bims-microg 2025-01-12 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–01–12
thirty-two papers selected by
Marcus Karlstetter, Universität zu Köln

Typical development of synaptic and neuronal properties can proceed without microglia in the cortex and thalamus.
SIX1 aggravates the progression of spinal cord injury in mice by promoting M1 polarization of microglia.
18 kDa TSPO targeting drives polarized human microglia towards a protective and restorative neurosteroidome profile.
C3aR1-Deletion Delays Retinal Degeneration in a White-Light Damage Mouse Model.
The protein kinase C modulator bryostatin-1 therapeutically targets microglia to attenuate neuroinflammation and promote remyelination.
Chemerin-9 is neuroprotective in APP/PS1 transgenic mice by inhibiting NLRP3 inflammasome and promoting microglial clearance of Aβ.
Menopausal hormone therapy is associated with worse levels of Alzheimer's disease biomarkers in APOE ε4-carrying women: An observational study.
Neuroprotective role of sialic-acid-binding immunoglobulin-like lectin-11 in humanized transgenic mice.
Evidence for glial reactivity using positron-emission tomography imaging of translocator Protein-18 kD [TSPO] in both sham and nerve-injured rats in a preclinical model of orofacial neuropathic pain.
Characterizing Microglial Signaling Dynamics During Inflammation Using Single-Cell Mass Cytometry.
Biomimetic Membrane Vesicles Reprogram Microglia Polarization and Remodel the Immunosuppressive Microenvironment of Glioblastoma via PERK/HIF-1α/Glycolysis Pathway.
Microglial Responses to Alzheimer's Disease Pathology: Insights From "Omics" Studies.
Monocyte-derived macrophages act as reinforcements when microglia fall short in Alzheimer's disease.
Microglia depletion reduces neurodegeneration and remodels extracellular matrix in a mouse Parkinson's disease model triggered by α-synuclein overexpression.
Human longevity and Alzheimer's disease variants act via microglia and oligodendrocyte gene networks.
Neuroimmunometabolism: How Metabolism Orchestrates Immune Response in Healthy and Diseased Brain.
Dissecting the evolving cellular landscape of a remyelinating microenvironment.
Inflammatory Stimulation Upregulates the Receptor Transporter Protein 4 (RTP4) in SIM-A9 Microglial Cells.
Semaglutide restores astrocyte-vascular interactions and blood-brain barrier integrity in a model of diet-induced metabolic syndrome.
Adoptive Transfer of CX3CR1-Transduced Tregs Homing to the Forebrain in Lipopolysaccharide-Induced Neuroinflammation and 3xTg Alzheimer's Disease Models.
Human iPSC-derived microglial cells protect neurons from neurodegeneration in long-term cultured adhesion brain organoids.
Inhibiting the Cholesterol Storage Enzyme ACAT1/SOAT1 in Aging Apolipoprotein E4 Mice Alters Their Brains' Inflammatory Profiles.
Regulation of the microglial polarization for alleviating neuroinflammation in the pathogenesis and therapeutics of major depressive disorder.
Hyperreflective retinal foci are associated with retinal degeneration after optic neuritis in neuromyelitis optica spectrum disorders and multiple sclerosis.
Prolonged incubation with Δ9-tetrahydrocannabinol but not with cannabidiol induces synaptic alterations and mitochondrial impairment in immature and mature rat organotypic hippocampal slices.
Cholesterol metabolites modulate ionotropic P2X4 and P2X7 receptor current in microglia cells.
SMOC2 promotes microglia activity and neuroinflammation in Alzheimer's disease.
Cpeb1 remodels cell type-specific translational program to promote fear extinction.
Identification of EcoHIV-Infected Cells in Microglia-Manipulated Transgenic Mice.
Modulatory Effects of Mdivi-1 on OxLDL-Induced Metabolic Alterations, Inflammatory Responses, and Foam Cell Formation in Human Monocytes.
LFA-1: A potential key player in microglia-mediated neuroprotection against oxygen-glucose deprivation in vitro.
Anti-neuroinflammatory and Neuroprotective Effects of T-006 on Alzheimer's Disease Models by Modulating TLR4-Mediated MyD88/ NF-κB Signaling.

Nat Neurosci. 2025 Jan 06.

Typical development of synaptic and neuronal properties can proceed without microglia in the cortex and thalamus.

Mary O'Keeffe, Sam A Booker, Darren Walsh, Mosi Li, Chloe Henley, Laura Simões de Oliveira, Mingshan Liu, Xingran Wang, Maria Banqueri, Katherine Ridley, Kosala N Dissanayake, Cristina Martinez-Gonzalez, Kirsty J Craigie, Deepali Vasoya, Tom Leah, Xin He, David A Hume, Ian Duguid, Matthew F Nolan, Jing Qiu, David J A Wyllie, Owen R Dando, Alfredo Gonzalez-Sulser, Jian Gan, Clare Pridans, Peter C Kind, Giles E Hardingham.

Brain-resident macrophages, microglia, have been proposed to have an active role in synaptic refinement and maturation, influencing plasticity and circuit-level connectivity. Here we show that several neurodevelopmental processes previously attributed to microglia can proceed without them. Using a genetically modified mouse that lacks microglia (Csf1r∆FIRE/∆FIRE), we find that intrinsic properties, synapse number and synaptic maturation are largely normal in the hippocampal CA1 region and somatosensory cortex at stages where microglia have been implicated. Seizure susceptibility and hippocampal-prefrontal cortex coherence in awake behaving animals, processes that are disrupted in mice deficient in microglia-enriched genes, are also normal. Similarly, eye-specific segregation of inputs into the lateral geniculate nucleus proceeds normally in the absence of microglia. Single-cell and single-nucleus transcriptomic analyses of neurons and astrocytes did not uncover any substantial perturbation caused by microglial absence. Thus, the brain possesses remarkable adaptability to execute developmental synaptic refinement, maturation and connectivity in the absence of microglia.

DOI: https://doi.org/10.1038/s41593-024-01833-x
Sci Rep. 2025 Jan 08. 15(1): 1283

SIX1 aggravates the progression of spinal cord injury in mice by promoting M1 polarization of microglia.

Zhonghua Xu, Manhui Zhu, Hua Xie, Jiacheng Zhu, Hongming Zheng, Xiaojuan Liu, Yuting Zhang, Jinbo Liu.

  Inflammation aggravates secondary damage following spinal cord injury (SCI). M1 microglia induce inflammation and exert neurotoxic effects, whereas M2 microglia exert anti-inflammatory and neuroprotective effects. The sine oculis homeobox (SIX) gene family consists of six members, including sine oculis homeobox homolog 1 (SIX1)-SIX6. SIX1 is expressed in microglia and promotes inflammation. This study aimed to evaluate the role and underlying mechanisms of SIX1 in microglia polarization in vitro (LPS-treated mouse microglia; BV2 cells) and in vivo (a mouse model of SCI). SIX1 expression was increased in the microglia of mice with SCI. SIX1 was positively correlated with the M1 microglia marker inducible nitric oxide synthase (iNOS) and negatively correlated with the M2 microglia marker arginase 1 (Arg1) in mice with SCI. Knockdown of SIX1 promoted functional recovery by enhancing M2 microglia polarization in mice with SCI. The transcription, expression, and activity of enhancer of zeste homolog 2 (EZH2) were decreased in LPS-stimulated BV2 cells. Downregulation of EZH2 promoted SIX1 expression in LPS-treated BV2 cells by inhibiting the methylation of the SIX1 promoter. SIX1 enhanced the transcription of vascular endothelial growth factor-C (VEGF-C) in LPS-stimulated BV2 cells with downregulated EZH2. VEGF-C promoted M1 polarization and inhibited M2 polarization in BV2 cells by binding to vascular endothelial growth factor receptor 3 (VEGFR3). Overall, the results suggest that SIX1 promotes M1 polarization of microglia following SCI by upregulating the VEGF-C/VEGFR3 axis, whereas the blockade of SIX1 can improve the recovery of locomotor function following SCI, demonstrating a novel strategy for the treatment of SCI.

Keywords:  Microglia; Polarization; Sine oculis homeobox homolog 1 (SIX1); Spinal cord injury (SCI); Vascular endothelial growth factor-C (VEGF-C)

DOI:  https://doi.org/10.1038/s41598-024-82121-3
Cell Mol Life Sci. 2025 Jan 06. 82(1): 34

18 kDa TSPO targeting drives polarized human microglia towards a protective and restorative neurosteroidome profile.

