bims-microg Biomed News
on Microglia in health and disease
Issue of 2025–05–18
28 papers selected by
Marcus Karlstetter, Universität zu Köln
  1. Immunotherapy-related cognitive impairment after CAR T cell therapy in mice.
  2. Microglial TMEM119 binds to amyloid-β to promote its clearance in an Aβ-depositing mouse model of Alzheimer's disease.
  3. Intermittent fasting reduces alpha-synuclein pathology and functional decline in a mouse model of Parkinson's disease.
  4. NeuroD1 induces microglial apoptosis and cannot induce microglia-to-neuron cross-lineage reprogramming.
  5. Microglial MS4A4A Protects against Epileptic Seizures in Alzheimer's Disease.
  6. Investigating post-infection anxiety- and depression-like behaviors in a SARS-CoV-2 mouse model.
  7. Traffic-related diesel pollution particles impair the lysosomal functions of human iPSC-derived microglia.
  8. Dampening of Microglial Activation With Nasal Foralumab Administration in Moderate Alzheimer's Disease Dementia.
  9. Adipocyte metabolic state regulates glial phagocytic function.
  10. Single-Cell RNA-Seq Reveals Aging-Related Impairment of Microglial Efferocytosis Contributing to Apoptotic Cells Accumulation After Retinal Injury.
  11. Microglia Single-Cell RNA-Seq Enables Robust and Applicable Markers of Biological Aging.
  12. Human and Mouse Alzheimer's Seeds Differentially Affect Amyloid Deposition and Microglia-Dependent Plaque Response in Aged Mice.
  13. SGLT2 Inhibition by Enavogliflozin Significantly Reduces Aβ Pathology and Restores Cognitive Function via Upregulation of Microglial AMPK Signaling in 5XFAD Mouse Model of Alzheimer's Disease.
  14. OPA1 Enhances Microglial Amyloid-β Clearance and Alleviates Cognitive Impairments in an Alzheimer's Disease Model.
  15. Retrotransposon Protein L1 ORF1p Expression in Aging Central Nervous System.
  16. Reduction of D2 receptors on microglia leads to ZBP1-mediated PANoptosis of mPFC in Parkinson's disease depression mice.
  17. Deer Antler Uridine Regulates Glycolysis in Microglia via HSP90/HIF-1α to Improve Cognitive Impairment in Alzheimer's Disease Mice.
  18. TSPO deficiency exacerbates acute brain damage after intracerebral hemorrhage in male mice.
  19. Non-linear microglial, inflammatory and oligodendrocyte dynamics across stages of Alzheimer's disease.
  20. Single intracerebroventricular TNFR2 agonist injection impacts remyelination in the cuprizone model.
  21. PU.1 dictates β-amyloid-induced TREM2 expression upregulation in microglia in a transgenic model of Alzheimer's disease.
  22. NTN-1 attenuates amyloid-β-mediated microglial neuroinflammation and memory impairment via the NF-κB pathway and NLRP3 inflammasome in a rat model of Alzheimer's disease.
  23. Microglial TAK1 promotes neurotoxic astrocytes and cognitive impairment in LPS-induced hippocampal neuroinflammation.
  24. The potential and challenges of TREM2-targeted therapy in Alzheimer's disease: insights from the INVOKE-2 study.
  25. Coupling relationship between glucose and oxygen metabolisms to serve as an imaging biomarker for Alzheimer's disease.
  26. Mechanisms of Acetate in Alleviating SETDB1-Linked Neuroinflammation and Cognitive Impairment in a Mouse Model of OSA.
  27. Suppressing TLR4 alleviates cerebral injury in heatstroke rats through the modulation of microglial polarization.
  28. Oleanolic Acid Alleviates Neuronal Ferroptosis in Subarachnoid Hemorrhage by Inhibiting KEAP1-Nrf2 and NF-κB Pathways.
  1. Cell. 2025 May 07. pii: S0092-8674(25)00391-5. [Epub ahead of print]
    Immunotherapy-related cognitive impairment after CAR T cell therapy in mice.
    Anna C Geraghty, Lehi Acosta-Alvarez, Maria C Rotiroti, Selena Dutton, Michael R O'Dea, Wonju Kim, Vrunda Trivedi, Rebecca Mancusi, Kiarash Shamardani, Karen Malacon, Pamelyn J Woo, Naiara Martinez-Velez, Theresa Pham, Noemi N Reche-Ley, Gabriel Otubu, Enrique H Castenada, Kamsi Nwangwu, Haojun Xu, Sara B Mulinyawe, Daniel B Zamler, Lijun Ni, Kevin Cross, Justin Rustenhoven, Jonathan Kipnis, Shane A Liddelow, Crystal L Mackall, Robbie G Majzner, Michelle Monje.
      Immunotherapies have revolutionized cancer care for many tumor types, but their potential long-term cognitive impacts are incompletely understood. Here, we demonstrated in mouse models that chimeric antigen receptor (CAR) T cell therapy for both central nervous system (CNS) and non-CNS cancers impaired cognitive function and induced a persistent CNS immune response characterized by white matter microglial reactivity, microglial chemokine expression, and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis were disrupted. Single-nucleus sequencing studies of human frontal lobe from patients with or without previous CAR T cell therapy for brainstem tumors confirmed reactive states of microglia and oligodendrocytes following treatment. In mice, transient microglial depletion or CCR3 chemokine receptor blockade rescued oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function following CAR T cell therapy. Taken together, these findings illustrate targetable neural-immune mechanisms underlying immunotherapy-related cognitive impairment.
    Keywords:  ALL; CAR T cell therapy; CRCI; DMG; IRCI; acute lymphoblastic leukemia; cancer therapy-related cognitive impairment; chemokines; diffuse midline glioma; immunotherapy-related cognitive impairment; microglia; myelin; oligodendrocytes
    DOI:  https://doi.org/10.1016/j.cell.2025.03.041
  2. Immunity. 2025 May 09. pii: S1074-7613(25)00181-5. [Epub ahead of print]
    Microglial TMEM119 binds to amyloid-β to promote its clearance in an Aβ-depositing mouse model of Alzheimer's disease.
    Jing Liu, Zhimeng Wang, Wenwen Liang, Zhenhao Zhang, Yusen Deng, Xiaowei Chen, Zongren Hou, Yuanzhi Xie, Qi Wang, Yuan Li, Chaobo Bai, Da Li, Fan Mo, Huinan Wang, Dongmei Wang, Junliang Yuan, Yukai Wang, Zhao-Qian Teng, Baoyang Hu.
      The progression of Alzheimer's disease (AD) involves temporal dynamics of microglial activation. Restoring or maintaining microglial homeostasis has emerged as a promising therapeutic strategy to combat AD. Transmembrane protein 119 (TMEM119) is a homeostatic marker of microglia but has not been fully studied under AD pathological conditions. Here, we observed that amyloid-beta (Aβ) induced a decrease in TMEM119 expression in microglia, and TMEM119 deficiency increased AD progression in the 5×FAD mouse model. TMEM119 bound to Aβ oligomers and recruited low-density lipoprotein receptor 1, which in turn degraded TMEM119 itself. Overexpression of TMEM119 in microglia enhanced their phagocytic activity and alleviated cognitive deficits in 5xFAD mice. Administration of the small molecules Kartogenin and SRI-011381, which we found enhanced TMEM119 expression, substantially promoted Aβ clearance and improved cognitive function in AD mice, even during the mid-stage of the disease. These findings identify TMEM119 as a promising therapeutic target for AD.
