bims-microg 2025-04-27 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–04–27
twenty-two papers selected by
Marcus Karlstetter, Universität zu Köln

Microglia drive amyloid-β clearance in immunized patients with Alzheimer's disease.
Pathological α-synuclein dysregulates epitranscriptomic writer METTL3 to drive neuroinflammation in microglia.
Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice.
Age-Dependent Regulation of Hippocampal Inflammation by the Mitochondrial Translocator Protein in Mice.
Glial changes and gene expression in Alzheimer's disease from snRNA-Seq and spatial transcriptomics.
The effect of C-reactive protein and interleukin-3 on mild cognitive impairment with APOE ɛ4.
Microglia specific Csf1r haploinsufficiency induces depressive-like behaviors by promoting NLRP6/caspase-1 signaling in mice.
Microglia endotoxin tolerance is retained after enforced repopulation.
Neuroimmune crosstalk in chronic neuroinflammation: microglial interactions and immune modulation.
FTY720 Modulating Microglia-Mediated Cholesterol Recycling via TREM2 Promotes Remyelination Following Ischemic Damage.
Targeting microglia-Th17 feed-forward loop to suppress autoimmune neuroinflammation.
A 3D human iPSC-derived multi-cell type neurosphere system to model cellular responses to chronic amyloidosis.
Physiological roles of embryonic microglia and their perturbation by maternal inflammation.
FABP7 Expression Modulates the Response of Astrocytes to Induced Endotoxemia.
Prenatally derived macrophages support choroidal health and decline in age-related macular degeneration.
Infection of a β-galactosidase-deficient mouse strain with Theiler's murine encephalomyelitis virus reveals limited immunological dysregulations in this lysosomal storage disease.
ApoM-bound S1P acts via endothelial S1PR1 to suppress choroidal neovascularization and vascular leakage.
Chronic starvation induces microglial cell depletion in an activity-based anorexia model.
MHCII reduction is insufficient to protect mice from alpha-synuclein-induced degeneration and the Parkinson's HLA locus exhibits epigenetic regulation.
Enriched environment alleviates NLRP3 inflammasome mediated neuroinflammation in diabetes complicated with depression rats.
Anti-inflammatory effects of 64Zn-aspartate is accompanied by cognitive improvements in rats with Aβ1-40-induced alzheimer disease.
Balancing Anti-Inflammation and Neurorepair: The Role of Mineralocorticoid Receptor in Regulating Microglial Phenotype Switching After Traumatic Brain Injury.

Nat Med. 2025 Apr 22.

Microglia drive amyloid-β clearance in immunized patients with Alzheimer's disease.

DOI: https://doi.org/10.1038/s41591-025-03677-9
Cell Rep. 2025 Apr 23. pii: S2211-1247(25)00389-4. [Epub ahead of print]44(5): 115618

Pathological α-synuclein dysregulates epitranscriptomic writer METTL3 to drive neuroinflammation in microglia.

Cameron Miller, Alyssa Ealy, Amanda Gregory, Chelva Janarthanam, William Albers, Gabriel Richardson, Huajun Jin, Gary Zenitsky, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G Kanthasamy.

  Recent reports suggest dysregulation of the N6-methyladenosine (m6A) RNA modification may contribute to the pathology of neurodegenerative diseases. Herein, we show the m6A methyltransferase complex including METTL3-the catalytic component of the nuclear-localized complex-is robustly upregulated in human microglia and astrocytes exposed to αSynf and Mn. Subcellular localization studies reveal METTL3 was predominantly cytoplasmic following Mn insult but remained nuclear following αSynf stimulation in activated microglia. Functional analysis revealed METTL3 and downstream m6A readers, including YTHDF2 and IGF2BP1-3, may regulate the proinflammatory secretome of activated microglia. Notably, methyltransferase activity and m6A abundance were significantly increased following Mn and αSynf treatment. METTL3 in Mn and αSynfin vivo models of neuroinflammation, along with human postmortem tissues from Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB) patients, was significantly upregulated. This was further confirmed by single-cell RNA sequencing (scRNA-seq) analysis. Overall, we demonstrate the m6A writer METTL3 may function as a major regulator of chronic neuroinflammation in synucleinopathies.

Keywords:  Alzheimer’s disease; CP: Molecular biology; CP: Neuroscience; METTL3; Parkinson’s disease; m6A; manganese; microglia; neuroinflammation; neurotoxicity

DOI:  https://doi.org/10.1016/j.celrep.2025.115618
Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00380-8. [Epub ahead of print]44(5): 115609

Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice.

Netherlands Brain Bank

  Microglia are parenchymal brain macrophages that are established during embryogenesis and form a self-containing cellular compartment that resists seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMΦs) accumulate in the brain of aging mice with distinct topologies, including the nigrostriatum and medulla but not the frontal cortex. Parenchymal MoMΦs adopt bona fide microglia morphology and expression profiles. Due to their hematopoietic stem cell (HSC) derivation, monocyte-derived microglia (MoMg) are unlike yolk-sac-derived cells, targets of clonal hematopoiesis (CH). Indeed, using a chimeric transfer model, we show that the hematopoietic expression of DNMT3AR882H, a prominent human CH variant, renders MoMg pathogenic and promotes motor deficits resembling atypical Parkinsonian disorders. Collectively, we establish that MoMg progressively seed the brain of healthy aging mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can cause brain pathology.