Lorenzo Germelli, Elisa Angeloni, Eleonora Da Pozzo, Chiara Tremolanti, Martina De Felice, Chiara Giacomelli, Laura Marchetti, Beatrice Muscatello, Elisabetta Barresi, Sabrina Taliani, Federico Da Settimo Passetti, Maria Letizia Trincavelli, Claudia Martini, Barbara Costa.

  An aberrant pro-inflammatory microglia response has been associated with most neurodegenerative disorders. Identifying microglia druggable checkpoints to restore their physiological functions is an emerging challenge. Recent data have shown that microglia produce de novo neurosteroids, endogenous molecules exerting potent anti-inflammatory activity. Here, the role of neurosteroidogenesis in the modulation of microgliosis was explored in human microglia cells. In particular, CYP11A1 inhibition or TSPO pharmacological stimulation, crucial proteins involved in the rate limiting step of the neurosteroidogenic cascade, were employed. CYP11A1 inhibition led microglia to acquire a dysfunctional and hyperreactive phenotype, while selective TSPO ligands promoted the establishment of an anti-inflammatory one. Analysis of specific neurosteroid levels (neurosteroidome) identified allopregnanolone/pregnanolone as crucial metabolites allowing controlled activation of microglia. Importantly, the neurosteroid shift towards a greater androgenic/estrogenic profile supported the transition from pro-inflammatory to neuroprotective microglia, suggesting the therapeutic potential of de novo microglial neurosteroidogenesis stimulation for neuroinflammatory-related disorders.

Keywords:  18 kDa Translocator Protein (TSPO); Microglia; Neuroinflammation; Neurosteroidome; TSPO ligand

DOI:  https://doi.org/10.1007/s00018-024-05544-1
Invest Ophthalmol Vis Sci. 2025 Jan 02. 66(1): 15

C3aR1-Deletion Delays Retinal Degeneration in a White-Light Damage Mouse Model.

Verena Behnke, Anne Wolf, Mandy Hector, Thomas Langmann.

Purpose: In the aging retina, persistent activation of microglia is known to play a key role in retinal degenerative diseases like age-related macular degeneration (AMD). Furthermore, dysregulation of the alternative complement pathway is generally accepted as the main driver for AMD disease progression and microglia are important producers of local complement and are equipped with complement receptors themselves. Here, we investigate the involvement of anaphylatoxin signaling, predominantly on Iba1+ cell activity, in light-induced retinal degeneration as a model for dry AMD, using anaphylatoxin receptor knockout (KO) mice.
Methods: Bright white light with an intensity of 10,000 lux was applied for 30 minutes to complement component 3a receptor 1 (C3ar1) or complement component 5a receptor 1 (C5ar1) KO and wildtype (WT) mice. Analyses of transcriptome changes and migration activity of Iba1+ cells as well as retinal thickness were performed 4 days after light exposure.
Results: Full body KO mice of either C3aR1 or C5aR1 were tested, but none led to mitigated migration of Iba1+ cells to the subretinal space or decreased expression of complement factors after light damage compared to WT mice. However, a partial rescue of retinal thickness was shown in C3aR1 KO mice, which was mirrored by significant less membrane attack complex (MAC) occurrence in the outer retina.
Conclusions: We conclude that deletion of the anaphylatoxin receptor C3aR1 cannot modulate mononuclear phagocytes but diminishes retinal degeneration through interference with the complement pathway and thus decreased MAC assembling. C3aR1-targeted therapy may be considered for patients with dry AMD.

DOI: https://doi.org/10.1167/iovs.66.1.15
Sci Transl Med. 2025 Jan 08. 17(780): eadk3434

The protein kinase C modulator bryostatin-1 therapeutically targets microglia to attenuate neuroinflammation and promote remyelination.

Payam Gharibani, Efrat Abramson, Shruthi Shanmukha, Matthew D Smith, Wesley H Godfrey, Judy J Lee, Jingwen Hu, Maryna Baydyuk, Marie-France Dorion, Xiaojing Deng, Yu Guo, Andrew J Calle, Soonmyung A Hwang, Jeffrey K Huang, Peter A Calabresi, Michael D Kornberg, Paul M Kim.

In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance among demyelination, neurodegeneration, and myelin repair. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the lack of therapies aimed at promoting remyelination and slowing disease progression for individuals with MS. Here, we found that the protein kinase C (PKC)-modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound with an established human safety profile, shifts the transcriptional programs of microglia and CNS-associated macrophages from a proinflammatory phenotype to a regenerative phenotype in vitro and in vivo. Treatment of microglia with bryo-1 stimulated scavenger pathways, phagocytosis, and secretion of factors that prevented the activation of neuroinflammatory reactive astrocytes while also promoting neuroaxonal health and oligodendrocyte differentiation. In line with these findings, systemic treatment of mice with bryo-1 augmented remyelination after a focal demyelinating injury. Our results demonstrate the potential of bryo-1 and possibly a wider class of PKC modulators as myelin-regenerative and supportive agents in MS and other neurologic diseases.

DOI: https://doi.org/10.1126/scitranslmed.adk3434
J Neuroinflammation. 2025 Jan 08. 22(1): 5

Chemerin-9 is neuroprotective in APP/PS1 transgenic mice by inhibiting NLRP3 inflammasome and promoting microglial clearance of Aβ.

Jiawei Zhang, Yaxuan Zhang, Lan Liu, Mengyuan Zhang, Xiaojie Zhang, Jiangshan Deng, Fei Zhao, Qing Lin, Xue Zheng, Bing Fu, Yuwu Zhao, Xiuzhe Wang.

   BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder worldwide, and microglia are thought to play a central role in neuroinflammatory events occurring in AD. Chemerin, an adipokine, has been implicated in inflammatory diseases and central nervous system disorders, yet its precise function on microglial response in AD remains unknown.
METHODS: The APP/PS1 mice were treated with different dosages of chemerin-9 (30 and 60 µg/kg), a bioactive nonapeptide derived from chemerin, every other day for 8 weeks consecutively. The primary mouse microglia were stimulated by amyloid beta 42 (Aβ42) oligomers followed by treatment with chemerin-9 in vitro. ChemR23 inhibitor α-NETA was further used to investigate whether the effects of chemerin-9 were ChemR23-dependent.
RESULTS: We found that the expression of chemerin and ChemR23 was increased in AD. Intriguingly, treatment with chemerin-9 significantly ameliorated Aβ deposition and cognitive impairment of the APP/PS1 mice, with decreased microglial proinflammatory activity and increased phagocytic activity. Similarly, chemerin-9-treated primary microglia showed increased phagocytic ability and decreased NLRP3 inflammasome activation. However, the ChemR23 inhibitor α-NETA abolished the neuroprotective microglial response of chemerin-9.
CONCLUSIONS: Collectively, our data demonstrate that chemerin-9 ameliorates cognitive deficits in APP/PS1 transgenic mice by boosting a neuroprotective microglial phenotype.

Keywords:  Alzheimer's disease; ChemR23; Chemerin; Microglia; NLRP3 inflammasome; Phagocytosis

DOI:  https://doi.org/10.1186/s12974-024-03325-y
Alzheimers Dement. 2025 Jan 09.

Menopausal hormone therapy is associated with worse levels of Alzheimer's disease biomarkers in APOE ε4-carrying women: An observational study.

Ainara Jauregi-Zinkunegi, Carey E Gleason, Barbara Bendlin, Ozioma Okonkwo, Bruce P Hermann, Kaj Blennow, Henrik Zetterberg, Eef Hogervorst, Sterling C Johnson, Rebecca Langhough, Kimberly D Mueller, Davide Bruno.