    Keywords:  Alzheimer’s disease; LRP1; TMEM119; microglial homeostasis
    DOI:  https://doi.org/10.1016/j.immuni.2025.04.018
  3. Nat Commun. 2025 May 14. 16(1): 4470
    Intermittent fasting reduces alpha-synuclein pathology and functional decline in a mouse model of Parkinson's disease.
    Éva M Szegő, Lennart Höfs, Anna Antoniou, Elisabeth Dinter, Nadine Bernhardt, Anja Schneider, Donato A Di Monte, Björn H Falkenburger.
      Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron degeneration and α-synuclein (aSyn) accumulation. Environmental factors play a significant role in PD progression, highlighting the potential of non-pharmacological interventions. This study investigates the therapeutic effects of intermittent fasting (IF) in an rAAV-aSyn mouse model of PD. IF, initiated four weeks post-induction of aSyn pathology, improved motor function and reduced dopaminergic neuron and axon terminal degeneration. Additionally, IF preserved dopamine levels and synaptic integrity in the striatum. Mechanistically, IF enhanced autophagic activity, promoting phosphorylated-aSyn clearance and reducing its accumulation in insoluble brain fractions. Transcriptome analysis revealed IF-induced modulation of inflammation-related genes and microglial activation. Validation in primary cultures confirmed that autophagy activation and inflammatory modulators (CCL17, IL-36RN) mitigate aSyn pathology. These findings suggest that IF exerts neuroprotective effects, supporting further exploration of IF and IF-mimicking therapies as potential PD treatments.
    DOI:  https://doi.org/10.1038/s41467-025-59249-5
  4. Neuron. 2025 May 13. pii: S0896-6273(25)00353-8. [Epub ahead of print]
    NeuroD1 induces microglial apoptosis and cannot induce microglia-to-neuron cross-lineage reprogramming.
    Yanxia Rao, Siling Du, Baozhi Yang, Yuqing Wang, Yuxin Li, Ruofan Li, Tian Zhou, Xiangjuan Du, Yang He, Yafei Wang, Xin Zhou, Ti-Fei Yuan, Ying Mao, Bo Peng.
      
    DOI:  https://doi.org/10.1016/j.neuron.2025.05.006
  5. Adv Sci (Weinh). 2025 May 11. e2417733
    Microglial MS4A4A Protects against Epileptic Seizures in Alzheimer's Disease.
    Meng Jiang, Qingqing Li, Jianhui Chen, Ruochong Li, Jun Yao, Yong Hu, Haizheng Zhang, Lixin Cai, Maoguo Luo, Yu Sun, Wenwen Zeng.
      Alzheimer's disease (AD) is a predominant neurodegenerative disorder worldwide, with epileptic seizures being a common comorbidity that can exacerbate cognitive deterioration in affected individuals, thus highlighting the importance of early therapeutic intervention. It is determined that deletion of Ms4a4a, an AD-associated gene, exacerbates seizures in amyloid β (Aβ)-driven AD mouse model. MS4A4A is significantly upregulated in brain lesions in patients with epilepsy. Single-cell sequencing reveals that MS4A4A is highly expressed in microglia within these lesions, linked to enhanced phagocytic activity. Mechanistic investigation delineates that deletion of Ms4a4a impairs microglial phagocytosis, accompanied by diminished calcium influx and disruptions in mitochondrial metabolic fitness. The cytosolic fragment of Ms4a4a is anchored to the cytoskeletal components, supporting its critical role in mediating phagocytosis. Induction of Ms4a4a through central delivery of LNP-Il4 alleviates seizure conditions. Collectively, these findings identify Ms4a4a as a potential therapeutic target for managing seizures in AD treatment.
    Keywords:  Alzheimer's disease; MS4A4A; epilepsy; microglia; phagocytosis
    DOI:  https://doi.org/10.1002/advs.202417733
  6. Theranostics. 2025 ;15(12): 5738-5755
    Investigating post-infection anxiety- and depression-like behaviors in a SARS-CoV-2 mouse model.
    Qian Ge, Shan Zhou, Jose Porras, Panfeng Fu, Ting Wang, Jianyang Du, Kun Li.
      Rationale: The COVID-19 pandemic, driven by SARS-CoV-2, has resulted in a wide range of neuropsychiatric symptoms associated with post-acute sequelae (PASC). However, the mechanisms by which SARS-CoV-2 impacts the brain and leads to persistent behavioral changes remain poorly understood. We hypothesize that SARS-CoV-2 exposure induces neuroinflammation and microglial activation, leading to anxiety- and depression-like behaviors in mice. Methods: We established a SARS-CoV-2 mouse model using the virulent SARS2-N501YMA30 strain to investigate its impact on the central nervous system (CNS). We assessed neuroinvasion via immunostaining of dsRNA and markers for neuronal, astrocyte, and microglia in brain slices. Behavioral changes were evaluated at 2 weeks, 2 months, and 4 months post-infection. Molecular and cellular analyses included bulk RNA-seq, Golgi-Cox staining, field excitatory postsynaptic potential (fEPSP) recordings, immunofluorescence, and quantitative real-time PCR (qRT-PCR) to assess gene expression, neuronal morphology, and microglial activation in the brain. Results: We demonstrated that intranasal inoculation of SARS2-N501YMA30 results in viral dissemination to multiple brain regions, including the amygdala and the prefrontal cortex (PFC). Behavioral assays indicated a marked elevation in anxiety- and depression-like behaviors post-infection. A comparative analysis of RNA expression profiles disclosed alterations in the post-infected brains. Additionally, we observed dendritic spine remodeling on neurons within the amygdala after infection. Infection with SARS2-N501YMA30 was associated with microglial activation and a subsequent increase in microglia-dependent neuronal activity in the amygdala. Transcriptomic analysis of infected brains revealed the upregulation of inflammatory and cytokine-related pathways, implicating neuroinflammation in the pathogenesis of neuronal hyperactivity and behavioral abnormality. Conclusion: Our findings provide evidence that SARS-CoV-2 neuroinvasion plays a critical role in the development of lasting behavioral sequelae observed in PASC. These data provide critical insights into the neurological consequences of SARS-CoV-2 infection and underscore microglia as a potential therapeutic target for ameliorating virus-induced neurobehavioral abnormalities.
    Keywords:  Amygdala; Anxiety- and depression-like behaviors.; Microglia; Post-acute sequelae of COVID-19; SARS-CoV-2
    DOI:  https://doi.org/10.7150/thno.102752
  7. Environ Int. 2025 May 05. pii: S0160-4120(25)00218-1. [Epub ahead of print]199 109467
    Traffic-related diesel pollution particles impair the lysosomal functions of human iPSC-derived microglia.