Keywords:  ARCH; CH; CHIP; CP: Immunology; CP: Neuroscience; DNMT3A R882H; HSC; brain macrophages; clonal hematopoiesis; microglia; monocytes

DOI:  https://doi.org/10.1016/j.celrep.2025.115609
Aging Cell. 2025 Apr 24. e70039

Age-Dependent Regulation of Hippocampal Inflammation by the Mitochondrial Translocator Protein in Mice.

Kei Onn Lai, Jia Hui Wong, Nevin Tham, Lauren Fairley, Roshan Ratnakar Naik, Yulan Wang, Sarah R Langley, Anna M Barron.

  The mitochondrial translocator protein (TSPO) is a biomarker of inflammation associated with neurodegenerative diseases, widely regarded to be upregulated in the aging brain. Here we investigated the interaction between aging and TSPO immunomodulatory function in the mouse hippocampus, a region severely affected in Alzheimer's Disease (AD). Surprisingly, we found that TSPO levels were decreased in brain innate immune populations in aging. Aging resulted in a reversal of TSPO knockout transcriptional signatures following inflammatory insult. TSPO deletion drastically exacerbated inflammatory transcriptional responses in the aging hippocampus, while dampening inflammation in the young hippocampus. This age-dependent effect of TSPO was linked to NF-kβ and interferon regulatory transcriptional networks. Drugs that disrupt the cell cycle and induce DNA damage, such as heat shock protein and topoisomerase inhibitors, were identified to mimic the inflammatory transcriptional signature characterizing aging in TSPO knockout mice most closely. These findings indicate that TSPO plays a protective role in brain aging. This TSPO-aging interaction is an important consideration in the interpretation of TSPO-targeted biomarker and therapeutic studies, as well as in vitro studies that cannot model the aging brain.

Keywords:  LPS; aging; hippocampus; mitochondria; neuroinflammation; translocator protein

DOI:  https://doi.org/10.1111/acel.70039
J Alzheimers Dis. 2025 Apr 23. 13872877251330320

Glial changes and gene expression in Alzheimer's disease from snRNA-Seq and spatial transcriptomics.

Songren Wei, Chenyang Li, Wenxuan Li, Fumiao Yuan, Jingjing Kong, Xi Su, Peng Huang, Hongbo Guo, Jiangping Xu, Haitao Sun.

  BackgroundAlzheimer's disease (AD) is characterized by cortical atrophy, glutamatergic neuron loss, and cognitive decline. However, large-scale quantitative assessments of cellular changes during AD pathology remain scarce.ObjectiveThis study aims to integrate single-nuclei sequencing data from the Seattle Alzheimer's Disease Cortical Atlas (SEA-AD) with spatial transcriptomics to quantify cellular changes in the prefrontal cortex and temporal gyrus, regions vulnerable to AD neuropathological changes (ADNC).MethodsWe mapped differentially expressed genes (DEGs) and analyzed their interactions with pathological factors such as APOE expression and Lewy bodies. Cellular proportions were assessed, focusing on neurons, glial cells, and immune cells.ResultsRORB-expressing L4-like neurons, though vulnerable to ADNC, exhibited stable cell numbers throughout disease progression. In contrast, astrocytes displayed increased reactivity, with upregulated cytokine signaling and oxidative stress responses, suggesting a role in neuroinflammation. A reduction in synaptic maintenance pathways indicated a decline in astrocytic support functions. Microglia showed heightened immune surveillance and phagocytic activity, indicating their role in maintaining cortical homeostasis.ConclusionsThe study underscores the critical roles of glial cells, particularly astrocytes and microglia, in AD progression. These findings contribute to a better understanding of cellular dynamics and may inform therapeutic strategies targeting glial cell function in AD.

Keywords:  APOE; Alzheimer's disease; Alzheimer's disease neuropathologic change; differential expressed genes; single nuclei sequencing; spatial transcriptomics

DOI:  https://doi.org/10.1177/13872877251330320
J Alzheimers Dis. 2025 Apr 22. 13872877251333149

The effect of C-reactive protein and interleukin-3 on mild cognitive impairment with APOE ɛ4.

Alzheimer's Disease Neuroimaging Initiative

  BackgroundThe apolipoprotein E ε4 allele (APOE ε4) and inflammation are associated with Alzheimer's disease (AD) pathology. Mild cognitive impairment (MCI) is considered the preclinical and early stage of AD. However, the comprehensive effects of APOE ε4 and inflammatory mediators on MCI patients with specific APOE ε4 genotypes remain poorly understood.ObjectiveOur study aimed to explore how different numbers of the APOE ε4 alleles affect plasma C-reactive protein (CRP) and interleukin-3 (IL-3) levels and their associations with brain structure.MethodsA total of 339 MCI patients from the Alzheimer's Disease Neuroimaging Initiative study were enrolled. We compared their plasma concentrations of CRP and IL-3, cognitive performance, and cerebrospinal fluid (CSF) AD biomarkers levels across different APOE ε4 genotypes. Structural magnetic resonance imaging was utilized to measure gray matter volume outcomes. Pearson correlation analysis was used to explore the associations between the above indicators.ResultsPlasma CRP levels increased in the APOE ε4 carriers, but IL-3 expression notably decreased, and the homozygous state is the most significant. A negative correlation between CRP and several cognitive abilities was observed only in APOE ε4 homozygotes. Additionally, a positive correlation between IL-3, cognitive scores, and CSF biomarker levels was confirmed only in APOE ε4 homozygotes. Imaging data demonstrated that the gray matter volume of the right middle frontal gyrus was associated with CRP only in APOE ε4 non-carriers.ConclusionsOur study demonstrated that peripheral inflammatory mediators' effect on cognitive function and brain structure in MCI patients differs based on their APOE ε4 allele carrier status.