   INTRODUCTION: Menopausal hormone therapy (MHT), along with the apolipoprotein E (APOE) ε4 allele, has been suggested as a possible risk factor for Alzheimer's disease (AD). However, the relationship between MHT and cerebrospinal fluid (CSF) biomarkers is unknown: we investigated this association, and whether APOE ε4 carrier status moderates it.
METHODS: In an observational study of 136 cognitively unimpaired female participants (Mage = 66.0; standard deviation = 6.3), we examined whether MHT use alone or in interaction with APOE ε4 carrier status was associated with CSF levels of phosphorylated tau (p-tau), amyloid beta (Aβ)40, Aβ42, p-tau/Aβ42, and Aβ42/40 ratios.
RESULTS: Significant interactions were found between APOE ε4 and MHT use for CSF biomarkers. APOE ε4 carriers who were MHT users showed worse levels of CSF p-tau/Aβ42 and Aβ42/40 ratios than all other users and non-users.
DISCUSSION: The presence of both APOE ε4 and MHT may be associated with elevated amyloid deposition and AD pathology in this sample of participants who demonstrated high familial AD risk.
HIGHLIGHTS: Significant interactions were found between apolipoprotein E (APOE) ε4 and menopausal hormone therapy (MHT) use for cerebrospinal fluid (CSF) phosphorylated tau (p-tau)/amyloid beta (Aβ)42 and Aβ42/40 ratios. APOE ε4 carriers who were MHT users showed worse levels of CSF biomarkers than non-users and non-carriers, both users and non-users. Younger age at MHT initiation was associated with worse levels of the p-tau/Aβ42 and Aβ42/40 ratios in carriers only. The presence of both APOE ε4 carriage and MHT use may be associated with elevated amyloid deposition and AD pathology. Further studies with larger sample sizes are necessary to confirm the differences observed in the current study.

Keywords:  Alzheimer's disease; apolipoprotein E ε4 allele; biomarker; cerebrospinal fluid; hormone therapy; menopause

DOI:  https://doi.org/10.1002/alz.14456
Front Neurosci. 2024 ;18 1504765

Neuroprotective role of sialic-acid-binding immunoglobulin-like lectin-11 in humanized transgenic mice.

Tawfik Abou Assale, Negin Afrang, Jannis Wissfeld, German Cuevas-Rios, Christine Klaus, Bettina Linnartz-Gerlach, Harald Neumann.

  Brain aging is a chronic process linked to inflammation, microglial activation, and oxidative damage, which can ultimately lead to neuronal loss. Sialic acid-binding immunoglobulin-like lectin-11 (SIGLEC-11) is a human lineage-specific microglial cell surface receptor that recognizes α-2-8-linked oligo-/polysialylated glycomolecules with inhibitory effects on the microglial inflammatory pathways. Recently, the SIGLEC11 gene locus was prioritized as a top tier microglial gene with potential causality to Alzheimer's disease, although its role in inflammation and neurodegeneration remains poorly understood. In this study, aged Siglec-11 transgenic (tg) mice, which expressed the human SIGLEC-11 receptor on microglia and tissue macrophages, were investigated. The brains of the Siglec-11 tg mice were analyzed in 6-month-old mature mice and 24-month-old aged mice using immunohistochemistry and transcriptomics. Results showed decreased density and fewer clusters of ionized calcium binding adaptor molecule 1 (Iba1)-positive microglial cells in the hippocampus and substantia nigra, as well as less lipid-laden microglia in the Siglec-11 tg in comparison to wildtype (WT) controls. Additionally, Siglec-11 tg mice exhibited less age-related neuronal loss in the substantia nigra pars compacta in comparison to WT mice. Transcriptome analysis revealed suppression of oxidative phosphorylation and inflammatory pathways in Siglec-11 tg brains at 6 months, with further suppression of complement and coagulation cascades at 24 months of age in comparison to WT mice. Gene transcript levels of the pro-inflammatory cytokines tumor necrosis factor alpha (Tnf) and interleukin 1 beta (Il-1β) as well as the oxidative stress markers cytochrome b-245 alpha and beta (Cyba and Cybb) and the nitric oxide synthase 2 (Nos2), were reduced in the brains of 24-month-old Siglec-11 tg mice relative to WT controls. Brains of 24-month-old Siglec-11 tg mice also exhibited lower gene transcription of complement components 3, 4, and integrin alpha M (C3, C4, and Itgam), along with the complement C1q subcomponents a-c (C1qa, C1qb, and C1qc). In summary, aged Siglec-11 tg mice displayed reduced brain inflammation and oxidative stress, as well as protection against age-related neuronal loss in the substantia nigra.

Keywords:  Siglec-11; aging; microglia; neurodegeneration; neuroinflammation; oxidative stress

DOI:  https://doi.org/10.3389/fnins.2024.1504765
Neurobiol Pain. 2025 Jan-Jun;17:17 100175

Evidence for glial reactivity using positron-emission tomography imaging of translocator Protein-18 kD [TSPO] in both sham and nerve-injured rats in a preclinical model of orofacial neuropathic pain.

Gaelle M Emvalomenos, James W M Kang, Sabrina Salberg, Crystal Li, Bianca Jupp, Matthew Long, Mohammad B Haskali, Sunil Kellapatha, OIivia I Davanzo, Hyunsol Lim, Richelle Mychasiuk, Kevin A Keay, Luke A Henderson.

  Chronic neuropathic pain is a debilitating condition that results from damage to the nervous system. Current treatments are largely ineffective, with limited understanding of the underlying mechanisms hindering development of effective treatments. Preclinical models of neuropathic pain have revealed that non-neural changes are important for the development of neuropathic pain, although these data are derived almost exclusively from post-mortem histological analyses. Although these static snapshots have provided valuable data, they cannot provide insights into non-neural cell changes that could be also assessed in human patients with chronic pain. In this study we used translocator protein 18 kDa (TSPO) PET imaging with [18F]PBR06 to visualise in-vivo, the activity of macrophages and microglia in a rodent preclinical model of trigeminal neuropathic pain. Using chronic constriction injury of the infraorbital nerve (ION-CCI) we compared temporal changes in TSPO binding in male rats, prior to, and up to 28 days after ION-CCI compared with both sham-injured and naïve counterparts. Unexpectedly, we found significant increases in TSPO signal in both ION-CCI and sham-injured rats within the trigeminal ganglion, spinal trigeminal nucleus and paratrigeminal nucleus during the initial phase following surgery and/or nerve injury. This increased TSPO binding returned to control levels by day 28. Qualitative histological appraisal of macrophage accumulation and glial reactivity in both ION-CCI and sham-injured rats indicated macrophage accumulation in the trigeminal ganglion and microglial reactivity in the brainstem trigeminal complex. These findings show, glial changes in the peripheral nerve and brain in both nerve-injured and sham-injured rats in a preclinical model of neuropathic pain which provides a platform for translation into human patients.

Keywords:  Chronic constriction injury; Macrophages; Microglia; Positron emission tomography; Spinal trigeminal nucleus; Trigeminal ganglion

DOI:  https://doi.org/10.1016/j.ynpai.2024.100175
Glia. 2025 Jan 08.

Characterizing Microglial Signaling Dynamics During Inflammation Using Single-Cell Mass Cytometry.

Sushanth Kumar, August D Kahle, Austin B Keeler, Eli R Zunder, Christopher D Deppmann.

  Microglia play a critical role in maintaining central nervous system (CNS) homeostasis and display remarkable plasticity in their response to inflammatory stimuli. However, the specific signaling profiles that microglia adopt during such challenges remain incompletely understood. Traditional transcriptomic approaches provide valuable insights, but fail to capture dynamic post-translational changes. In this study, we utilized time-resolved single-cell mass cytometry (CyTOF) to measure distinct signaling pathways activated in microglia upon exposure to bacterial and viral mimetics-lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (Poly(I:C)), respectively. Furthermore, we evaluated the immunomodulatory role of astrocytes on microglial signaling in mixed cultures. Microglia or mixed cultures derived from neonatal mice were treated with LPS or Poly(I:C) for 48 h. Cultures were stained with a panel of 33 metal-conjugated antibodies targeting signaling and identity markers. High-dimensional clustering analysis was used to identify emergent signaling modules. We found that LPS treatment led to more robust early activation of pp38, pERK, pRSK, and pCREB compared to Poly(I:C). Despite these differences, both LPS and Poly(I:C) upregulated the classical reactivity markers CD40 and CD86 at later time points. Strikingly, the presence of astrocytes significantly blunted microglial responses to both stimuli, particularly dampening CD40 upregulation. Our studies demonstrate that single-cell mass cytometry effectively captures the dynamic signaling landscape of microglia under pro-inflammatory conditions. This approach may pave the way for targeted therapeutic investigations of various neuroinflammatory disorders. Moreover, our findings underscore the necessity of considering cellular context, such as astrocyte presence, in interpreting microglial behavior during inflammation.

