bims-microg 2025-04-06 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–04–06
twenty-six papers selected by
Marcus Karlstetter, Universität zu Köln

AhR activation mitigates graft-versus-host disease of the central nervous system by reducing microglial NF-κB signaling.
Microglia efferocytosis: an emerging mechanism for the resolution of neuroinflammation in Alzheimer's disease.
The Metabolomic Mind: Microbial Metabolite Programming of Microglia.
The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia.
Transforming Growth Factor β1 Protects Against Ischemic Demyelination via Regulating Microglial Lipid Metabolism Pathway.
Repair-associated macrophages increase after early-phase microglia attenuation to promote ischemic stroke recovery.
Influence of antipsychotic drugs on microglia-mediated neuroinflammation in schizophrenia: perspectives in an astrocyte-microglia co-culture model.
Phase 1, First-In-Human, Single-/Multiple-Ascending Dose Study of Iluzanebart in Healthy Volunteers.
Spermidine attenuates microglial activation, neuroinflammation, and neuronal injury in rat model of vascular dementia.
The NLRP3 inflammasome pathway contributes to chronic inflammation in experimental autoimmune uveitis.
Quercetin Improves Hippocampal Neurogenesis in Depression by Regulating the Level of Let-7e-5p in Microglia Exosomes.
SOX4 accelerates intervertebral disc degeneration via EZH2/NRF2 pathway in response to mitochondrial ROS-dependent NLRP3 inflammasome activation in nucleus pulposus cells.
Narirutin reduces microglia-mediated neuroinflammation by inhibiting the JAK2/STAT3 pathway in MPP+/MPTP-induced Parkinson's disease models.
LRRK2 Mediates α-Synuclein-Induced Neuroinflammation and Ferroptosis through the p62-Keap1-Nrf2 Pathway in Parkinson's Disease.
Hydrogen sulfide improves poststroke depression-induced inflammation in microglial cells by enhancing endoplasmic reticulum autophagy and inhibiting the cGAS-STING pathway.
Protocol for observing tunneling nanotube formation and function in both fixed and live primary mouse neurons and microglia coculture system.
Enhanced BBB penetration and microglia-targeting nanomodulator for the two-pronged modulation of chronically activated microglia-mediated neuroinflammation in Alzheimer's disease.
APOE4 impairs autophagy and Aβ clearance by microglial cells.
SAM Alleviates Neuroinflammation by Regulating M1/M2 Polarization of Microglia Through α7nAChR/Nrf2/HO-1 Signaling Pathway.
Microglial TLR4-Lyn kinase is a critical regulator of neuroinflammation, Aβ phagocytosis, neuronal damage, and cell survival in Alzheimer's disease.
Microglia modulate integrity of myelin and proliferation of oligodendrocyte precursor cells in murine model of bone cancer pain.
Synthesis, preclinical evaluation and pilot clinical study of a P2Y12 receptor targeting radiotracer [18F]QTFT for imaging brain disorders by visualizing anti-inflammatory microglia.
Strategic delivery of omega-3 fatty acids for modulating inflammatory neurodegenerative diseases.
Effects of Cigarette Smoking and 3-Day Smoking Abstinence on Translocator Protein 18 kDa Availability: A [18F]FEPPA Positron Emission Tomography Study.
Depression as a risk factor for Alzheimer's disease: A human post-mortem study.
Multi-omic landscape of human gliomas from diagnosis to treatment and recurrence.

Blood Adv. 2025 Mar 31. pii: bloodadvances.2024015000. [Epub ahead of print]

AhR activation mitigates graft-versus-host disease of the central nervous system by reducing microglial NF-κB signaling.

Alexander Zähringer, Ines Morgado, Daniel Erny, Florian Ingelfinger, Jana Gawron, Sangya Chatterjee, Valentin Wenger, Dominik Schmidt, Lennard Frederik Schwöbel, Rachael C Adams, Marlene Langenbach, Alina Hartmann, Natascha Osswald, Julian Wolf, Günther Schlunck, Priscilla S Briquez, Kathleen Grueter, Dietrich A Ruess, Ian Frew, Ann-Cathrin Burk, Verena Holzmüller, Bodo Grimbacher, David Michonneau, Geoffroy Andrieux, Gérard Socié, Julia Kolter, Melanie Börries, Marie Follo, Franziska Blaeschke, Lisa Sevenich, Marco Prinz, Robert Zeiser, Janaki Manoja Vinnakota.