Keywords:  Alzheimer's disease; C-reactive protein; apolipoprotein E type 4 allele; gray matter volume; interleukin-3; mild cognitive impairment; structural magnetic resonance imaging

DOI:  https://doi.org/10.1177/13872877251333149
Brain Behav Immun. 2025 Apr 17. pii: S0889-1591(25)00146-1. [Epub ahead of print]128 383-399

Microglia specific Csf1r haploinsufficiency induces depressive-like behaviors by promoting NLRP6/caspase-1 signaling in mice.

Rui-Kang Pang, Jia-Yi Zheng, Hao-You Xu, Yuan-Qi Zhao, Shan Su, Kai Le, Ye-Feng Cai, Shi-Jie Zhang, Xiao-Xiao Li.

  Depression is an early clinical manifestation of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), although the underlying molecular mechanisms remain poorly elucidated. The objective of this study was to investigate the mechanisms underpinning depressive behavior in the context of ALSP, utilizing microglial-specific Csf1r haploinsufficient mice. Our findings indicate that these mice exhibited depressive-like behaviors, as well as microglial hyper-ramification and aberrant synaptic pruning capacity. Blockade of CSF1R signaling with PLX3397 resulted in significant amelioration of depressive symptoms and restoration of normal microglial morphology and function. RNA sequencing analysis of microglia isolated from the medial prefrontal cortex (mPFC) of the brain indicated that NLRPs signaling pathways may play a significant role in the observed alterations in microglial Csf1r haploinsufficient mice. Notably, NLRP6, rather than NLRP3, was found to be upregulated, and the expression of caspase-1 exhibited colocalization with the microglial marker Iba1. Pharmacological inhibition of caspase-1 using VX-765 improved depressive-like behaviors, as well as microglial function. Taken together, our findings delineate a causal relationship between microglial Csf1r haploinsufficiency-induced activation of the NLRP6/caspase-1 signaling pathway and the manifestation of depressive-like behaviors in ALSP mice.

Keywords:  Caspase-1; Csf1r; Depression; Microglia; NLRP6

DOI:  https://doi.org/10.1016/j.bbi.2025.04.015
Brain Behav Immun. 2025 Apr 22. pii: S0889-1591(25)00144-8. [Epub ahead of print]

Microglia endotoxin tolerance is retained after enforced repopulation.

Tiago Medeiros-Furquim, Anneke Miedema, Edwin Schilder, Nieske Brouwer, Inge R Holtman, Susanne M Kooistra, Bart J L Eggen.

  Microglia are crucial for CNS homeostasis and are involved in a wide range of neurodegenerative and neuroinflammatory diseases. Systemic inflammation and infections can contribute to neurodegeneration later in life by affecting microglia. Like other innate immune cells, microglia can develop innate immune memory (IMM) in response to an inflammatory challenge, altering their response to subsequent stimuli. IMM can ameliorate or worsen CNS pathology, but it is unclear if IMM can be reversed to restore microglia functions. Here, we investigated whether microglia depletion-repopulation by inhibition of the colony-stimulating factor 1 receptor with BLZ945 reversed LPS-induced endotoxin tolerance in mice. Repopulated microglia displayed a reduced expression of homeostatic genes and genes related to mitochondrial respiration and TCA cycle metabolism and an increased expression of immune effector and activation genes. Nonetheless the blunted inflammatory gene response after LPS-preconditioning was retained after a depletion-repopulation cycle. Our study highlights the persistence of endotoxin tolerance in microglia after a depletion-repopulation cycle which might impact the potential effectiveness of strategies targeted at microglia depletion for clinical applications.

Keywords:  BLZ945; CSF1R; CSF1R-inhibitor; Depletion; Endotoxin tolerance; Innate immune memory; Microglia; Neuroinflammation; Repopulation; Sotuletinib

DOI:  https://doi.org/10.1016/j.bbi.2025.04.014
Front Cell Neurosci. 2025 ;19 1575022

Neuroimmune crosstalk in chronic neuroinflammation: microglial interactions and immune modulation.

Ludmila Müller, Svetlana Di Benedetto.

  Neuroinflammation is a fundamental feature of many chronic neurodegenerative diseases, where it contributes to disease onset, progression, and severity. This persistent inflammatory state arises from the activation of innate and adaptive immune responses within the central nervous system (CNS), orchestrated by a complex interplay of resident immune cells, infiltrating peripheral immune cells, and an array of molecular mediators such as cytokines, chemokines, and extracellular vesicles. Among CNS-resident cells, microglia play a central role, exhibiting a dynamic spectrum of phenotypes ranging from neuroprotective to neurotoxic. In chronic neurodegenerative diseases, sustained microglial activation often leads to the amplification of inflammatory cascades, reinforcing a pathogenic cycle of immune-mediated damage. Intercellular communication within the inflamed CNS is central to the persistence and progression of neuroinflammation. Microglia engage in extensive crosstalk with astrocytes, neurons, oligodendrocytes, and infiltrating immune cells, shaping both local and systemic inflammatory responses. These interactions influence key processes such as synaptic pruning, phagocytosis, blood-brain barrier integrity, and cytokine-mediated signaling. Understanding the mechanisms of cell-cell signaling in this context is critical for identifying therapeutic strategies to modulate the immune response and restore homeostasis. This review explores the key players in CNS neuroinflammation, with a focus on the role of microglia, the molecular pathways underlying intercellular communication, and potential therapeutic approaches to mitigate neuroinflammatory damage in chronic neurodegenerative diseases.