Keywords:  CyTOF; Neuroinflammation; astrocytes; lipopolysaccharide (LPS); mass cytometry; microglia; poly(I:C); signaling pathways

DOI:  https://doi.org/10.1002/glia.24670
Adv Healthc Mater. 2025 Jan 05. e2404782

Biomimetic Membrane Vesicles Reprogram Microglia Polarization and Remodel the Immunosuppressive Microenvironment of Glioblastoma via PERK/HIF-1α/Glycolysis Pathway.

Yinghan Guo, Lulu Jin, Zhipeng Shen, Linfeng Fan, Xian Yu, Yirui Kuang, Lingxin Cai, Jiayin Zhou, Zihang Chen, Feng Yan, Jianmin Zhang, Minfeng Tong, Jianlie Yuan, Zhengwei Mao, Gao Chen.

  The malignant interaction between tumor cells and immune cells is one of the important reasons for the rapid progression and refractoriness of glioblastoma (GBM). As an essential metabolic center of M2 macrophages, the inhibition of protein kinase RNA-like endoplasmic reticulum kinase (PERK) leads to the reduction of M2 macrophages. Nevertheless, the restriction of the blood-brain barrier (BBB) and non-specific cell targeting hinder the application of PERK inhibitors in GBM. Herein, the optimal NP-M-M2pep is developed successfully, which has shown the capacity of BBB penetration and specific targeting of M2 microglia. In addition to inhibiting the polarization of M2 microglia, the administration of iPERK@NP-M-M2pep reprogrammed M2 microglia into M1 ones in vitro via PERK/HIF-1α/glycolysis pathway. Efficient brain accumulation of nanoparticles is achieved after tail vein injection, with effective inhibition of GBM progression after one course of treatment. The glioma-associated microglia and macrophages (GAM) with M2 type are induced to M1 and the immunosuppressive TME is remodeled by upregulating immunostimulatory cells and downregulating immunosuppressive cells. In summary, the biomimetic membrane vesicles (BMVs) specifically delivered iPERK to GAMs offer an inspiring strategy to reprogram microglia polarization, re-educate immunosuppressive TME, and inhibit the progression of GBM.

Keywords:  M2 macrophage/microglia; PERK; biomimetic hybrid liposome; glioblastoma; immunosuppressive microenvironment

DOI:  https://doi.org/10.1002/adhm.202404782
Glia. 2025 Jan 06.

Microglial Responses to Alzheimer's Disease Pathology: Insights From "Omics" Studies.

Aquene N Reid, Suman Jayadev, Katherine E Prater.

  Human genetics studies lent firm evidence that microglia are key to Alzheimer's disease (AD) pathogenesis over a decade ago following the identification of AD-associated genes that are expressed in a microglia-specific manner. However, while alterations in microglial morphology and gene expression are observed in human postmortem brain tissue, the mechanisms by which microglia drive and contribute to AD pathology remain ill-defined. Numerous mouse models have been developed to facilitate the disambiguation of the biological mechanisms underlying AD, incorporating amyloidosis, phosphorylated tau, or both. Over time, the use of multiple technologies including bulk tissue and single cell transcriptomics, epigenomics, spatial transcriptomics, proteomics, lipidomics, and metabolomics have shed light on the heterogeneity of microglial phenotypes and molecular patterns altered in AD mouse models. Each of these 'omics technologies provide unique information and biological insight. Here, we review the literature on the approaches and findings of these methods and provide a synthesis of the knowledge generated by applying these technologies to mouse models of AD.

Keywords:  Alzheimer's disease; lipidomics; metabolomics; microglia; mouse; transcriptomics

DOI:  https://doi.org/10.1002/glia.24666
Nat Neurosci. 2025 Jan 06.

Monocyte-derived macrophages act as reinforcements when microglia fall short in Alzheimer's disease.

Miguel A Abellanas, Maitreyee Purnapatre, Chiara Burgaletto, Michal Schwartz.

The central nervous system (CNS) is endowed with its own resident innate immune cells, the microglia. They constitute approximately 10% of the total cells within the CNS parenchyma and act as 'sentinels', sensing and mitigating any deviation from homeostasis. Nevertheless, under severe acute or chronic neurological injury or disease, microglia are unable to contain the damage, and the reparative activity of monocyte-derived macrophages (MDMs) is required. The failure of the microglia under such conditions could be an outcome of their prolonged exposure to hostile stimuli, leading to their exhaustion or senescence. Here, we describe the conditions under which the microglia fall short, focusing mainly on the context of Alzheimer's disease, and shed light on the functions performed by MDMs. We discuss whether and how MDMs engage in cross-talk with the microglia, why their recruitment is often inadequate, and potential ways to augment their homing to the brain in a well-controlled manner.

DOI: https://doi.org/10.1038/s41593-024-01847-5
NPJ Parkinsons Dis. 2025 Jan 09. 11(1): 15

Microglia depletion reduces neurodegeneration and remodels extracellular matrix in a mouse Parkinson's disease model triggered by α-synuclein overexpression.

Zhen Zhang, Kun Niu, Taoying Huang, Jiali Guo, Gongbikai Xarbat, Xiaoli Gong, Yunke Gao, Feiyang Liu, Shan Cheng, Wenting Su, Fei Yang, Zhaoyuan Liu, Florent Ginhoux, Ting Zhang.

Chronic neuroinflammation with sustained microglial activation occurs in Parkinson's disease (PD), yet the mechanisms and exact contribution of these cells to the neurodegeneration remains poorly understood. In this study, we induced progressive dopaminergic neuron loss in mice via rAAV-hSYN injection to cause the neuronal expression of α-synuclein, which produced neuroinflammation and behavioral alterations. We administered PLX5622, a colony-stimulating factor 1 receptor inhibitor, for 3 weeks prior to rAAV-hSYN injection, maintaining it for 8 weeks to eliminate microglia. This chronic treatment paradigm prevented the development of motor deficits and concomitantly preserved dopaminergic neuron cell and weakened α-synuclein phosphorylation. Gene expression profiles related to extracellular matrix (ECM) remodeling were increased after microglia depletion in PD mice, which were further validated on protein level. We demonstrated that microglia exert adverse effects during α-synuclein-overexpression-induced neuronal lesion formation, and their depletion remodels ECM and aids recovery following insult.

DOI: https://doi.org/10.1038/s41531-024-00846-4
Brain. 2025 Jan 09. pii: awae339. [Epub ahead of print]

Human longevity and Alzheimer's disease variants act via microglia and oligodendrocyte gene networks.

Andrew C Graham, Eftychia Bellou, Janet C Harwood, Umran Yaman, Meral Celikag, Naciye Magusali, Naiomi Rambarack, Juan A Botia, Carlo Sala Frigerio, John Hardy, Valentina Escott-Price, Dervis A Salih.

  Ageing underlies functional decline of the brain and is the primary risk factor for several neurodegenerative conditions, including Alzheimer's disease (AD). However, the molecular mechanisms that cause functional decline of the brain during ageing, and how these contribute to AD pathogenesis, are not well understood. The objective of this study was to identify biological processes that are altered during ageing in the hippocampus and that modify Ad risk and lifespan, and then to identify putative gene drivers of these programmes. We integrated common human genetic variation associated with human lifespan or Ad from genome-wide association studies with co-expression transcriptome networks altered with age in the mouse and human hippocampus. Our work confirmed that genetic variation associated with Ad was enriched in gene networks expressed by microglia responding to ageing and revealed that they were also enriched in an oligodendrocytic gene network. Compellingly, longevity-associated genetic variation was enriched in a gene network expressed by homeostatic microglia whose expression declined with age. The genes driving this enrichment include CASP8 and STAT3, highlighting a potential role for these longevity-associated genes in the homeostatic functions of innate immune cells, and these genes might drive 'inflammageing'. Thus, we observed that gene variants contributing to ageing and AD balance different aspects of microglial and oligodendrocytic function. Furthermore, we also highlight putative Ad risk genes, such as LAPTM5, ITGAM and LILRB4, whose association with Ad falls below genome-wide significance but show strong co-expression with known Ad risk genes in these networks. Indeed, five of the putative risk genes highlighted by our analysis, ANKH, GRN, PLEKHA1, SNX1 and UNC5CL, have subsequently been identified as genome-wide significant risk genes in a subsequent genome-wide association study with larger sample size, validating our analysis. This work identifies new genes that influence ageing and AD pathogenesis, and highlights the importance of microglia and oligodendrocytes in the resilience of the brain against ageing and AD pathogenesis. Our findings have implications for developing markers indicating the physiological age of the brain and new targets for therapeutic intervention.

