), reversed the depression-like behavior and decreased neurogenesis induced by nicotine exposure in adolescents. These results demonstrate a novel role of microglia in depression-like behavior induced by adolescent nicotine exposure and suggest that enhancing the function of microglia in the hippocampus may be a potential strategy for the treatment of depression induced by adolescent nicotine exposure.

Keywords:  Adolescence; Depression; Microglia; Nicotine; hippocampus

DOI:  https://doi.org/10.1016/j.intimp.2025.115060
CNS Neurosci Ther. 2025 Jun;31(6): e70390

Role of MS4A7 in Regulating Microglial Polarization and Neuroinflammation in Spinal Cord Injury via the cGAS-STING-NLRP3 Axis.

Xiangrui Li, Junpeng Liu, Youliang Deng, Fang Xing, Xihua Lu, Zhen Zhang, Changsheng Li.

   BACKGROUND AND OBJECTIVES: Spinal cord injury (SCI) leads to debilitating neurological deficits primarily due to the inflammatory response triggered by secondary injury mechanisms. Microglial activation and polarization significantly influence this response, with pro-inflammatory (M1) polarization exacerbating damage and anti-inflammatory (M2) polarization promoting repair. MS4A7, a membrane-bound protein involved in immune regulation, has been implicated in inflammation, but its role in SCI remains unexplored. This study investigates the function of MS4A7 in modulating microglial polarization and its downstream effects on the inflammatory response in SCI, focusing on the cGAS-STING-NLRP3 axis.
METHODS: A combination of in vivo and in vitro approaches, including mouse SCI models and BV2 microglial cells, was employed. Differential gene expression analysis was conducted using the GSE93561 dataset. MS4A7 expression was modulated using shRNA and overexpression plasmids. Microglial polarization was assessed via immunofluorescence, RT-qPCR, and ELISA for M1 (iNOS, IL-1β, TNF-α) and M2 (Arg1, IL-10, CD206) markers. Pyroptosis and inflammasome activation were examined using PI staining, LDH release, and NLRP3/GSDMD assays. The role of the cGAS-STING pathway was evaluated using activators (diABZI) and inhibitors (C-176), and NLRP3 inflammasome activity was pharmacologically inhibited with MCC950.
RESULTS: MS4A7 was significantly upregulated in SCI tissues (p < 0.01). Knockdown of MS4A7 reduced M1 markers (iNOS, IL-1β, and TNF-α) and increased M2 markers (Arg1, IL-10, and CD206), promoting anti-inflammatory polarization (p < 0.05). Conversely, MS4A7 overexpression enhanced M1 polarization and pyroptosis through the NLRP3 inflammasome. In vivo, MS4A7 knockdown improved locomotor recovery (BMS score, p < 0.05) and alleviated pain-related behaviors (PWL and PWT, p < 0.01). The cGAS-STING pathway mediated NLRP3 activation, with pharmacological inhibition mitigating pro-inflammatory effects and favoring tissue repair.
CONCLUSIONS: In this study, we found that MS4A7 exacerbates inflammation and promotes M1 polarization via the cGAS-STING-NLRP3 axis in SCI. Targeting MS4A7 and its associated pathways offers potential therapeutic strategies to mitigate neuroinflammation and enhance recovery. These findings provide new insights into the molecular mechanisms underlying SCI pathophysiology and highlight MS4A7 as a promising therapeutic target.

Keywords:  MS4A7; cGAS‐STING pathway; inflammasome; microglial polarization; motor function; pain; spinal cord injury

DOI:  https://doi.org/10.1111/cns.70390
Mol Neurobiol. 2025 Jun 19.

VISTA Alleviates Microglia-Mediated Neuroinflammation After Cerebral Ischemia-Reperfusion Injury via Regulating ACOD1/Itaconic Acid Metabolism.

Yilei Sun, Dan Liu, Yanchen Liu, Lijun Chi.