Keywords:  astrocytes; cytokines; immune cells; microglia; neurodegenerative diseases; neuroimmune crosstalk; neuroinflammation; neurons

DOI:  https://doi.org/10.3389/fncel.2025.1575022
Stroke. 2025 Apr 22.

FTY720 Modulating Microglia-Mediated Cholesterol Recycling via TREM2 Promotes Remyelination Following Ischemic Damage.

Jian-Bing Yu, Chen Hong, Xue-Wei Ren, Wei Guo, Ye-Fan Chen, Juan Ji, Xi-Yue Zhang, Xiu-Lan Sun.

   BACKGROUND: Following ischemic white matter damage, microglia are responsible for phagocytosing and degrading cholesterol-rich myelin debris, storing them as lipid droplets. However, our understanding of how microglia process this engulfed material remains limited. Our previous findings identified FTY720 as a high-affinity ligand for microglial TREM2 (triggering receptor expressed on myeloid cells 2). Therefore, we aimed to reveal the role of FTY720 targeting TREM2 in regulating microglial cholesterol metabolism during remyelination.
METHODS: Chronic ischemic white matter damage was induced by bilateral carotid artery stenosis in male wild-type and TREM2-/- mice. FTY720 was administered daily via intraperitoneal injection for 28 days following bilateral carotid artery stenosis surgery. Cognitive function, white matter integrity, accumulation of cholesterol and lipid droplets in microglia, and oligodendrocyte differentiation were evaluated using behavioral tests, transmission electron microscopy, immunofluorescence, and biochemical analyses. In vitro coculture systems were used to evaluate cholesterol transfer and remyelination efficacy.
RESULTS: FTY720 significantly alleviated cognitive deficits and promoted remyelination in bilateral carotid artery stenosis mice, as evidenced by enhanced performance in the Morris water maze and reduced demyelination observed via transmission electron microscopy and immunofluorescence. This therapeutic effect was absent in TREM2-/- bilateral carotid artery stenosis mice. Mechanistically, FTY720 promoted the redistribution of ABCA1 (ATP-binding cassette transporter A1) from lysosomes to the cell membrane in microglia via TREM2, which facilitated cholesterol efflux and reduced the accumulation of intracellular cholesterol and lipid droplets. Additionally, in vitro coculture experiments revealed that FTY720 enhanced cholesterol transfer from microglia to oligodendrocytes through TREM2, thereby promoting oligodendrocyte myelination.
CONCLUSIONS: Our study suggested that FTY720 regulated the recycling of myelin-derived cholesterol from microglia through TREM2, supplying cholesterol to oligodendrocytes and supporting remyelination, thus offering a novel therapeutic target for ischemic white matter damage.

Keywords:  cholesterol; fingolimod hydrochloride; microglia; remyelination; stroke

DOI:  https://doi.org/10.1161/STROKEAHA.124.049745
J Neuroinflammation. 2025 Apr 24. 22(1): 118

Targeting microglia-Th17 feed-forward loop to suppress autoimmune neuroinflammation.

Jun Xiao, Zihan Meng, Yao Lu, Zongchang Nie, Yujie Liu, Zhi Yao, Yingchi Zhang, Long Li.

  Microglia and Th17 cells are the major immunopathogenic cells in multiple sclerosis and its animal model of immune aspects, experimental autoimmune encephalomyelitis (EAE). While studies have highlighted the distinct roles of microglia and Th17 cells in EAE, it remains unclear whether microglia, as potential professional antigen-presenting cells, activate and stabilize the effector program of EAE-pathogenic Th17 cells in vivo; and if so, whether the Th17 could in turn reinforce the active state of the microglia. Our data demonstrate in an array of mouse models, including active/passive-EAE and transgenic mice, a microglia-Th17 feed-forward activation loop drives EAE disease progression through a mechanism dependent on both MHC-II, proinflammatory cytokines, inflammatory chemokines as well as STING→NF-κB pathway in the microglia and effector cytokines produced by the pathogenic Th17 cells. We also captured and identified the molecular properties of the feed-forward loop, which are two-cell entities of microglia-Th17, and proved them as the functional units of antigen presentation and bi-directional activation between the two cell types. Moreover, ACT001, an orphan drug to treat glioblastoma, disrupts this feed-forward activation loop by inhibiting the STING→NF-κB pathway in microglia, thereby alleviating EAE. These findings emphasize the importance of interactions and bi-directional activations between microglia and Th17 in the autoimmune neuroinflammation, and provide rationale for further investigation on ACT001 as therapeutic option for autoimmune inflammatory diseases driven by similar mechanisms.

Keywords:  ACT001; Experimental autoimmune encephalomyelitis; Microglia; Th17

DOI:  https://doi.org/10.1186/s12974-025-03427-1
J Neuroinflammation. 2025 Apr 24. 22(1): 119

A 3D human iPSC-derived multi-cell type neurosphere system to model cellular responses to chronic amyloidosis.

Stefan Wendt, Ada J Lin, Sarah N Ebert, Declan J Brennan, Wenji Cai, Yanyang Bai, Da Young Kong, Stefano Sorrentino, Christopher J Groten, Christopher Lee, Jonathan Frew, Hyun B Choi, Konstantina Karamboulas, Mathias Delhaye, Ian R Mackenzie, David R Kaplan, Freda D Miller, Brian A MacVicar, Haakon B Nygaard.