Keywords:  Alzheimer’s disease; ageing; homeostasis; microglia; myelin; oligodendrocytes

DOI:  https://doi.org/10.1093/brain/awae339
Am J Physiol Endocrinol Metab. 2025 Jan 09.

Neuroimmunometabolism: How Metabolism Orchestrates Immune Response in Healthy and Diseased Brain.

Anil Kumar Rana, Babita Bhatt, Chitralekha Gusain, Surya Narayan Biswal, Debashree Das, Mohit Kumar.

  Neuroimmunometabolism describes how neuroimmune cells, such as microglia, adapt their intracellular metabolic pathways to alter their immune functions in the CNS. Emerging evidence indicates that neurons also orchestrate the microglia mediated immune response through neuro-immune crosstalk perhaps through metabolic signalling. However, little is known about how the brain's metabolic microenvironment and microglial intracellular metabolism orchestrate the neuroimmune response in healthy and diseased brains. This review addresses the balance of immunometabolic substrates in healthy and diseased brains, their metabolism by brain resident microglia, and the potential impact of metabolic dysregulation of these substrates on the neuroimmune response and pathophysiology of psychiatric disorders. This review also suggests metabolic reprogramming of microglia as a preventive strategy for the management of neuroinflammation-related brain disorders including psychiatric diseases.

Keywords:  Depression; Immunometabolism; Microglia; Neuroinflammation; Psychiatric diseases

DOI:  https://doi.org/10.1152/ajpendo.00331.2024
bioRxiv. 2024 Dec 25. pii: 2024.12.25.630253. [Epub ahead of print]

Dissecting the evolving cellular landscape of a remyelinating microenvironment.

George S Melchor, Maryna Baydyuk, Zeeba Manavi, Jingwen Hu, Jeffrey K Huang.

Demyelination, or the loss of myelin in the central nervous system (CNS) is a hallmark of multiple sclerosis (MS) and occurs in various forms of CNS injury and neurodegenerative diseases. The regeneration of myelin, or remyelination, occurs spontaneously following demyelination. The lysophosphatidylcholine (LPC)-induced focal demyelination model enables investigations into the mechanisms of remyelination, providing insight into the molecular basis underlying an evolving remyelinating microenvironment over a tractable time course. Here, we present a detailed analysis using high-resolution single nucleus RNA sequencing to investigate gene expression dynamics across multiple cell populations involved in the remyelination process. We examine three specific time points following focal demyelinating injury in mice, and by delineating activation states within the heterogeneous cell populations of demyelinated lesions, we highlight changes in gene expression within subclusters of each cell population from the early stages of injury response to the initiation and maintenance of remyelination. Our findings reveal how shifts in microglial, astrocytic and fibroblast activities within lesions are associated with efficient oligodendrocyte differentiation during remyelination.

DOI: https://doi.org/10.1101/2024.12.25.630253
Int J Mol Sci. 2024 Dec 21. pii: 13676. [Epub ahead of print]25(24):

Inflammatory Stimulation Upregulates the Receptor Transporter Protein 4 (RTP4) in SIM-A9 Microglial Cells.

Wakako Fujita, Yusuke Kuroiwa.

  The receptor transporter protein 4 (RTP4) is a receptor chaperone protein that targets class A G-protein coupled receptor (GPCR)s. Recently, it has been found to play a role in peripheral inflammatory regulation, as one of the interferon-stimulated genes (ISGs). However, the detailed role of RTP4 in response to inflammatory stress in the central nervous system has not yet been fully understood. While we have previously examined the role of RTP4 in the brain, particularly in neuronal cells, this study focuses on its role in microglial cells, immunoreactive cells in the brain that are involved in inflammation. For this, we examined the changes in the RTP4 levels in the microglial cells after exposure to inflammatory stress. We found that lipopolysaccharide (LPS) treatment (0.1~1 µg/mL, 24 h) significantly upregulated the RTP4 mRNA levels in the microglial cell line, SIM-A9. Furthermore, the interferon (IFN)-β mRNA levels and extracellular levels of IFN-β were also increased by LPS treatment. This upregulation was reversed by treatment with neutralizing antibodies targeting either the interferon receptor (IFNR) or toll-like receptor 4 (TLR4), and with a TLR4 selective inhibitor, or a Janus kinase (JAK) inhibitor. On the other hand, the mitogen-activated protein kinase kinase (MEK) inhibitor, U0126, significantly enhanced the increase in RTP4 mRNA following LPS treatment, whereas the PKC inhibitor, calphostin C, had no effect. These findings suggest that in microglial cells, LPS-induced inflammatory stress activates TLR4, leading to the production of type I IFN, the activation of IFN receptor and JAK, and finally, the induction of RTP4 gene expression. Based on these results, we speculate that RTP4 functions as an inflammation-responsive molecule in the brain. However, further research is needed to fully understand its role.

Keywords:  LPS; RTP4; microglia

DOI:  https://doi.org/10.3390/ijms252413676
Diabetol Metab Syndr. 2025 Jan 04. 17(1): 2

Semaglutide restores astrocyte-vascular interactions and blood-brain barrier integrity in a model of diet-induced metabolic syndrome.

Vanessa Estato, Nathalie Obadia, Paulo Henrique Chateaubriand, Vivian Figueiredo, Marcela Curty, Mariana Costa Silva, Renata Gabriela Lustosa Ferreira, Juliane Santa-Ritta, Marcela Campos Baroni, Alessandra Aragão, João Oliveira Góes Neno, Clara Avelar Mendes Vasconcellos, Joana Costa D'Avila, Marcelo Gomes Granja, Hugo Caire de Castro Faria-Neto.

   INTRODUCTION: Metabolic syndrome (MetS) is a metabolic disorder related to obesity and insulin resistance and is the primary determinant of the development of low-intensity chronic inflammation. This continuous inflammatory response culminates in neuroimmune-endocrine dysregulation responsible for the metabolic abnormalities and morbidities observed in individuals with MetS. Events such as the accumulation of visceral adipose tissue, increased plasma concentrations of free fatty acids, tissue hypoxia, and sympathetic hyperactivity in individuals with MetS may contribute to the activation of the innate immune response, which compromises cerebral microcirculation and the neurovascular unit, leading to the onset or progression of neurodegenerative diseases.
OBJECTIVE: This study aimed to evaluate the effects of chronic treatment with a GLP-1 receptor agonist (semaglutide) on cerebral microcirculation and neurovascular unit (NVU) integrity.
METHODS: C57BL/6 mice were fed a standard normolipidic diet or a high-fat diet (HFD) for 24 weeks and then treated for 4 weeks with semaglutide (HFD SEMA) or saline solution (HFD SAL). At the end of pharmacological treatment, biochemical analyses, immunohistochemistry analysis, and intravital microscopy of the brain microcirculation were carried out to quantify leukocyte-endothelium interactions and to assess structural capillary density, astrocyte coverage on cerebral vessels and microglial activation.
RESULTS: We observed that SEMA attenuates high-fat diet-induced metabolic alterations in mice fed with HFD for 24 weeks. SEMA also reversed cerebral microcirculation effects of HFD by reducing capillary rarefaction and the interaction of leukocytes in postcapillary brain venules. The HFD-SEMA group exhibited improved astrocyte coverage on vessels. However, SEMA did not reverse microglial activation.
CONCLUSIONS: Semaglutide can reverse microvascular rarefaction in metabolic syndrome by restoring the integrity of the neurovascular unit. Adverse dietary stimuli can compromise microglial homeostasis that is not reversed by semaglutide.

Keywords:  BBB; Metabolic syndrome; Microvascular rarefaction; Neurovascular unit

DOI:  https://doi.org/10.1186/s13098-024-01528-0
Int J Mol Sci. 2024 Dec 21. pii: 13682. [Epub ahead of print]25(24):

Adoptive Transfer of CX3CR1-Transduced Tregs Homing to the Forebrain in Lipopolysaccharide-Induced Neuroinflammation and 3xTg Alzheimer's Disease Models.