    Sohvi Ohtonen, Henna Jäntti, Luca Giudice, Ahmed Mohamed, Anastasia Shakirzyanova, Táňa Závodná, Ilya Belevich, Hong Yan, Angélica María Sabogal-Guáqueta, Liudmila Saveleva, Mari-Anna Väänänen, Ashley Rillo-Albert, Elisa Perciballi, Daniela Ferrari, Minna-Mari Tervo, Mireia Gómez-Budia, Zdeněk Krejčík, Päivi Aakko-Saksa, Jari Koistinaho, Šárka Lehtonen, Katja M Kanninen, Jan Topinka, Eija Jokitalo, Alejandra Sierra, Martina Schmidt, Amalia M Dolga, Pasi I Jalava, Paula Korhonen, Tarja Malm.
      Exposure to air pollution is associated with neurological diseases. Traffic is a major source of air pollution, consisting of a complex mixture of ultrafine particles, that can invade the brain and induce a microglia-mediated inflammatory response. However, the exact mechanisms of how traffic-related particles impact human microglia remain poorly understood. This study investigates the effects of diesel exhaust particles (DEPs) on human induced pluripotent stem cell-derived microglia-like cells (iMGL). We exposed iMGLs to three different DEPs and studied the impact on the iMGL transcriptome and functionality, focusing on cytokine secretion, mitochondrial respiration, lysosomal function, and phagocytosis. A20 particles were collected from a heavy-duty engine run with petroleum diesel. For A0, the same engine was run with renewable diesel. E6 was produced with a modern 2019 model diesel passenger car run with renewable diesel. RNAseq revealed activation of the cytokine storm pathway and inhibition of the autophagy pathway in iMGLs after exposure to particles derived from older diesel emission technology (A20, A0). Particles from the modern diesel engine technology (E6) did not alter microglial transcriptome after 24 h exposure. A20 and A0 exposure led to impaired lysosomal functions in iMGLs. In contrast, E6 did not cause major alterations in microglia functions. In addition, we show that response to particles is more pronounced in human iMGLs compared to mouse primary microglia. To conclude, particles from older emission technology impair phago-lysosomal functions of iMGLs, but modern alternatives with filtration do not induce drastic changes in the functionality of iMGLs.
    Keywords:  Air pollution; Diesel; Human microglia; Lysosome; iPSC
    DOI:  https://doi.org/10.1016/j.envint.2025.109467
  8. Clin Nucl Med. 2025 May 13.
    Dampening of Microglial Activation With Nasal Foralumab Administration in Moderate Alzheimer's Disease Dementia.
    Tarun Singhal, Steven Cicero, Seth A Gale, Nicolas Horan, Shipra Dubey, Gad A Marshall, Howard L Weiner.
      A 78-year-old man with moderate Alzheimer disease (AD) dementia was treated with nasal-foralumab, a fully human anti-CD3 monoclonal antibody, as part of a Food and Drug Administration expanded-access-program, based on previously demonstrated efficacy of anti-CD3 antibody in animal models. 18F-PBR06-PET, utilizing a second-generation 18-kDa-translocator-protein ligand targeting microglia, showed diffuse reduction of radiotracer uptake throughout the brain, following 3 months of nasal-foralumab compared with baseline. In particular, precuneus, posterior cingulate and anterior cingulate gyri, regions that had high levels of amyloid deposition on a baseline 18F-Florbetapir-PET scan, showed reduction in microglial activation after nasal-foralumab treatment for 3 months.
    Keywords:  Alzheimer’s disease; TSPO-PET; microglia; nasal foralumab; neuroinflammation
    DOI:  https://doi.org/10.1097/RLU.0000000000005955
  9. Cell Rep. 2025 May 14. pii: S2211-1247(25)00475-9. [Epub ahead of print]44(5): 115704
    Adipocyte metabolic state regulates glial phagocytic function.
    Mroj Alassaf, Aditi Madan, Sunidhi Ranganathan, Shannon Marschall, Jordan J Wong, Zachary H Goldberg, Ava E Brent, Akhila Rajan.
      Excess dietary sugar profoundly impacts organismal metabolism and health, yet it remains unclear how metabolic adaptations in adipose tissue influence other organs, including the brain. Here, we show that a high-sugar diet (HSD) in Drosophila reduces adipocyte glycolysis and mitochondrial pyruvate uptake, shifting metabolism toward fatty acid oxidation and ketogenesis. These metabolic changes trigger mitochondrial oxidation and elevate antioxidant responses. Adipocyte-specific manipulations of glycolysis, lipid metabolism, or mitochondrial dynamics non-autonomously modulate Draper expression in brain ensheathing glia, key cells responsible for neuronal debris clearance. Adipocyte-derived ApoB-containing lipoproteins maintain basal Draper levels in glia via LpR1, critical for effective glial phagocytic activity. Accordingly, reducing ApoB or LpR1 impairs glial clearance of degenerating neuronal debris after injury. Collectively, our findings demonstrate that dietary sugar-induced shifts in adipocyte metabolism substantially influence brain health by modulating glial phagocytosis, identifying adipocyte-derived ApoB lipoproteins as essential systemic mediators linking metabolic state with neuroprotective functions.
    Keywords:  ApoB; CP: Metabolism; CP: Neuroscience; Drosophila; OxPhos; adipokine; glycolysis; high-sugar diet; injury-response; ketogenesis; lipid metabolism; mitochondria; neurodegeneration; pyronic sensor
    DOI:  https://doi.org/10.1016/j.celrep.2025.115704
  10. Aging Cell. 2025 May 15. e70097
    Single-Cell RNA-Seq Reveals Aging-Related Impairment of Microglial Efferocytosis Contributing to Apoptotic Cells Accumulation After Retinal Injury.
    Pan Liu, Qi Wang, Shuimiao Wang, Ying Liu, Qiqi Chen, Wanyun Qin, Xinna Liu, Xinqi Ye, Yexuan Jiao, Huiping Yuan, Zhengbo Shao.
      Aging is associated with increased retinal cell apoptosis, which contributes to decreases in retinal function. Apoptotic retinal cell clearance relies on microglial efferocytosis, but the impact of aging on this process has not been fully elucidated. In this study, we aimed to shed light on this by using single-cell RNA sequencing (sc-RNA-seq) to compare young and aged mouse retinal transcriptional profiles, in which 74,412 retinal cells from young and aged mice were classified into 10 transcriptionally distinct retinal cell types, and differentially expressed genes between young versus aged retinas were mainly associated with cellular senescence and apoptosis. Furthermore, ligand-receptor interactions (e.g., AXL-GAS6, MERTK-GAS6) between microglia and other retinal cells were strengthened in aged, compared to young retinas. Additionally, among microglia, Subcluster 4 was found under partial clustering to be associated with efferocytosis, of which aged microglia had downregulated efferocytosis-associated genes. The impact of aging on microglial efferocytosis was further verified in vitro by doxorubicin (DOX)-induced senescent BV2 microglia, and in vivo by a retinal ischemia/reperfusion (I/R) injury mouse model. In vitro, DOX-treated BV2 microglia had significantly lowered efferocytosis, as well as efferocytosis-related MerTK and Axl protein expression; this was also present in vivo in aged retinas post-I/R injury, with increased co-localization of ionized calcium-binding adapter molecule 1+ microglia with apoptotic retinal cells, along with reduced efferocytosis-related protein expression. Overall, microglial efferocytosis of apoptotic cells decreased with aging, suggesting that modulating this process could serve as a possible therapeutic target for age-related retinal diseases.