BACKGROUND: Alzheimer's disease (AD) is characterized by progressive amyloid beta (Aβ) deposition in the brain, with eventual widespread neurodegeneration. While the cell-specific molecular signature of end-stage AD is reasonably well characterized through autopsy material, less is known about the molecular pathways in the human brain involved in the earliest exposure to Aβ. Human model systems that not only replicate the pathological features of AD but also the transcriptional landscape in neurons, astrocytes and microglia are crucial for understanding disease mechanisms and for identifying novel therapeutic targets.
METHODS: In this study, we used a human 3D iPSC-derived neurosphere model to explore how resident neurons, microglia and astrocytes and their interplay are modified by chronic amyloidosis induced over 3-5 weeks by supplementing media with synthetic Aβ1 - 42 oligomers. Neurospheres under chronic Aβ exposure were grown with or without microglia to investigate the functional roles of microglia. Neuronal activity and oxidative stress were monitored using genetically encoded indicators, including GCaMP6f and roGFP1, respectively. Single nuclei RNA sequencing (snRNA-seq) was performed to profile Aβ and microglia driven transcriptional changes in neurons and astrocytes, providing a comprehensive analysis of cellular responses.
RESULTS: Microglia efficiently phagocytosed Aβ inside neurospheres and significantly reduced neurotoxicity, mitigating amyloidosis-induced oxidative stress and neurodegeneration following different exposure times to Aβ. The neuroprotective effects conferred by the presence of microglia was associated with unique gene expression profiles in astrocytes and neurons, including several known AD-associated genes such as APOE. These findings reveal how microglia can directly alter the molecular landscape of AD.
CONCLUSIONS: Our human 3D neurosphere culture system with chronic Aβ exposure reveals how microglia may be essential for the cellular and transcriptional responses in AD pathogenesis. Microglia are not only neuroprotective in neurospheres but also act as key drivers of Aβ-dependent APOE expression suggesting critical roles for microglia in regulating APOE in the AD brain. This novel, well characterized, functional in vitro platform offers unique opportunities to study the roles and responses of microglia to Aβ modelling key aspects of human AD. This tool will help identify new therapeutic targets, accelerating the transition from discovery to clinical applications.

DOI: https://doi.org/10.1186/s12974-025-03433-3
Front Cell Neurosci. 2025 ;19 1552241

Physiological roles of embryonic microglia and their perturbation by maternal inflammation.

Tsukasa Shimamura, Masashi Kitashiba, Kazutaka Nishizawa, Yuki Hattori.

  The interplay between the nervous and immune systems is well documented in the context of adult physiology and disease. Recent advances in understanding immune cell development have highlighted a significant interaction between neural lineage cells and microglia, the resident brain macrophages, during developmental stages. Throughout development, particularly from the embryonic to postnatal stages, diverse neural lineage cells are sequentially generated, undergo fate determination, migrate dynamically to their appropriate locations while maturing, and establish connections with their surroundings to form neural circuits. Previous studies have demonstrated that microglia contribute to this highly orchestrated process, ensuring the proper organization of brain structure. These findings underscore the need to further investigate how microglia behave and function within a broader framework of neurodevelopment. Importantly, recent epidemiological studies have suggested that maternal immune activation (MIA), triggered by various factors, such as viral or bacterial infections, environmental stressors, or other external influences, can affect neurogenesis and neural circuit formation, increasing the risk of neurodevelopmental disorders (NDDs) in offspring. Notably, many studies have revealed that fetal microglia undergo significant changes in response to MIA. Given their essential roles in neurogenesis and vascular development, inappropriate activation or disruption of microglial function may impair these critical processes, potentially leading to abnormal neurodevelopment. This review highlights recent advances in rodent models and human studies that have shed light on the behaviors and multifaceted roles of microglia during brain development, with a particular focus on the embryonic stage. Furthermore, drawing on insights from rodent MIA models, this review explores how MIA disrupts microglial function and how such disturbances may impair brain development, ultimately contributing to the onset of NDDs.

Keywords:  brain; development; maternal immune activation; maternal inflammation; microglia; neurodevelopmental disorder; neuron; psychiatric disorder

DOI:  https://doi.org/10.3389/fncel.2025.1552241
Glia. 2025 Apr 18.

FABP7 Expression Modulates the Response of Astrocytes to Induced Endotoxemia.

Mariana Bresque, Daniel Esteve, Garret Balmer, Haylee L Hamilton, Joshua S Stephany, Mariana Pehar, Marcelo R Vargas.

  Fatty acid binding proteins (FABPs) are a family of small proteins involved in fatty acid (FA) subcellular trafficking. In the adult central nervous system, FABP7, one of the members of this family, is highly expressed in astrocytes and participates in lipid metabolism, regulation of gene expression, and energy homeostasis. Reactive astrocytes in Alzheimer's disease and amyotrophic lateral sclerosis animal models upregulate FABP7 expression. This upregulation may contribute to the pro-inflammatory phenotype that astrocytes display during neurodegeneration and is detrimental for co-cultured neurons. Here, we explore how FABP7 expression modulates astrocyte response to inflammatory stimuli. Our results showed that silencing FABP7 expression in astrocyte cultures before treatment with different inflammatory stimuli decreases the expression of a luciferase reporter expressed under the control of NF-κB -response elements. Correspondingly, FABP7-silenced astrocytes display decreased nuclear translocation of the NF-κB-p65 subunit in response to these stimuli. Moreover, silencing FABP7 decreases the toxicity of stimulated astrocytes toward co-cultured motor neurons. Similar results were obtained after silencing FABP7 in human astrocytes differentiated from induced pluripotent stem cells. Finally, knockdown of astrocytic FABP7 expression in vivo reduces glial activation in the cerebral cortex of mice after systemic bacterial lipopolysaccharide (LPS) administration. In addition, whole transcriptome RNA sequencing analysis from the cerebral cortex of LPS-treated mice showed a differential inflammatory transcriptional profile, with attenuation of NF-κB-dependent transcriptional response after FABP7 knockdown. Together, our results highlight the potential of FABP7 as a target to modulate neuroinflammation in the central nervous system.