Hyejin Yang, Juwon Yang, Namgyeong Park, Deok-Sang Hwang, Seon-Young Park, Soyoung Kim, Hyunsu Bae.

  CX3CR1-transduced regulatory T cells (Tregs) have shown potential in reducing neuroinflammation by targeting microglial activation. Reactive microglia are implicated in neurological disorders, and CX3CR1-CX3CL1 signaling modulates microglial activity. The ability of CX3CR1-transduced Tregs to inhibit LPS-induced neuroinflammation was assessed in animal models. CX3CR1 Tregs were administered to LPS-induced and 3xTg Alzheimer's mouse models, resulting in reduced proinflammatory marker expression in both the cortices and hippocampi. In the 3xTg Alzheimer's model, neuroinflammation was significantly reduced, demonstrating the efficacy of CX3CR1 Tregs even in chronic neuroinflammatory conditions. These findings highlight the therapeutic potential of CX3CR1 Treg therapy in modulating microglial activity and offer promising treatment strategies for neurodegenerative diseases.

Keywords:  3xTg mouse model; Alzheimer’s disease; lipopolysaccharide; microglia; neurodegeneration; neuroinflammation; regulatory T cell

DOI:  https://doi.org/10.3390/ijms252413682
Commun Biol. 2025 Jan 09. 8(1): 30

Human iPSC-derived microglial cells protect neurons from neurodegeneration in long-term cultured adhesion brain organoids.

Xianwei Chen, Guoqiang Sun, Lizhao Feng, E Tian, Yanhong Shi.

Brain organoid models have greatly facilitated our understanding of human brain development and disease. However, key brain cell types, such as microglia, are lacking in most brain organoid models. Because microglia have been shown to play important roles in brain development and pathologies, attempts have been made to add microglia to brain organoids through co-culture. However, only short-term microglia-organoid co-cultures can be established, and it remains challenging to have long-lasting survival of microglia in organoids to mimic long-term residency of microglia in the brain. In this study, we developed an adhesion brain organoid (ABO) platform that allows prolonged culture of brain organoids (greater than a year). Moreover, the long-term (LT)-ABO system contains abundant astrocytes and can support prolonged survival and ramification of microglia. Furthermore, we showed that microglia in the LT-ABO could protect neurons from neurodegeneration by increasing synaptic density and reducing p-Tau level and cell death in the LT-ABO. Therefore, the microglia-containing LT-ABO platform generated in this study provides a promising human cellular model for studying neuron-glia and glia-glia interactions in brain development and the pathogenesis of neurodegenerative diseases such as Alzheimer's disease.

DOI: https://doi.org/10.1038/s42003-024-07401-0
Int J Mol Sci. 2024 Dec 21. pii: 13690. [Epub ahead of print]25(24):

Inhibiting the Cholesterol Storage Enzyme ACAT1/SOAT1 in Aging Apolipoprotein E4 Mice Alters Their Brains' Inflammatory Profiles.

Thao N Huynh, Emma N Fikse, Adrianna L De La Torre, Matthew C Havrda, Catherine C Y Chang, Ta Yuan Chang.

  Aging and apolipoprotein E4 (APOE4) are the two most significant risk factors for late-onset Alzheimer's disease (LOAD). Compared to APOE3, APOE4 disrupts cholesterol homeostasis, increases cholesteryl esters (CEs), and exacerbates neuroinflammation in brain cells, including microglia. Targeting CEs and neuroinflammation could be a novel strategy to ameliorate APOE4-dependent phenotypes. Toll-like receptor 4 (TLR4) is a key macromolecule in inflammation, and its regulation is associated with the cholesterol content of lipid rafts in cell membranes. We previously demonstrated that in normal microglia expressing APOE3, inhibiting the cholesterol storage enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1/SOAT1) reduces CEs, dampened neuroinflammation via modulating the fate of TLR4. We also showed that treating myelin debris-loaded normal microglia with ACAT inhibitor F12511 reduced cellular CEs and activated ABC transporter 1 (ABCA1) for cholesterol efflux. This study found that treating primary microglia expressing APOE4 with F12511 also reduces CEs, activates ABCA1, and dampens LPS-dependent NFκB activation. In vivo, two-week injections of nanoparticle F12511, which consists of DSPE-PEG2000, phosphatidylcholine, and F12511, to aged female APOE4 mice reduced TLR4 protein content and decreased proinflammatory cytokines, including IL-1β in mice brains. Overall, our work suggests nanoparticle F12511 is a novel agent to ameliorate LOAD.

Keywords:  ACAT inhibitor; ATP binding cassette subfamily A member 1; Alzheimer’s disease; DSPE-PEG2000; F12511; LOAD; NFκB; TLR4; acyl-CoA:cholesterol acyltransferase; apolipoprotein E4 (APOE4); cholesterol; cholesteryl esters; interleukin-1 beta; late-onset Alzheimer’s disease; lipid rafts; microglia; phosphatidylcholine; sterol O-acyltransferase 1

DOI:  https://doi.org/10.3390/ijms252413690
Life Sci. 2025 Jan 03. pii: S0024-3205(25)00006-2. [Epub ahead of print] 123373

Regulation of the microglial polarization for alleviating neuroinflammation in the pathogenesis and therapeutics of major depressive disorder.

Yu-Fei Wang, Cong-Ya Chen, Lan Lei, Yi Zhang.

  Major depressive disorder (MDD), as a multimodal neuropsychiatric and neurodegenerative illness with high prevalence and disability rates, has become a burden to world health and the economy that affects millions of individuals worldwide. Neuroinflammation, an atypical immune response occurring in the brain, is currently gaining more attention due to its association with MDD. Microglia, as immune sentinels, have a vital function in regulating neuroinflammatory reactions in the immune system of the central nervous system. From the perspective of steady-state branching states, they can transition phenotypes between two extremes, namely, M1 and M2 phenotypes are pro-inflammatory and anti-inflammatory, respectively. It has an intermediate transition state characterized by different transcriptional features and the release of inflammatory mediators. The timing regulation of inflammatory cytokine release is crucial for damage control and guiding microglia back to a steady state. The dysregulation can lead to exorbitant tissue injury and neuronal mortality, and targeting the cellular signaling pathway that serves as the regulatory basis for microglia is considered an essential pathway for treating MDD. However, the specific intervention targets and mechanisms of microglial activation pathways in neuroinflammation are still unclear. Therefore, the present review summarized and discussed various signaling pathways and effective intervention targets that trigger the activation of microglia from its branching state and emphasizes the mechanism of microglia-mediated neuroinflammation associated with MDD.

Keywords:  Major depressive disorder; Microglia; Neurodegenerative disorder; Neuroinflammation; Polarization

DOI:  https://doi.org/10.1016/j.lfs.2025.123373
Eur J Neurol. 2025 Jan;32(1): e70038

Hyperreflective retinal foci are associated with retinal degeneration after optic neuritis in neuromyelitis optica spectrum disorders and multiple sclerosis.

Philipp Klyscz, Ifat Vigiser, Gilberto Solorza Buenrostro, Seyedamirhosein Motamedi, Carla Johanna Leutloff, Patrick Schindler, Tanja Schmitz-Hübsch, Friedemann Paul, Hanna Gwendolyn Zimmermann, Frederike Cosima Oertel.