    Keywords:  aging; apoptosis; efferocytosis; microglia; retina; single‐cell RNA sequencing
    DOI:  https://doi.org/10.1111/acel.70097
  11. Aging Cell. 2025 May 15. e70095
    Microglia Single-Cell RNA-Seq Enables Robust and Applicable Markers of Biological Aging.
    Natalie Stanley, Luvna Dhawka, Sneha Jaikumar, Yu-Chen Huang, Anthony S Zannas.
      "Biological aging clocks"-composite molecular markers thought to capture an individual's biological age-have been traditionally developed through bulk-level analyses of mixed cells and tissues. However, recent evidence highlights the importance of gaining single-cell-level insights into the aging process. Microglia are key immune cells in the brain shown to adapt functionally in aging and disease. Recent studies have generated single-cell RNA-sequencing (scRNA-seq) datasets that transcriptionally profile microglia during aging and development. Leveraging such datasets in humans and mice, we develop and compare computational approaches for generating transcriptome-wide summaries from microglia to establish robust and applicable aging clocks. Our results reveal that unsupervised, frequency-based summarization approaches, which encode distributions of cells across molecular subtypes, strike a balance in accuracy, interpretability, and computational efficiency. Notably, our computationally derived microglia markers achieve strong accuracy in predicting chronological age across three diverse single-cell datasets, suggesting that microglia exhibit characteristic changes in gene expression during aging and development that can be computationally summarized to create robust markers of biological aging. We further extrapolate and demonstrate the applicability of single-cell-based microglia clocks to readily available bulk RNA-seq data with an environmental input (early life stress), indicating the potential for broad utility of our models across genomic modalities and for testing hypotheses about how environmental inputs affect brain age. Such single-cell-derived markers can yield insights into the determinants of brain aging, ultimately promoting interventions that beneficially modulate health and disease trajectories.
    Keywords:  markers of biological aging; microglia; single‐cell RNA sequencing; transcriptomics
    DOI:  https://doi.org/10.1111/acel.70095
  12. Aging Cell. 2025 May 13. e70094
    Human and Mouse Alzheimer's Seeds Differentially Affect Amyloid Deposition and Microglia-Dependent Plaque Response in Aged Mice.
    Juana Andreo-Lopez, Cristina Nuñez-Diaz, Kelly Do Huynh, Marie Minh Thu Nguyen, Celia Da Cunha, Francisco J Cantero-Molina, Cynthia Campos-Moreno, Stefania Zimbone, Francesco Bellia, Maria Laura Giuffrida, Laura Trujillo-Estrada, Juan Antonio Garcia-Leon, Miriam Bettinetti-Luque, Nazaret Gamez, Catalina Valdes, Rodrigo Morales, Stefania Forner, Alessandra C Martini, Antonia Gutierrez, Frank M LaFerla, David Baglietto-Vargas.
      Alzheimer's disease (AD) is a complex neurodegenerative proteinopathy in which Aβ and tau misfold and aggregate into entities that structurally unsettle native proteins, mimicking a prion-like or "seeding" process. These Aβ and tau "seeds" can arrange in different conformations or strains that might display distinct pathogenic properties. Furthermore, recent evidence suggests that microglia play a key role in the amyloidogenic event and can modulate the propagation and aggregation processes. Here, we employed histological and molecular approaches to determine whether seeds from human AD brains compared to those from transgenic mice (3xTg-AD) are more prone to induce Aβ and tau aggregates in vivo, as well as potential differences in the microglial response to the plaque pathology. Brain homogenates were injected into the hippocampus of 3xTg-AD mice and hAβ-KI mice and examined at 18-20 months of age. The seeds from the human AD brain induced more aggressive amyloid pathology compared to seeds from aged 3xTg-AD mice. However, the AD seeds from aged transgenic mice triggered more tau pathology. Interestingly, such mice seeds impaired microglial clustering around plaques, leading to more severe neuritic pathology. Furthermore, the human AD seeds injected into the hippocampus of hAβ-KI mice were not able to induce plaque formation. These results suggest that multiple variables such as the AD seed, recipient model, and time are critical factors that can modulate the amyloid pathology onset and progression. Thus, more profound understanding of these factors will provide key insight into how amyloid and tau pathology progresses in AD.
    Keywords:  Alzheimer's disease; amyloid‐beta; inflammation; propagation; seeds; tau; transgenic mice
    DOI:  https://doi.org/10.1111/acel.70094
  13. Aging Cell. 2025 May 10. e70101
    SGLT2 Inhibition by Enavogliflozin Significantly Reduces Aβ Pathology and Restores Cognitive Function via Upregulation of Microglial AMPK Signaling in 5XFAD Mouse Model of Alzheimer's Disease.
    Jihui Han, Jaehoon Song, Eun Sun Jung, Ji Won Choi, Hye Young Ji, Inhee Mook-Jung.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. Metabolic dysfunctions, particularly type 2 diabetes mellitus (T2DM), have been implicated in AD pathogenesis, highlighting the potential for novel therapeutic approaches targeting shared underlying mechanisms. Here, we investigate sodium-glucose cotransporter 2 (SGLT2) inhibition as a therapeutic strategy for AD using Enavogliflozin, a potent SGLT2 inhibitor, in the 5XFAD mouse model. Five-month-old 5XFAD mice were treated with Enavogliflozin (0.1 or 1 mg/kg) or vehicle for 8 weeks. The higher dose significantly improved cognitive performance in Y-maze and Morris Water Maze tests, which correlated with enhanced synaptic plasticity and increased acetylcholine levels. Moreover, Enavogliflozin treatment reduced Aβ pathology and plaque burden, particularly affecting larger plaques. Mechanistically, SGLT2 inhibition attenuated neuroinflammation by suppressing NF-κB signaling and proinflammatory cytokine production while promoting microglial recruitment to plaques. In vitro and ex vivo analyses further revealed that Enavogliflozin enhances microglial phagocytic capacity via AMPK-mediated mitochondrial biogenesis and function. These findings highlight the multifaceted neuroprotective effects of SGLT2 inhibition in AD, demonstrating its potential to mitigate pathology and improve cognitive function. By uncovering its impact on neuroinflammation and microglial function, this study establishes SGLT2 inhibition as a promising therapeutic avenue for AD and other neurodegenerative disorders.