Keywords:  LPS; NF‐κB; astrocytes; inflammation; microglia

DOI:  https://doi.org/10.1002/glia.70023
J Exp Med. 2025 Jul 07. pii: e20242007. [Epub ahead of print]222(7):

Prenatally derived macrophages support choroidal health and decline in age-related macular degeneration.

Seth D Fortmann, Blake F Frey, Robert F Rosencrans, Yvonne Adu-Rutledge, Edgar Ready V, Kameron V Kilchrist, Robert S Welner, Michael E Boulton, Daniel R Saban, Maria B Grant.

Hallmark findings in age-related macular degeneration (AMD) include the accumulation of extracellular lipid and vasodegeneration of the choriocapillaris. Choroidal inflammation has long been associated with AMD, but little is known about the immune landscape of the human choroid. Using 3D multiplex immunofluorescence, single-cell RNA sequencing, and flow cytometry, we unravel the cellular composition and spatial organization of the human choroid and the immune cells within it. We identify two populations of choroidal macrophages with distinct FOLR2 expression that account for the majority of myeloid cells. FOLR2+ macrophages predominate in the nondiseased eye, express lipid-handling machinery, uptake lipoprotein particles, and contain high amounts of lipid. In AMD, FOLR2+ macrophages are decreased in number and exhibit dysfunctional lipoprotein metabolism. In mice, FOLR2+ macrophages are negative for the postnatal fate-reporter Ms4a3, and their depletion causes an accelerated AMD-like phenotype. Our results show that prenatally derived resident macrophages decline in AMD and are implicated in multiple hallmark functions known to be compromised in the disease.

DOI: https://doi.org/10.1084/jem.20242007
Front Immunol. 2025 ;16 1467207

Infection of a β-galactosidase-deficient mouse strain with Theiler's murine encephalomyelitis virus reveals limited immunological dysregulations in this lysosomal storage disease.

Rouven Wannemacher, Felix Stegmann, Deborah Eikelberg, Melanie Bühler, Dandan Li, Sayali Kalidas Kohale, Thanaporn Asawapattanakul, Tim Ebbecke, Marie-Kristin Raulf, Wolfgang Baumgärtner, Bernd Lepenies, Ingo Gerhauser.

   Introduction: A hallmark of many lysosomal storage diseases (LSD) is the alteration of immune responses, often starting before the onset of clinical disease. The present study aimed to investigate how GM1 gangliosidosis impacted the course of an acute central nervous system (CNS) virus infection before the clinical onset of LSD.
Methods: For this purpose, Glb1 -/- and wildtype control mice (both C57BL/6 background) were intracerebrally infected with the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) at the age of 5 weeks and sacrificed 4, 7, 14 and 98 days post infection, respectively. Histology, immunohistochemistry, and flow cytometry was used to assess viral load and immune cell activation and infiltration.
Results: Both wildtype and Glb1 -/- mice were able to clear the virus from the CNS and did not develop any clinical symptoms of TMEV-associated disease, thus indicating no overt alteration in susceptibility to TMEV infection. However, in the early phase post infection, Glb1 -/- mice displayed a slightly delayed T cell response as well as an increase in the number and activation of CNS microglia.
Discussion: These results suggest that already in the early stage of disease (before clinical onset) GM1 gangliosidosis causes an impaired T cell response and microglial hyperreactivity.

Keywords:  GM1 gangliosidosis; T cell activation; Theiler’s murine encephalomyelitis virus; brain; microglia activation; β-galactosidase deficiency

DOI:  https://doi.org/10.3389/fimmu.2025.1467207
Angiogenesis. 2025 Apr 23. 28(2): 24

ApoM-bound S1P acts via endothelial S1PR1 to suppress choroidal neovascularization and vascular leakage.

Bongnam Jung, Hitomi Yagi, Andrew Kuo, Tim F Dorweiler, Masanori Aikawa, Taku Kasai, Sasha A Singh, Andrew J Dannenberg, Zhongjie Fu, Colin Niaudet, Lois E H Smith, Timothy Hla.

  Neovascular age-related macular degeneration (nAMD) is a major cause of vision loss worldwide. Current standard of care is repetitive intraocular injections of vascular endothelial growth factor (VEGF) inhibitors, although responses may be partial and non-durable. We report that circulating sphingosine 1-phosphate (S1P) carried by apolipoprotein M (ApoM) acts through the endothelial S1P receptor 1 (S1PR1) to suppress choroidal neovascularization (CNV) in mouse laser-induced CNV, modeling nAMD. In humans, low plasma ApoM levels were associated with increased choroidal and retinal pathology. Additionally, endothelial S1pr1 knockout and overexpressing transgenic mice showed increased and reduced CNV lesion size, respectively. Systemic administration of ApoM-Fc, an engineered S1P chaperone protein, not only attenuated CNV to an equivalent degree as anti-VEGF antibody treatment but also suppressed pathological vascular leakage. We suggest that modulating circulating ApoM-bound S1P action on endothelial S1PR1 provides a novel therapeutic strategy to treat nAMD.