   BACKGROUND: Hyperreflective retinal foci (HRF) visualized by optical coherence tomography (OCT) potentially represent clusters of microglia. We compared HRF frequencies and their association with retinal neurodegeneration between people with clinically isolated syndrome (pwCIS), multiple sclerosis (pwMS), aquaporin 4-IgG positive neuromyelitis optica spectrum disorder (pwNMOSD), and healthy controls (HC)-as well as between eyes with (ON+eyes) and without a history of optic neuritis (ON-eyes).
METHODS: Cross-sectional data of pwCIS, pwMS, and pwNMOSD with previous ON and HC were acquired at Charité-Universitätsmedizin Berlin. HRF analysis was performed manually on the central macular OCT scan. Semi-manual OCT segmentation was performed to acquire the combined ganglion cell and inner plexiform layer (GCIPL), inner nuclear layer (INL), and peripapillary retinal nerve fiber layer (pRNFL) thickness. Group comparisons were performed by linear mixed models.
RESULTS: In total, 227 eyes from 88 patients (21 pwCIS, 32 pwMS, and 35 pwNMOSD) and 35 HCs were included. HRF in GCIPL and INL were more frequently detected in pwCIS, pwMS, and pwNMOSD than HCs (p < 0.001 for all comparisons) with pwCIS exhibiting the greatest numbers. ON+eyes of pwMS had less HRF in GCIPL than ON-eyes (p = 0.036), but no difference was seen in pwCIS and pwNMOSD. HRF GCIPL were correlated to GCIPL thickness in ON+eyes in pwMS (p = 0.040) and pwNMOSD (p = 0.031).
CONCLUSION: HRF occur in ON+eyes and ON-eyes across neuroinflammatory diseases. In pwMS and pwNMOSD, HRF frequency was positively associated with GCIPL thickness indicating that HRF formation might be dependent on retinal ganglion cells.

Keywords:  OCT; hyperreflective retinal foci; multiple sclerosis; neuromyelitis optica spectrum disorder

DOI:  https://doi.org/10.1111/ene.70038
Biomed Pharmacother. 2025 Jan 08. pii: S0753-3322(24)01684-6. [Epub ahead of print]183 117797

Prolonged incubation with Δ9-tetrahydrocannabinol but not with cannabidiol induces synaptic alterations and mitochondrial impairment in immature and mature rat organotypic hippocampal slices.

Costanza Mazzantini, Lorenzo Curti, Daniele Lana, Alessio Masi, Maria Grazia Giovannini, Giada Magni, Domenico E Pellegrini-Giampietro, Elisa Landucci.

  Cannabis derivatives are among the most widely used psychoactive substances in the world, which leads to growing medical concerns regarding its chronic use and abuse especially among adolescents. Exposure to THC during formative years produces long-term behavioral alterations that share similarities with symptoms of psychiatric and neurodevelopmental disorders. In this study, we have analyzed the functional and molecular mechanisms that might underlie these alterations. Rat organotypic hippocampal slices were cultured for 2 days (immature) or 10 days (mature) in vitro and then exposed for 7 days to THC (1 µM) or CBD (1 µM). At the end of the treatment, slices were analyzed by Western blotting, electrophysiological recordings, RT-PCR, and fluorescence microscopy to explore the molecular and functional changes in the hippocampus. A prolonged (7-day) exposure to THC reduced the expression levels of pre- (synaptophysin, vGlut1) and post-synaptic (PSD95) proteins in both immature and mature slices, whereas CBD significantly increased the expression levels of PSD95 only in immature slices. In addition, THC significantly reduced the passive properties and the intrinsic excitability of membranes and increased sEPSCs in CA1 pyramidal cells of immature but not mature slices. Exposure to both cannabinoids impaired mitochondrial function as detected by the reduction of mRNA expression levels of mitobiogenesis genes such as VDAC1, UCP2, and TFAM. Finally, THC but not CBD caused tissue disorganization and morphological modifications in CA1 pyramidal neurons, astrocytes and microglia in both immature and mature slices. These results are helpful to explain the specific vulnerability of adolescent brain to the effects of psychotropic cannabinoids.

Keywords:  1–7: Synaptophysin; PSD95; UCP2; VDAC1; microglia; sEPSCs

DOI:  https://doi.org/10.1016/j.biopha.2024.117797
Neuropharmacology. 2025 Jan 02. pii: S0028-3908(24)00463-5. [Epub ahead of print]266 110294

Cholesterol metabolites modulate ionotropic P2X4 and P2X7 receptor current in microglia cells.

Michele Barraco, Eva Kudova, Claudio Bucolo, Lucia Ciranna, Maria Angela Sortino, Mariangela Chisari.

  The central nervous system is a well-known steroidogenic tissue producing, among others, cholesterol metabolites such as neuroactive steroids, oxysterols and steroid hormones. It is well known that these endogenous molecules affect several receptor classes, including ionotropic GABAergic and NMDA glutamatergic receptors in neurons. It has been shown that also ionotropic purinergic (P2X) receptors are cholesterol metabolites' targets. Among P2X receptors, purinergic P2X4 and P2X7 receptors are expressed in microglia, the innate immune cells involved in the brain inflammatory response. In this study, we explore the ionotropic purinergic receptors modulation by cholesterol metabolites in microglia. Patch-clamp experiments were performed in BV2 cells, a murine microglia cell line, to evaluate effects of cholesterol metabolites using micro- and nanomolar concentrations. About P2X4 receptor, we found that testosterone butyrate (20 μM and 200 nM) and allopregnanolone (10 μM and 100 nM) both potentiated its current, while neither 25-hydroxycholesterol (10 μM and 100 nM) nor 17β-estradiol (1 μM) showed any effects. On the other hand, P2X7 receptor current was potentiated by allopregnanolone (10 μM) and 25-hydroxycholesterol (10 μM and 100 nM). Taken together, our data show that modulation of either P2X4 and P2X7 current is affected differently by cholesterol metabolites, suggesting a structure-activity relationship among these players. Identifying the possible link between purinergic transmission, microglia and cholesterol metabolites will allow to define new targets for drug development to treat neuroinflammation.

Keywords:  Microglia; Neuroactive steroids; Neuroinflammation; Oxysterols; P2X4 receptor; P2X7 receptor

DOI:  https://doi.org/10.1016/j.neuropharm.2024.110294
J Alzheimers Dis. 2025 Jan 10. 13872877241307337

SMOC2 promotes microglia activity and neuroinflammation in Alzheimer's disease.

Tianchi Wan, Chunkai Wang.

   BACKGROUND: Alzheimer's disease (AD), the leading cause of dementia, is characterized by cognitive decline and the accumulation of amyloid-β (Aβ). It affects millions, with numbers expected to double by 2050. SMOC2, implicated in inflammation and fibrosis, may play a role in AD pathogenesis, particularly in microglial cell function, offering a potential therapeutic target.
OBJECTIVE: Alzheimer's disease (AD) leads to neurodegeneration, affecting cognition, language, and personality, underscoring the urgency for effective treatments. Our study investigates the role of secreted modular calcium-binding protein 2 (SMOC2) in microglial cells and its impact on AD pathology.
METHODS: We introduced SMOC2 overexpression and interference vectors into microglial cells treated with Aβ. Activity and phagocytosis were assessed using CCK8 and flow cytometry. SMOC2 mRNA levels were quantified by qPCR, and protein levels of SMOC2, TGF-β1, p-NF-κB/NF-κB were analyzed by western blot. Aβ content was determined by ELISA, and immunofluorescence detected TNF-α, IL-1β, CD163, and CD206.
RESULTS: Aβ treatment inhibited microglial activity and phagocytosis, but SMOC2 disruption enhanced these functions (p < 0.05). SMOC2 overexpression increased its expression and Aβ levels, while interference reduced them (p < 0.001). SMOC2 overexpression also decreased TGF-β1, CD163, and CD206, and increased p-NF-κB/NF-κB, TNF-α, and IL-1β (p < 0.05).
CONCLUSIONS: SMOC2 plays a crucial role in microglial cell activity, phagocytosis, and polarization, potentially through the TGF-β1/NF-κB pathway, offering insights into AD pathogenesis.

Keywords:  Alzheimer's disease; NF-κB; SMOC2; TGF-β1; amyloid-β protein; microglia

DOI:  https://doi.org/10.1177/13872877241307337
Sci Adv. 2025 Jan 10. 11(2): eadr8687

Cpeb1 remodels cell type-specific translational program to promote fear extinction.

Juan Zhang, Chun-Qing Yang, Zhi-Qiang Liu, Shi-Ping Wu, Zu-Guang Li, Luo-Man Zhang, Hong-Wei Fan, Zi-Yuan Guo, Heng-Ye Man, Xiang Li, You-Ming Lu, Ling-Qiang Zhu, Dan Liu.