    Keywords:  Alzheimer's disease; SGLT2 inhibition; amyloid‐beta; anti‐diabetic drugs; cognitive function; neuroinflammation
    DOI:  https://doi.org/10.1111/acel.70101
  14. Aging Dis. 2025 Apr 20.
    OPA1 Enhances Microglial Amyloid-β Clearance and Alleviates Cognitive Impairments in an Alzheimer's Disease Model.
    Qing Wang, Mengqi Dong, Xue Xia, Xinyu Bao, Mengsha Hu, Lei Ye, Yun Xu.
      Amyloid deposition is thought to be a pathologic hallmark of Alzheimer disease (AD), which is associated with cognitive decline. Microglia play a crucial role in the pathology of AD, especially in the clearance of Aβ. Optic atrophy 1 (OPA1) is a GTPase primarily on the inner mitochondrial membrane, related to mitochondrial dynamics and cellular energy metabolism. Here, we found that decreased OPA1 expression and defective mitochondrial morphology in microglia during AD. Next, we utilized an OPA1 activator BGP-15, an OPA1 inhibitor myls22 and an OPA1 overexpression virus to investigate the role of OPA1 in AD. Our findings demonstrate that OPA1 promotes ATP production and Aβ clearance by microglia, leading to improved cognitive function. This may relate to down-regulation of hexokinase-2 (HK2) expression. These results suggest a critical role for OPA1 in Aβ clearance by microglia and a promising new direction for therapeutic approaches in AD.
    DOI:  https://doi.org/10.14336/AD.2025.0082
  15. Int J Mol Sci. 2025 May 04. pii: 4368. [Epub ahead of print]26(9):
    Retrotransposon Protein L1 ORF1p Expression in Aging Central Nervous System.
    Laura Vallés-Saiz, Aaron Abdelkader-Guillén, Jesús Ávila, Félix Hernández.
      The long-interspersed elements (LINE-1; L1) represent the main active family of retrotransposons in the human organism, comprising approximately 17% of its content. L1 sequence codifies for the two proteins involved in its retrotransposition: ORF1p, an RNA binding protein, and ORF2p, endowed with endonuclease and reverse transcriptase activity. The vast majority of L1 copies are inactive, with only a small percentage retaining their retrotransposition capacity, posing a threat to the organism due to its mutagenic potential. To mitigate such risks, mammals have evolved intricate regulatory mechanisms, including heterochromatin formation and RNA degradation pathways. Age-related diminution in these regulatory pathways may be particularly important within the Central Nervous System (CNS), where cellular regeneration is limited, and genomic integrity is critical for lifelong function. Here, we describe an age-associated upregulation of ORF1p in the mouse brain, indicating a potential role of L1 activity in aging. We further demonstrate the presence of ORF1p across diverse CNS cell types, including neurons, oligodendrocytes and microglia. Notably, we observe a correlation between ORF1p presence and microglial activation, a hallmark of neuroinflammation, during aging. This study advances our understanding of L1 dynamics in the CNS and underscores the significance of L1 in age-related neurological changes.
    Keywords:  LINE-1; ORP1p; aging; microglia; retrotransposons
    DOI:  https://doi.org/10.3390/ijms26094368
  16. Int Immunopharmacol. 2025 May 13. pii: S1567-5769(25)00799-4. [Epub ahead of print]158 114809
    Reduction of D2 receptors on microglia leads to ZBP1-mediated PANoptosis of mPFC in Parkinson's disease depression mice.
    Qiyue Zhao, Xinyao Zhang, Jing Zhang, Ying Zhang, Lu Jia, Sijia Guo, Mengqing Zhang, Haoran Wang, Yuling Wang, Yue Guan, Yi Zhang, Suibing Miao, Jin-Xia Zhu, Huijie Ma.
      Parkinson's disease depression (PDD) is a common non-motor symptom of Parkinson's disease (PD), characterized by complex neurobiological mechanisms that remain poorly understood. This study identifies ZBP1-mediated PANoptosis as a critical mechanism linking neuroinflammation, neuronal loss, and depressive behaviors in PDD. Using a 6-hydroxydopamine (6-OHDA)-induced PDD mouse model, we observed significant reductions in dopaminergic projections from the substantia nigra (SN) to the medial prefrontal cortex (mPFC), accompanied by neuronal loss and depressive-like behaviors. Microglial activation, driven by DRD2 downregulation, was found to impair mPFC neuronal function, as evidenced by altered local field potentials and reduced gamma, beta, and theta oscillations. Furthermore, ZBP1 expression was significantly upregulated in the mPFC of PDD mice, where it colocalized with CaMKII-positive neurons and facilitated the formation of PANoptosomes, a multimeric complex driving pyroptosis, apoptosis, and necroptosis. Knockdown of ZBP1 in the mPFC effectively suppressed PANoptosome formation, reduced neuronal injury, restored local field potentials, and alleviated depressive-like behaviors. These findings highlight ZBP1-mediated PANoptosis as a key pathological mechanism in PDD and suggest that targeting ZBP1 may represent a promising therapeutic strategy for mitigating neuronal loss and depressive symptoms in PDD.
    Keywords:  Dopamine D2 receptor (DRD2); Medial prefrontal cortex (mPFC); Microglia; PANoptosis; Parkinson's disease depression (PDD); Z-DNA binding protein 1 (ZBP1)
    DOI:  https://doi.org/10.1016/j.intimp.2025.114809
  17. CNS Neurosci Ther. 2025 May;31(5): e70416
    Deer Antler Uridine Regulates Glycolysis in Microglia via HSP90/HIF-1α to Improve Cognitive Impairment in Alzheimer's Disease Mice.
    Yongjian Liu, Chenyang Han, Li Guo, Wenyan Li, Shasha Wu, Jian Sheng, Liping Zhai, Heping Shen.
       AIM: To investigate the role and mechanism of uridine (URI), an active component in deer antler, in improving cognitive impairment in Alzheimer's disease (AD) mice.
    METHOD: The APP/PS1 mouse model was used for AD. After URI gavage administration, cognitive behavioral changes in mice were detected using the Morris water maze, eight-arm maze, and novel object recognition tests. Levels of inflammatory cytokines and lactate, pyruvate in the cortex were measured. The proportions of IBA-1 and CD86 cells in tissues were detected, and the expression of key glycolysis proteins was examined. Network pharmacology was employed to analyze the targets of URI-AD-glycolysis. AAV-CMV-shHSP90 was injected to knock down brain HSP90 levels to further explore the anti-AD mechanism of URI. In vitro, primary microglia were used to detect the proportion of CD86+ M1 cells and glycolysis levels.
    RESULT: URI can improve cognitive impairment in AD mice, with significant changes in cognitive ability and behavior. URI reduces glycolysis levels, the proportion of M1 cells (CD86+), and the activation degree of microglia, while inhibiting the activation of HSP90-HIF-1α. Network pharmacology analysis revealed that HSP90 is a major target of URI. When HSP90 is inhibited, the effect of URI is diminished. In vitro experiments showed that URI can inhibit the M1 polarization of microglia and reduce glycolysis levels.