  Cerebral ischemia-reperfusion injury (CIRI) induces significant microglial inflammation. V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA), a novel inhibitory immune checkpoint, participates in myeloid cell metabolism. This study aims to investigate the molecular mechanisms of VISTA's protective effects on CIRI by modulating microglial metabolism. In this study, differentially expressed genes (DEGs) were extracted from GSE77986 to identify hub gene VISTA. Transient middle cerebral artery occlusion (tMCAO) and oxygen-glucose deprivation and reoxygenation (OGD/R) were conducted to mimic CIRI. AAVMG1.2-VSIR was injected intracerebroventricularly into Cx3cr1Cre mice, while over-expression plasmids were transfected into BV2 to intervene VISTA. The mice underwent LONGA scoring, H&E, Nissl, and TTC staining. Western blot and qRT-PCR were conducted for VISTA, IL-6, TNFα, IL-1β, and IL-10. Microglial proliferation was assessed by Edu staining and CCK8. RNA-sequencing (RNA-seq) analysis was used to investigate downstream pathways. Tricarboxylic acid (TCA) cycle intermediates were measured using ELISA. ACOD1/IκBα/NF-κB pathway was validated by Western blot. Eight DE-ICGs were identified through differential analysis, with VSIR exhibiting the highest expression. Additionally, VISTA was found decreased in microglia around the infarction site. Compared with CIRI group, VISTA reduced the infarct volume, improved neurological deficit, and decreased IL-6, TNFα, and IL-1β, while increasing IL-10, and suppressing microglia proliferation. RNA-seq showed that the DEGs primarily participated in microglial glucose metabolism and the IκBa/NF-κB pathway. VISTA promoted ACOD1 expression and itaconate (ITA). The protective function on CIRI and inhibitory effect on IκBa/NF-κB of VISTA were abrogated by ACOD1 knockdown.

Keywords:  ACOD1; Cerebral ischemia–reperfusion injury; Immune checkpoint; TCA cycle; VISTA

DOI:  https://doi.org/10.1007/s12035-025-05106-x
Am J Pathol. 2025 Jun 18. pii: S0002-9440(25)00201-9. [Epub ahead of print]

HIF-1α-induced astrocytic D-dopachrome tautomerase activates microglial inflammatory response following spinal cord injury.

Aicheng Li, Mengdi Li, Si Xu, Li Niu, Shaolan Li, Yue Zhou, Zhilong Cao, Rixin Cai, Bingqiang He, Aisong Guo, Aihong Li, Honghua Song, Yongjun Wang, Yingjie Wang.

  Spinal cord injury (SCI) often results in severe hypoxia and excessive activation of neuroinflammation, which aggravates neuropathology and neurological dysfunction. D-dopachrome tautomerase (D-DT), the homolog of macrophage migration inhibitory factor (MIF), is a key proinflammatory mediator implicated in inflammatory diseases of multiple tissues. However, its relation with hypoxia and the potential impact on neuroinflammation following SCI remain elusive. Herein, the dynamic expression of D-DT, p65NF-κB and the downstream proinflammatory cytokines TNF-α, IL-1β and IL-6 at the lesion site was determined following SCI. D-DT inhibitor 4-CPPC was applied to evaluate its effects on the inflammatory responses of the injured tissues. By using in vitro cell model, the D-DT-mediated activation of microglia and the underlying regulatory mechanism were also investigated, showing that CD74/MAPKs signaling was driven by D-DT to activate microglial inflammation. Analysis of rat D-DT promoter identified the binding element of HIF-1α. Hypoxia or DMOG stimulation of astrocytes was shown efficient in promoting the expression of HIF-1α and D-DT, while incubation of the microglia with the astrocytes conditional medium (ACM) was able to increase the production of TNF-α, IL-1β and IL-6. Pharmacological treatment of the subjects with 4-CPPC or LW6 following SCI remarkably promoted the recovery of rat locomotor function. The results have presented a novel neuropathological function of D-DT, which might be beneficial for development of potential drug targeting neuroinflammation.

Keywords:  D-DT; Spinal cord injury; astrocyte; hypoxia; inflammatory response; microglia

DOI:  https://doi.org/10.1016/j.ajpath.2025.05.015
J Neurol Sci. 2025 Jun 16. pii: S0022-510X(25)00202-3. [Epub ahead of print]475 123585

Microglia energy metabolism: A new perspective on Alzheimer's disease treatment.

Qing-Lin Wu, Xiong Yang, Jia-Xin Luo, Li Liu, Ya Zhou, Mei-Hong Lu.