Protein translation is crucial for fear extinction, a process vital for adaptive behavior and mental health, yet the underlying cell-specific mechanisms remain elusive. Using a Tet-On 3G genetic approach, we achieved precise temporal control over protein translation in the infralimbic medial prefrontal cortex (IL) during fear extinction. In addition, our results reveal that the disruption of cytoplasmic polyadenylation element binding protein 1 (Cpeb1) leads to notable alterations in cell type-specific translational programs, thereby affecting fear extinction. Specifically, Cpeb1 deficiency in neurons activates the translation of heterochromatin protein 1 binding protein 3, which enhances microRNA networks, whereas in microglia, it suppresses the translation of chemokine receptor 1 (Cx3cr1), resulting in an aged-like microglial phenotype. These coordinated alterations impair spine formation and plasticity. Our study highlights the critical role of cell type-specific protein translation in fear extinction and provides an insight into therapeutic targets for disorders with extinction deficits.

DOI: https://doi.org/10.1126/sciadv.adr8687
J Vis Exp. 2024 Dec 20.

Identification of EcoHIV-Infected Cells in Microglia-Manipulated Transgenic Mice.

Hailong Li, Makensie Walker, Hao Ji, Aliaksandra Sikirzhytskaya, Marina Aksenova, Michael Shtutman, Vitali Sikirzhytski, Charles F Mactutus, Rosemarie M Booze.

Combined antiretroviral therapy (cART) has dramatically improved the quality of life for people living with HIV (PLWH). However, over 4 million PLWH are over the age of fifty and experience accompanying HIV-associated neurocognitive disorders (HAND). To understand how HIV impacts the central nervous system, a reliable and feasible model of HIV is necessary. Previously, a novel biological system using chimeric HIV (EcoHIV) inoculation was developed in a rat model to investigate neurocognitive impairments and synaptic dysfunction. Nevertheless, a significant challenge remains in clarifying EcoHIV's neuroanatomical distribution, particularly its differential expression in various cell types in the brain. In the current study, EcoHIV with mScarlet fluorescence labeling was modified and retro-orbitally injected into Tmem119-EGFP knock-in mice (which express enhanced green fluorescence protein primarily in microglia) to determine if microglia are the major cell type responsible for viral expression and reservoirs of HIV in the brain. The current data show that: (1) in vitro, EcoHIV-mScarlet fluorescence signals were predominantly localized in microglia-like cells among primary rodent brain cells; (2) in vivo, injection of EcoHIV-mScarlet into Tmem119-EGFP mice induced significant HIV expression in the mouse brain. The co-localization of mScarlet and EGFP signals suggests that microglia are the main cell type harboring HIV in the brain. Overall, EcoHIV in rodents offers a valuable biological system to study microglial alterations, viral reservoirs in the brain, and the neurological mechanisms of HIV-associated neurocognitive disorders.

DOI: https://doi.org/10.3791/67150
bioRxiv. 2024 Dec 17. pii: 2024.12.12.628145. [Epub ahead of print]

Modulatory Effects of Mdivi-1 on OxLDL-Induced Metabolic Alterations, Inflammatory Responses, and Foam Cell Formation in Human Monocytes.

Negin Mosalmanzadeh, Rafael Moura Maurmann, Kierstin Davis, Brenda Landvoigt Schmitt, Liza Makowski, Brandt D Pence.

Atherosclerosis, a major contributor to cardiovascular disease, involves lipid accumulation and inflammatory processes in arterial walls, with oxidized low-density lipoprotein (OxLDL) playing a central role. OxLDL is increased during aging and stimulates monocyte transformation into foam cells and induces metabolic reprogramming and pro-inflammatory responses, accelerating atherosclerosis progression and contributing to other age-related diseases. This study investigated the effects of Mdivi-1, a mitochondrial fission inhibitor, and S1QEL, a selective complex I-associated reactive oxygen species (ROS) inhibitor, on OxLDL-induced responses in monocytes. Healthy monocytes isolated from participants were treated with OxLDL, with or without Mdivi-1 or S1QEL, and assessed for metabolic shifts, inflammatory cytokine expression, foam cell formation, and ROS production. OxLDL treatment elevated glycolytic activity (ECAR) and expression of pro-inflammatory cytokines IL1B and CXCL8, promoting foam cell formation and mitochondrial ROS (mtROS) production. Mdivi-1 and S1QEL effectively reduced OxLDL-induced glycolytic reprogramming, inflammatory cytokine levels, and foam cell formation while limiting mtROS. These findings suggest that both Mdivi-1 and S1QEL modulate key monocyte responses to OxLDL, providing insights into potential therapeutic approaches for age-related diseases.

DOI: https://doi.org/10.1101/2024.12.12.628145
PLoS One. 2025 ;20(1): e0314020

LFA-1: A potential key player in microglia-mediated neuroprotection against oxygen-glucose deprivation in vitro.

Robin Jansen, Marc Pawlitzki, Michael Gliem, Sven G Meuth, Stefanie Schreiber, Michael-W Görtler, Jens Neumann.

For the last 38 years, all neuroprotective agents for patients with ischemic stroke have failed in clinical trials. The innate immune system, particularly microglia, is a much-discussed target for neuroprotective agents. Promising results for neuroprotection by inhibition of integrins with drugs such as natalizumab in animal stroke models have not been translated into clinical practice. Our present study reveals the relevance of a β2 integrin, lymphocyte function-associated antigen-1 (LFA-1), as a potential key player in protecting neuronal cell death after oxygen-glucose deprivation in organotypic hippocampal cell cultures. In addition, we identified microglial cells as effector cells for LFA-1-mediated neuroprotection. The counterpart of LFA-1 on microglia is unclear, but we show strong expression of ICAM-5 in hippocampal neurons, suggesting a critical role for direct crosstalk between microglia and neurons for neuronal survival under oxygen-glucose deprivation. The enigma of neuroprotection after ischemic stroke remains to be solved, and our findings highlight the continuing importance and lack of understanding of integrin-mediated pathways after ischemic stroke and the need for further intensive research.

DOI: https://doi.org/10.1371/journal.pone.0314020
CNS Neurol Disord Drug Targets. 2025 Jan 08.

Anti-neuroinflammatory and Neuroprotective Effects of T-006 on Alzheimer's Disease Models by Modulating TLR4-Mediated MyD88/ NF-κB Signaling.

Haiyun Chen, Xiao Chang, Jiemei Zhou, Guiliang Zhang, Jiehong Cheng, Zaijun Zhang, Jieyu Xing, Chunyan Yan, Zheng Liu.

   INTRODUCTION: Neuroinflammation derived from the activation of the microglia is considered a vital pathogenic factor of Alzheimer's Disease (AD). T-006, a tetramethylpyrazine derivative, has been found to alleviate cognitive deficits via inhibiting tau expression and phosphorylation in AD transgenic mouse models. Recently, T-006 has been proven to dramatically decrease the levels of total Amyloid β (Aβ) peptide and Glial Fibrillary Acidic Protein (GFAP) and suppress the expression of ionized calcium binding adaptor molecule-1 (Iba-1) in APP/PS1 mice. Therefore, we have further investigated the effects of T-006 on neuroinflammation in AD-like pathology.
METHODS: The anti-inflammatory effects of T-006 and its underlying mechanisms were evaluated in Lipopolysaccharide (LPS)-induced AD rats. The potential protective effects against LPS-activated microglia-mediated neurotoxicity were also measured.
RESULTS: T-006 significantly improved the cognitive impairment in LPS-induced AD rats by inhibiting the microglia/astrocyte activation. Further cellular assays found that T-006 significantly reserved the anomalous elevation of inflammatory cytokines in LPS-induced BV2 microglial cells in a concentration-dependent manner, while T-006 treatment alone showed no effects on the normal cultured cells. T-006 also reduced the levels of Toll-like Receptor 4 (TLR4)/Myeloid Differentiation protein-88 (MyD88)/NF-κB signaling-related proteins in BV2 cells exposed to LPS stimulation. TAK242, which selectively inhibits TLR4, slightly lessened the effects of T-006 in LPS-treatment BV2 cells without significance. Importantly, T-006 protected neurons against LPS-induced neuroinflammation by inhibiting the Reactive Oxygen Species (ROS) production and maintaining mitochondrial function.
CONCLUSION: T-006 inhibited TLR4-mediated MyD88/NF-κB signaling pathways to suppress neuroinflammation in the LPS-induced AD rat model.

Keywords:  Alzheimer's disease.; MyD88/NF-κB signaling pathways; T-006; TLR4; Tetramethylpyrazine derivative; microglial activation; neuroinflammation

DOI:  https://doi.org/10.2174/0118715273337232241121113048