    CONCLUSION: URI can inhibit microglial glycolysis and M1 polarization via HSP90/HIF-1α, thereby improving cognitive behavioral deficits in AD mice due to neuroinflammation. Uridine in deer antler is a novel small molecule for anti-AD.
    Keywords:  Alzheimer's disease; cognitive impairment; glycolysis; microglia; uridine
    DOI:  https://doi.org/10.1111/cns.70416
  18. J Cereb Blood Flow Metab. 2025 May 15. 271678X251340509
    TSPO deficiency exacerbates acute brain damage after intracerebral hemorrhage in male mice.
    Frederick Bonsack, Rajaneekar Dasari, Ashwin Thomas, Hongyan Xu, Sangeetha Sukumari-Ramesh.
      Intracerebral hemorrhage (ICH) is a stroke subtype with no effective treatment despite high morbidity and mortality rates. The delineation of the mechanisms of brain damage after ICH is critical to identifying novel molecular targets for therapeutic intervention. Apart from the augmented expression of 18 kDa translocator protein (TSPO) in microglia/macrophages post-ICH and its potential to track neuroinflammation, the precise function of TSPO after brain damage remains largely enigmatic. In the present study, we employed transgenic animal models, such as global and myeloid-specific conditional knockouts, to elucidate the functional role of TSPO in ICH-induced acute brain damage. Neurological deficits, neurodegeneration, and neuroinflammation were assessed at 3-days post-ICH in male and female mice. Male TSPO global knockout and conditional knockout exhibited enhanced neurobehavioral deficits with a concomitant increase in neurodegeneration and neuroinflammation compared to their respective controls. Interestingly, their female counterparts did not exhibit augmented brain damage compared to the respective controls. Mechanistically, studies employing RNA-Seq and subsequent functional validation demonstrate that TSPO could regulate brain cholesterol efflux, which could partly be responsible for enhanced brain damage in TSPO KO male mice after ICH, warranting further investigation.
    Keywords:  Intracerebral hemorrhage; TSPO; macrophages; microglia; neuroinflammation
    DOI:  https://doi.org/10.1177/0271678X251340509
  19. Neurobiol Dis. 2025 May 08. pii: S0969-9961(25)00166-4. [Epub ahead of print]211 106950
    Non-linear microglial, inflammatory and oligodendrocyte dynamics across stages of Alzheimer's disease.
    Aurélien M Badina, Kelly Ceyzériat, Quentin Amossé, Alexandre Tresh, Laurene Abjean, Léa Guénat, Emilie Vauthey, Stergios Tsartsalis, Philippe Millet, Benjamin B Tournier.
      Alzheimer's disease (AD) is characterized by cognitive decline and neuropathological hallmarks including Aβ plaques and Tau tangles. Emerging evidence indicates oligodendrocyte (OL) dysfunction and demyelination also contribute to disease progression. Here, we analyzed OL markers and inflammatory gene expression in human hippocampal samples at early and late AD stages. In early AD, we observed OL and myelinating pathways downregulation, alongside microglial and astrocytic activation, as well as upregulated chemokine CCL2 and peripheral immune infiltration markers. In late stages, expression of OL-related genes and myelination pathways increase, with a higher NG2/MBP ratio, coinciding with decreased microglial coverage and peripheral immune markers. These findings indicate that early neuroinflammation may impair OL function, while attenuated immune activity in late AD allows partial OL recovery. This study provides insights into stage-specific inflammatory and myelin-related changes in AD, supporting the relevance of understanding oligodendrocyte dynamics and potential regenerative responses for future therapeutic strategies.
    Keywords:  Alzheimer's disease; Microglia; Myelination; Neuroinflammation; Oligodendrocytes; Peripheral immune infiltration
    DOI:  https://doi.org/10.1016/j.nbd.2025.106950
  20. J Mol Med (Berl). 2025 May 10.
    Single intracerebroventricular TNFR2 agonist injection impacts remyelination in the cuprizone model.
    Valentina Pegoretti, Ate Boerema, Kim Kats, Juan M Dafauce Garcia, Roman Fischer, Roland E Kontermann, Klaus Pfizenmaier, Jon D Laman, Ulrich L M Eisel, Wia Baron.
      The development of therapeutics that enhances the regeneration of myelin sheaths following demyelination is predicted to prevent neurodegeneration. A promising target to enhance remyelination is the immunomodulatory cytokine tumor necrosis factor alpha (TNFα) and its receptors TNFR1 and TNFR2. TNFR2 on oligodendrocyte lineage cells and microglia coordinates different protective functions, such as proliferation of oligodendrocyte progenitor cells, survival of mature oligodendrocytes, and release of anti-inflammatory cytokines, in animal models of inflammation and demyelination. Here, we find in the cuprizone model that following demyelination, fewer axons are unmyelinated in the corpus callosum at an early stage of remyelination after single TNFR2 agonist delivery in the lateral ventricle, while astrocyte and microglia number and coverage are unchanged. Towards later stages of remyelination, TNFR2 agonist treatment maintains the number of oligodendrocyte lineage cells, and large caliber axons have thinner myelin. Hence, even short-term stimulation of TNFR2 has a positive impact on the remyelination processes. This study informs further on the beneficial implications of TNFR2 signaling on oligodendrocyte lineage cells and remyelination, emphasizing its potential therapeutic value for demyelinating diseases, including multiple sclerosis. KEY MESSAGES: Single TNFR2 agonist treatment in the lateral ventricle following cuprizone-induced demyelination impacts remyelination by: Leading to a lower percentage of unmyelinated axons at early stages. Preserving the number of oligodendrocyte lineage cells in the corpus callosum at later stages. Covering large calibre axons with thinner myelin sheaths at later stages.
    Keywords:  Cuprizone model; Multiple sclerosis; Nanotomy; Oligodendrocyte lineage cells; Remyelination; Tumor necrosis factor receptor 2
    DOI:  https://doi.org/10.1007/s00109-025-02549-6
  21. Front Aging Neurosci. 2025 ;17 1537388
    PU.1 dictates β-amyloid-induced TREM2 expression upregulation in microglia in a transgenic model of Alzheimer's disease.
    Zhen Wei, Xiaodong Pan, Xiaoli Cui, Jing Zhang, Xiaoman Dai, Yuqi Zeng, Xiaochun Chen.
       Introduction: Microglial dysfunction is characteristic of Alzheimer's disease (AD), with triggering receptor expressed on myeloid cells 2 (TREM2) and transcription factor PU.1 playing crucial roles. However, the relationship between TREM2 and PU.1 remains unclear.
    Methods: We investigated TREM2 and PU.1 expression patterns in the 5×FAD mouse AD model. Experimental approaches included quantitative PCR, western blotting, immunofluorescence staining, chromatin immunoprecipitation, and luciferase reporter assays to examine the interaction between PU.1 and TREM2. The phagocytic function of microglial cells was evaluated using Aβ42 and Nile red fluorescent microsphere phagocytosis assays.