Keywords:  Age-related macular degeneration; Angiogenesis; Apolipoprotein M; High-density lipoprotein; Sphingosine 1-phosphate; Vascular leak

DOI:  https://doi.org/10.1007/s10456-025-09975-7
Sci Rep. 2025 Apr 23. 15(1): 14132

Chronic starvation induces microglial cell depletion in an activity-based anorexia model.

Valerie Verspohl, Miranda van Egmond, Lilly Kneisel, Friederike Reese, Anna C Thelen, Nele Korten, Maren Neumann, Lena Schaack, Clara Voelz, Larissa Käver, Beate Herpertz-Dahlmann, Cordian Beyer, Jochen Seitz, Stefanie Trinh.

Anorexia nervosa (AN) is a severe psychiatric disease with a largely unknown pathophysiology. AN leads to reduced brain volume and a disbalance of the gut microbiome suggesting the involvement of the gut-brain-axis. Also, in the activity-based anorexia (ABA) animal model mimicking AN brain volume loss is observed. This study investigated the impact of chronic starvation on brain cell populations and evaluated the potential protective effects of omega-3 fatty acids (FA) and probiotics in rats. We used a chronic ABA model and provided daily oral supplementation of omega-3 FA and probiotics. Immunohistochemistry and qPCR were used to analyze GFAP-positive astrocytes, IBA1-positive microglia, OLIG1/2-positive oligodendrocytes, MAP2-positive neurons and Ki-67-positive proliferating cells in the cerebral cortex and corpus callosum. We found a significant reduction of astrocytes and microglia in all ABA groups, likely due to reduced proliferating cells. Reduced running wheel activity and reduced amount of food needed to sustain body weight were observed in animals with supplementation with omega-3 FA and probiotics but we did not observe alterations in brain cells that could be attributed to these supplementations. Our results indicate that glial cell depletion potentially underlies the diminished brain volume found in ABA rats. Omega-3 FA and probiotics show potential for reducing AN-related symptoms and merit further study as a therapeutic approach.

DOI: https://doi.org/10.1038/s41598-025-98237-z
Sci Rep. 2025 Apr 21. 15(1): 13705

MHCII reduction is insufficient to protect mice from alpha-synuclein-induced degeneration and the Parkinson's HLA locus exhibits epigenetic regulation.

Elizabeth M Kline, Janna E Jernigan, Christopher D Scharer, Jeffrey Maurer, Sakeenah L Hicks, Mary K Herrick, Rebecca L Wallings, Sean D Kelly, Jianjun Chang, Kelly B Menees, Nikolaus R McFarland, Jeremy M Boss, Malú Gámez Tansey, Valerie Joers.

  Major histocompatibility complex class II (MHCII) molecules are antigen presentation proteins and increased in post-mortem Parkinson's disease (PD) brain. Attempts to decrease MHCII expression have led to neuroprotection in PD mouse models. Our group reported that a single nucleotide polymorphism (SNP) at rs3129882 in the MHCII gene Human Leukocyte Antigen (HLA) DRA is associated with increased MHCII transcripts and surface protein and increased risk for late-onset idiopathic PD. We therefore hypothesized that decreased MHCII may mitigate dopaminergic degeneration. During an ongoing α-synuclein lesion, mice with MHCII reduction in systemic and brain innate immune cells (LysMCre + I-Abfl/fl or CRE+) displayed brain T cell repertoire shifts and greater preservation of the dopaminergic phenotype in nigrostriatal terminals. Next, we investigated a human cohort to characterize the immunophenotype of subjects with and without the high-risk GG genotype at the rs3129882 SNP. We confirmed that the high-risk GG genotype is associated with peripheral changes in MHCII inducibility, frequency of CD4 + T cells, and differentially accessible chromatin regions within the MHCII locus. Although our mouse studies indicate that myeloid MHCII reduction coinciding with an intact adaptive immune system is insufficient to fully protect dopamine neurons from α-synuclein-induced degeneration, our data are consistent with the overwhelming evidence implicating antigen presentation in PD pathophysiology.

Keywords:  Alpha-synuclein; Antigen presentation; HLA; MHCII; Microglia; Parkinson’s disease; T cells

DOI:  https://doi.org/10.1038/s41598-025-95679-3
Sci Rep. 2025 Apr 23. 15(1): 14214

Enriched environment alleviates NLRP3 inflammasome mediated neuroinflammation in diabetes complicated with depression rats.

Hongyan Wang, Qingfang Liang, Zhifei Wen, Wenlian Ma, Shuyang Ji, Hong Zhang, Xiangeng Zhang.

  Depression is a serious and common complication of diabetes, with a well-established link between the two conditions. Recent studies indicate that activation of the NLRP3 inflammasome in hippocampal microglia plays a key role in the pathogenesis of diabetes complicated with depression (DD). While environmental enrichment (EE) has demonstrated significant anti-neuroinflammatory effects, its potential to alleviate neuroinflammation specifically induced by DD remains unclear. The DD rat model was established using a combination of a high-fat diet, streptozotocin injection, and chronic unpredictable mild stress. The effects of EE on NLRP3 inflammasome activation in the hippocampal microglia of DD rats were examined through a series of behavioral tests (open field test, forced swim test, and elevated plus maze), along with enzyme-linked immunosorbent assays, hematoxylin and eosin staining, TdT-mediated dUTP nick-end labeling staining, Western blot analysis, and immunofluorescence. Compared to the control group, DD rats exhibited impaired glucose metabolism and increased depressive-like behaviors, alongside hippocampal neuronal damage and elevated apoptosis rates. Activation of the NLRP3 inflammasome in hippocampal microglia was observed, with upregulation of the NLRP3 signaling pathway and inhibition of the PI3K/AKT signaling pathway. EE significantly mitigated these effects, reducing hippocampal neuroinflammation and alleviating depressive behaviors in DD rats. Neuroinflammation in the hippocampus is a key mechanism underlying the pathogenesis of DD. This study demonstrated that EE reduces neuroinflammation, likely by inhibiting the activation of the NLRP3 inflammasome in hippocampal microglia.