  Alzheimer's disease (AD) is a progressive age-associated neurodegenerative disorder characterized by systemic cerebral metabolic disturbances. Neuroimaging and biochemical analyses reveal three hallmark features: decreased glucose utilization, mitochondrial bioenergetic deficits, and impaired energy homeostasis within hippocampal circuits. Emerging evidence highlights the pivotal role of microglia, the brain's specialized immune guardians, whose metabolic plasticity forms a self-reinforcing pathological cycle with AD progression. During early disease stages, oxidative phosphorylation (OXPHOS)-dependent M2 microglia mediate neuroprotective functions through efficient β-amyloid (Aβ) phagocytosis. However, progressive metabolic reprogramming drives a pathological shift toward glycolysis-dominant M1, characterized by heightened proinflammatory cytokine secretion and compromised clearance capacity. Notably, AD-associated pathological aggregates disrupt microglial metabolic adaptation, suppress mitophagy processes, and perpetuate sustained neuroinflammatory responses. The metabolic flexibility of microglia allows them to adapt to different energy demands. This study reviews the roles of major metabolic pathways and metabolic regulators of microglia in AD and the link between AD pathology and microglia energy metabolism, and describes the potential of relevant drugs and non-drug approaches in AD treatment, revealing metabolic regulation as a new target for AD therapy.

Keywords:  Alzheimer's disease; Energy metabolism; Inflammatory; Microglia; Mitochondrial; Treatment

DOI:  https://doi.org/10.1016/j.jns.2025.123585
Epilepsy Curr. 2025 Jun 16. 15357597251348961

Forged Without FIRE: Normal Brain Development in the Absence of Microglia.

Nicholas H Varvel.

DOI: https://doi.org/10.1177/15357597251348961
STAR Protoc. 2025 Jun 18. pii: S2666-1667(25)00308-9. [Epub ahead of print]6(3): 103902

Protocol for sex-specific isolation of microglia, oligodendrocyte precursor cells, and astrocytes from neonatal rats using shake-off technique.

Gen Hamanaka, Tomonori Hoshino, Hidehiro Ishikawa, Akane Mizutani, Akihiro Shindo, Ken Arai.

  Disease-related glial changes often show sex-specific differences, yet protocols for sex-specific isolation are limited. Here, we present a protocol for sex-specific isolation of microglia, oligodendrocyte precursor cells (OPCs), and astrocytes from neonatal rats using the shake-off technique. We describe steps for determining pup sex at post-natal days 1-2 and for dissecting, dissociating, and plating cortex cells. We then detail isolation procedures for each cell type. Downstream applications include immunocytochemistry, quantitative PCR, and RNA sequencing to assess cell-specific functions.

Keywords:  Cell Differentiation; Cell culture; Cell isolation; Neuroscience

DOI:  https://doi.org/10.1016/j.xpro.2025.103902
J Vis Exp. 2025 May 30.

Mitochondrial Preparation from Microglia for Glycan Analysis.

Meghana Madabhushi, Tana V Palomino, Mallikarjun H Patil, David C Muddiman, Daniel J Tyrrell, Juhi Samal.

Understanding the glycosylation patterns of mitochondrial proteins in microglia is critical for determining their role in neurodegenerative diseases. Here, we present a novel and high-throughput methodology for glycomic analysis of mitochondrial proteins isolated from cultured microglia. This method involves the isolation of mitochondria from microglial cultures, quality assessment of mitochondrial samples, followed by an optimized protein extraction to maximize glycan detection, and infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) high-resolution accurate mass (HRAM) mass spectrometry to provide detailed profiles of mitochondrial glycosylation. This protocol emphasizes the importance of maintaining mitochondrial integrity during isolation and employs stringent quality control to ensure reproducibility, including measuring mitochondrial purity after extraction. This approach allows for the comprehensive profiling of glycosylation changes in microglial mitochondria under various experimental conditions in vitro, which offers insight into mitochondrial changes associated with neurodegenerative diseases. This approach could be adapted to other in vitro treatments, other cultured cell types, or primary cells. Through this standardized approach, we aim to advance the understanding of microglial mitochondrial glycans, contributing to the broader field of neurodegenerative research.

DOI: https://doi.org/10.3791/68179