    Results: TREM2 and PU.1 expression significantly correlated with brain β-amyloid (β) deposition. PU.1 directly interacted with the TREM2 promoter region, promoting its transcription and potently impacting microglial phagocytosis. PU.1 overexpression amplified TREM2 expression, while PU.1 knockdown reduced it.
    Discussion: Our findings reveal a novel regulatory mechanism where PU.1 directly modulates TREM2 transcription in activated microglia during AD progression. These insights highlight the potential of TREM2 and PU.1 as therapeutic targets in AD treatment.
    Keywords:  5 × FAD; Alzheimer’s disease; PU.1/Spi1; TREM2; microglia; β-amyloid
    DOI:  https://doi.org/10.3389/fnagi.2025.1537388
  22. Front Aging Neurosci. 2025 ;17 1516399
    NTN-1 attenuates amyloid-β-mediated microglial neuroinflammation and memory impairment via the NF-κB pathway and NLRP3 inflammasome in a rat model of Alzheimer's disease.
    Tianhang Wang, Yanchen Liu, Yidan Lu, Lijun Chi.
       Introduction: Neuroinflammation driven by microglial activation represents a pivotal pathological mechanism underlying brain injury in Alzheimer's disease (AD), with NLRP3 inflammasome activation being a hallmark feature of this process. Netrin-1 (NTN-1) was recently shown to have potent anti-inflammatory and anti-apoptotic properties in a range of inflammatory diseases; however, its potential effect on neuroinflammation in AD treatment has not been well examined. Accordingly, this study aimed to investigate the effects of NTN-1 on cognitive impairment and to explore the anti-inflammatory properties related to the NLRP3 inflammasome and NF-κB signaling in Aβ1-42-induced rat models.
    Methods: We assessed the effects of NTN-1 on neurobehavioral function, microglial activation and neuroinflammation mechanisms in Aβ1-42-treated rats using the Morris water maze test and Western blotting.
    Results: Our results indicated that microinjections of NTN-1 attenuated Aβ1-42-induced memory and cognitive dysfunction and significantly inhibited microglial proliferation and NLRP3 inflammasome activation in the hippocampus and cortex of AD rats. Additionally, NTN-1 effectively prevented proinflammatory factor (IL1β and IL18) release and NF-κB signaling upstream activation.
    Discussion: Overall, the results of the present study indicated that exogenous NTN-1 treatment prevented neuroinflammation and cognitive deficits by inhibiting microglial activation, which is possibly mediated by the NF-κB signaling pathway and NLRP3 inflammasome activation in Aβ1-42-simulated rat models. NTN-1 emerges as a promising therapeutic candidate for mitigating microglia-mediated neuropathology in AD through its anti-inflammatory properties.
    Keywords:  Alzheimer's disease (AD); NF-κB; NLRP3 inflammasome; amyloid-β (Aβ); apoptosis-associated speck like protein (ASC); microglia; netrin-1; neuroinflammation
    DOI:  https://doi.org/10.3389/fnagi.2025.1516399
  23. J Biol Chem. 2025 May 09. pii: S0021-9258(25)02075-7. [Epub ahead of print] 110225
    Microglial TAK1 promotes neurotoxic astrocytes and cognitive impairment in LPS-induced hippocampal neuroinflammation.
    Xiao Han, Xin Cao, Qianqian Ju, Chengxin Ge, Yongqi Lin, Jinhong Shi, Xinhua Zhang, Cheng Sun, Haoming Li.
      The peripheral immune system has a strong effect on the central nervous system (CNS). Systemic lipopolysaccharides (LPS) administration triggers robust microglial activation and induces significant inflammatory responses in the hippocampus. This study investigates the role of Transforming Growth Factor-β-Activated Kinase 1 (TAK1) in mediating LPS-induced hippocampal neuroinflammation and cognitive impairment. Our findings reveal that LPS induces activation of microglial TAK1, which in turn actives downstream effector NF-κB/p65 to release pro-inflammatory cytokines. The activated microglia also promote astrocytes to polarize into a neurotoxic phenotype (A1-like phenotype), and cause the loss of newborn neurons in the hippocampal dentate gyrus (DG). However, TAK1 reduction inhibits microglial responses, limits neurotoxic astrocytes, rescues newborn neurons, and subsequently improves LPS-induced cognitive deficits, suggesting that targeting TAK1 may be an effective strategy for alleviating neuroinflammation. The interaction between TAK1 activation, microglial responses, and the transition of neurotoxic astrocytes enhances our understanding of the cellular dynamics driving LPS-induced neuroinflammation, suggesting that TAK1 may be a therapeutic target for treating cognitive impairment.
    Keywords:  Astrocyte; Hippocampus; Microglia; Neuroinflammation; TAK1
    DOI:  https://doi.org/10.1016/j.jbc.2025.110225
  24. Front Aging Neurosci. 2025 ;17 1576020
    The potential and challenges of TREM2-targeted therapy in Alzheimer's disease: insights from the INVOKE-2 study.
    Ya-Nan Ma, Xiqi Hu, Kenji Karako, Peipei Song, Wei Tang, Ying Xia.
      Alzheimer's disease (AD) is a severe neurodegenerative disorder with a growing global burden. With the rising incidence of AD, the need for novel therapeutic targets has become increasingly critical. TREM2, a receptor expressed on microglial cells, plays a crucial role in modulating neuroinflammation and clearing pathological substrates, making it a promising candidate for AD therapy. However, the recent clinical trial INVOKE-2 failed to demonstrate significant clinical benefits of the TREM2-targeted antibody AL002, raising doubts about the efficacy of TREM2-targeted methods. This article examines the role of TREM2 in AD pathogenesis, evaluates potential reasons for the disappointing outcomes of the INVOKE-2 trial, and discusses future directions for TREM2-based therapies. Factors such as treatment timing, dosage optimization, patient genetic variability, and combination therapy strategies are identified as critical determinants of therapeutic success. Future studies should aim to refine treatment strategies, identify precise indications, and explore the potential for combination therapies to enhance efficacy.
    Keywords:  Alzheimer’s disease; TREM2; immune regulation; microglial; targeted therapy
    DOI:  https://doi.org/10.3389/fnagi.2025.1576020
  25. Sci Rep. 2025 May 15. 15(1): 16838
    Coupling relationship between glucose and oxygen metabolisms to serve as an imaging biomarker for Alzheimer's disease.
    Ze Yang, Jinhua Sheng, Qiao Zhang, Jay Tsai Chien Chou, Yu Xin, Luyun Wang.