Keywords:  Diabetes mellitus with depression; Enriched environment; Hippocampus; NLRP3; Neuroinflammation

DOI:  https://doi.org/10.1038/s41598-025-98312-5
Sci Rep. 2025 Apr 24. 15(1): 14272

Anti-inflammatory effects of 64Zn-aspartate is accompanied by cognitive improvements in rats with Aβ1-40-induced alzheimer disease.

Max Temnik, Mariia Rudyk, Alexandr Balakin, Sergey Gurin, Taisa Dovbynchuk, Roman Byshovets, Nataliia Dzubenko, Ganna Tolstanova, Larysa Skivka.

  Alzheimer disease (AD) is a debilitating progressive dementia, whose pathophysiology is not fully understood. Chronic inflammation is now widely accepted as one of the key features of AD pathogenesis. Because of this, anti-inflammatory preparations are considered as putative disease modifying agents. A new compound of zinc aspartate with enriched light atoms 64Zn (64Zn-asp) was evaluated as a possible anti-AD agent using Aβ1-40-induced AD model. Intrahippocampal Aβ1-40 injection resulted in pronounced neuroinflammation, as was evidenced by increased phagocytic activity, augmented reactive oxygen species generation, and up-regulated CD86 and CD206 expression by microglia. In rats with Aβ1-40-induced AD, persistent systemic inflammation was also registered, as was ascertained by significantly increased white blood cell-based inflammatory indices and development of anemia of inflammation. Neuro- and systemic inflammation in rats was accompanied by hippocampal dopamine neuron loss, as well as by impairment of short-term and remote spatial memory and cognitive flexibility. Intravenous 64Zn-asp administration rats with AD was associated with returning all microglia indicators to normal range. All aforementioned features of systemic inflammation were not observed in these animals. Anti-inflammatory 64Zn-asp effect was strongly correlated with improvement of short-term spatial memory and cognitive flexibility, and moderately-with betterment of remote spatial memory. These results demonstrated that i.v. 64Zn-asp administration could reverse the inflammatory and, as a result, cognitive effects of intra-hippocampal Aβ1-40 in rats. Therefore, its use may be a viable approach in the complex therapeutic strategy for AD.

Keywords:  Alzheimer disease; Anti-inflammatory agent; Cognitive improvement; Inflammation; Neuroinflammation; Stable light isotope enriched zinc aspartate

DOI:  https://doi.org/10.1038/s41598-025-97830-6
CNS Neurosci Ther. 2025 Apr;31(4): e70404

Balancing Anti-Inflammation and Neurorepair: The Role of Mineralocorticoid Receptor in Regulating Microglial Phenotype Switching After Traumatic Brain Injury.

Bin Zhang, Miao Bai, Mengshi Yang, Yumei Wang, Xueling Zhang, Xiyu Chen, Min Gao, Baiyun Liu, Guangzhi Shi.

   BACKGROUND: As potent anti-inflammatory agents, glucocorticoids (GCs) have been widely used in the treatment of traumatic brain injury (TBI). However, their use remains controversial. Our previous study indicated that although dexamethasone (DEX) exerted anti-inflammatory effects and protected the blood-brain barrier (BBB) by activating the glucocorticoid receptor (GR) after TBI, it also impeded tissue repair processes due to excessive anti-inflammation. Conversely, fludrocortisone, acting as a specific mineralocorticoid receptor (MR) agonist, has shown potential in controlling neuroinflammation and promoting neurorepair, but the underlying mechanisms need further exploration.
OBJECTIVE: This study aimed to explore the impact of the MR agonist fludrocortisone on microglia polarization, angiogenesis, functional rehabilitation, and associated mechanisms after TBI.
METHODS: We established a mice controlled cortical impact model, and then immunofluorescence staining, western blot, rt-PCR, and MRI were performed to investigate microglia polarization, angiogenesis, and brain edema in the ipsilateral hemisphere after TBI and fludrocortisone treatment. Subsequently, functional tests including morris water maze, sucrose preference test, and forced swimming test were conducted to evaluate the effects of fludrocortisone treatment on neurofunction after TBI.
RESULTS: Our results revealed that fludrocortisone suppressed neuroinflammation, enhanced angiogenesis and neuronal survival, and promoted functional rehabilitation by inducing a shift in microglia phenotype from M1 to M2 via the JAK/STAT6/PPARγ pathway. Additionally, the PI3K/Akt/HIF-1α pathway was involved in VEGF expression and in the process of angiogenesis.
CONCLUSION: Fludrocortisone, the specific MR agonist, exerted anti-neuroinflammatory and neuroprotective effects by regulating phenotypic switching of microglia from M1 to M2 rather than suppressing all types of microglia. Our study provided a theoretical basis for the therapeutic strategy of GCs targeting neuroinflammation after TBI.

Keywords:  fludrocortisone; mineralocorticoid receptor microglia polarization; neuroinflammation; traumatic brain injury

DOI:  https://doi.org/10.1111/cns.70404