      CD33 rs3865444 polymorphism is closely associated with the risk of Alzheimer's disease (AD), and CD33 is part of the sialic acid-binding Ig-superfamily of lectins (SIGLECs). Immunostaining experiments in previous studies have confirmed the expression of CD33 in human brain microglial cells, and an increase in CD33 mRNA expression in the brain microglial cells of patients with cognitive impairment has been observed. The minor allele CD33 rs3865444 (A) has a protective effect against Alzheimer's disease pathology and is associated with reduced CD33 expression and clearance of amyloid-beta plaques. The risk allele CD33 rs3865444 (C) can cause abnormal activation of microglial cells, thereby inducing neuroinflammation, accompanied by an increase in metabolic levels. We hypothesize that the CD33 rs3865444 polymorphism may affect the coupling between glucose metabolism and neuronal activity, thereby influencing individual cognitive trajectories and the progression of cognitive impairment. In this study, we included 107 patients with mild cognitive impairment, among whom the limbic-orbital frontal cortex glucose-oxygen coupling (G/O) coefficient of the CD33 rs3865444 CC group was significantly reduced. Additionally, the results of the mediation analysis showed that the glucose-oxygen coupling coefficient completely mediated the effect of the CD33 rs3865444 polymorphism on the rate of clinical dementia rating increase.
    Keywords:  CD33 rs3865444; Cognitive trajectory; Functional MRI (fMRI); Glycometabolism; Mild cognitive impairment; Oxygen metabolism
    DOI:  https://doi.org/10.1038/s41598-025-01927-x
  26. J Inflamm Res. 2025 ;18 5931-5950
    Mechanisms of Acetate in Alleviating SETDB1-Linked Neuroinflammation and Cognitive Impairment in a Mouse Model of OSA.
    Zhan Zhao, Li Xiang, Jau-Shyong Hong, Yubao Wang, Jing Feng.
       Background: Microglia-mediated neuroinflammation is crucial for obstructive sleep apnea (OSA)-induced cognitive impairment. We aimed to investigate roles of acetate (ACE) and SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) in neuroinflammation of OSA.
    Methods: After C57BL/6J mice were exposed to OSA-associated intermittent hypoxia (IH) or normoxia for four weeks, the composition of the gut microbiota (GM) and the levels of serum short-chain fatty acids (SCFAs) were measured by 16S rRNA and GC-MS methods, respectively. To assess the effect of ACE on IH mice, glyceryl triacetate (GTA) was gavaged in IH-exposed mice and the cognitive function, microglial activation, and hippocampal neuronal death were examined. Moreover, ACE-treated BV2 microglia cells were also utilized for further mechanistic studies.
    Results: IH disrupts the gut microbiome, reduces microbiota-SCFAs, and impairs cognitive function. Gavage with GTA significantly mitigated these cognitive deficits. Following IH exposure, we observed substantial increases in SETDB1 both in vivo and in vitro, along with elevated levels of histone H3 lysine 9 trimethylation (H3K9me3). Genetic or pharmacological inhibition of SETDB1 in microglia led to decreased induction of proinflammatory factors, as well as reduced reactive oxygen species (ROS) generation. Mechanistically, SETDB1 was found to upregulate the transcription factors p-signal transducer and activator of transcription 3 (p-STAT3) and p-NF-κB. In vitro, ACE supplementation effectively repressed high SETDB1 and H3K9me3 levels, thereby inhibiting microglial pro-inflammatory responses induced by IH. In vivo, ACE supplementation significantly reduced hippocampal levels of p-STAT3, p-NF-κB, and pro-inflammatory cytokines while also protecting neuronal integrity.
    Conclusion: This study provides the first evidence that H3K9 methyltransferase SETDB1 promotes microglial pro-inflammatory response distinct from its previously shown role in macrophages. Our findings also identify ACE supplementation as a promising dietary intervention for OSA-related cognitive impairment with SETDB1 serving as both a mechanistic biomarker and potential therapeutic target.
    Keywords:  NF-κB; OSA; SETDB1; STAT3; acetate; neuroinflammation
    DOI:  https://doi.org/10.2147/JIR.S510690
  27. Int J Hyperthermia. 2025 Dec;42(1): 2503312
    Suppressing TLR4 alleviates cerebral injury in heatstroke rats through the modulation of microglial polarization.
    Xiaomin Wu, Ting He, Chunli Yang, Shujing Xue, Qianqian Yuan, Feifei Chen, Juan Liu, Guanghua Li.
       OBJECTIVE: This study aims to explore the neuroprotective effects of inhibiting TLR4 on brain damage resulting from heatstroke (HS) and to clarify the underlying molecular mechanisms involved.
    METHODS: In this study, we successfully established a HS rat model. The TLR4 antagonist TAK-242 was administered to evaluate its impact on neurological dysfunction, brain edema, learning and memory deficits, and histopathological alterations in the hippocampus.
    RESULTS: The inhibition of TLR4 using TAK-242 led to a significant reduction in neurological dysfunction and brain edema in rats subjected to HS. Additionally, TAK-242 improved learning and memory impairments associated with HS and alleviated histopathological changes observed in the hippocampus. The treatment also resulted in a decrease in CD68-positive microglia and reduced expression levels of iNOS and TNF-α, while increasing CD206-positive cells and the expression of Arg-1 and IL-10. Furthermore, TAK-242 effectively reversed the elevated protein levels of TLR4, MyD88, and NF-κB induced by HS.
    CONCLUSION: These findings indicate that TLR4 inhibition through TAK-242 may be a promising therapeutic strategy for neuroprotection in HS by modulating microglial polarization.
    Keywords:  Heatstroke; TAK-242; microglia; polarization; toll-like receptor 4
    DOI:  https://doi.org/10.1080/02656736.2025.2503312
  28. Drug Dev Res. 2025 May;86(3): e70105
    Oleanolic Acid Alleviates Neuronal Ferroptosis in Subarachnoid Hemorrhage by Inhibiting KEAP1-Nrf2 and NF-κB Pathways.
    Lang Bojuan, Zhou Youdong, Wang Lei, Xue Lixin, Ma Jinyang.
      Oleanolic acid (OA) is a pentacyclic triterpenoid compound, and we previously report that it ameliorates neurological injury in subarachnoid hemorrhage (SAH) model. However, the underlying mechanism is not clear. The aim of this study was to explore the effect and mechanism of OA on SAH. In this study, network pharmacology was applied to screen the targets of OA in SAH treatment. Based on these targets, protein-protein interaction network was constructed, and k-means cluster analysis was used to screen the core targets of OA in SAH treatment. In vitro SAH model was constructed with hemin-induced neuron HT22 and microglia BV2. Then cell counting Kit 8, flow cytometry, western blot, qPCR were performed to evaluate the effects of OA on neurons and microglia. 93 targets were identified as the core targets of OA in SAH treatment. Notably, these targets are closely related to neuroinflammation and oxidative stress responses. OA had good binding activity with KEAP1, NFKB1 and IKBA. OA significantly alleviated the inhibitory effect of hemin on HT22 cell viability. OA significantly inhibited the expression of CD86, promoted the expression of CD206, and promoted the transformation of microglia from M1 type to M2 type. Additionally, OA could inhibit the activation of NF-κB and KEAP1/Nrf2 pathways. In conclusion, OA ameliorates inflammatory response, oxidative stress and ferroptosis in SAH, and suppresses neuronal injury by inhibiting NF-κB and KEAP1/Nrf2 pathways.
    Keywords:  ferroptosis; inflammation; oleanolic acid; oxidative stress; subarachnoid hemorrhage
    DOI:  https://doi.org/10.1002/ddr.70105
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