Acute Graft-versus-Host Disease (GVHD) that occurs after allogeneic hematopoietic cell transplantation (allo-HCT) can affect the central nervous system (CNS). The majority of allo-HCT patients receive antibiotic treatment, which alters the microbiome and essential microbiome-derived metabolites. We investigated the impact of microbiome modifications on CNS-GVHD and therapeutic strategies to overcome the microbiome-derived metabolite depletion. Antibiotic treatment of mice undergoing allo-HCT increased microglia numbers in the brain, indicating increased inflammation. In addition, microglia morphology shifted towards a highly branched phenotype. Consistent with a pro-inflammatory phenotype microglia exhibited increased NF-κB and Src activity. Antibiotic treatment caused the depletion of the bacteria-derived arylhydrocarbon receptor (AhR) ligand indole-3-acetate in the brain. Conversely, treatment of primary microglia with the AhR-ligand- 6-formylindolo (3, 2-b) carbazole (FICZ) reduced NF-κB activity and phagocytic potential. Microglia expansion and morphological changes were reversed by AhR-ligand-FICZ-treatment. Moreover, the AhR-ligand indole-3-acetate was also reduced in the CNS of patients that developed acute GVHD concomitant with increased microglial NF-κB expression. In summary, we demonstrated that antibiotic treatment and a subsequent decrease of AhR-ligands resulted in increased microglia activation during CNS-GVHD. FICZ-treatment hampered CNS inflammation by inhibiting NF-κB activity, thereby providing a metabolic modifier to interfere with pathogenic microglia signaling and CNS-GVHD in vivo.

DOI: https://doi.org/10.1182/bloodadvances.2024015000
J Neuroinflammation. 2025 Mar 30. 22(1): 96

Microglia efferocytosis: an emerging mechanism for the resolution of neuroinflammation in Alzheimer's disease.

Yongping Chen, Yuhong Kou, Yang Ni, Haotian Yang, Cailin Xu, Honggang Fan, Huanqi Liu.

  Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by significant neuroinflammatory responses. Microglia, the immune cells of the central nervous system, play a crucial role in the pathophysiology of AD. Recent studies have indicated that microglial efferocytosis is an important mechanism for clearing apoptotic cells and cellular debris, facilitating the resolution of neuroinflammation. This review summarizes the biological characteristics of microglia and the mechanisms underlying microglial efferocytosis, including the factors and signaling pathways that regulate efferocytosis, the interactions between microglia and other cells that influence this process, and the role of neuroinflammation in AD. Furthermore, we explore the role of microglial efferocytosis in AD from three perspectives: its impact on the clearance of amyloid plaques, its regulation of neuroinflammation, and its effects on neuroprotection. Finally, we summarize the current research status on enhancing microglial efferocytosis to alleviate neuroinflammation and improve AD, as well as the future challenges of this approach as a therapeutic strategy for AD.

Keywords:  Alzheimer’s disease; Efferocytosis; Microglia; Neurodegenerative disease; Neuroinflammation

DOI:  https://doi.org/10.1186/s12974-025-03428-0
Neuroimmunomodulation. 2025 Apr 03. 1-15

The Metabolomic Mind: Microbial Metabolite Programming of Microglia.

Branden G Verosky, Michael T Bailey, Tamar L Gur.

The gut microbiota is increasingly recognized as a critical regulator of brain function, influencing neurodevelopment, adult brain physiology, and disease vulnerability in part through its interactions with microglia, the resident immune cells of the central nervous system. Emerging evidence demonstrates that microbial metabolites, beginning prenatally and persisting throughout the lifespan, regulate fundamental aspects of microglial biology including maturation, metabolic function, and activation. Microglia from germ-free mice exhibit persistent immaturity, altered energy metabolism, and blunted inflammatory responses, which are partially reversible by restoring microbial communities or supplementing key microbial metabolites. Short-chain fatty acids, tryptophan-derived indoles, and other bacterial metabolites derived from the gut microbiota shape microglial function to modulate neurons and synaptic architecture, and influence neuroinflammatory processes. These findings reveal distinct metabolite-driven pathways linking microbial composition to microglial phenotypes, positioning the microbiome as a potential key influencer of neurodevelopmental trajectories and the pathophysiology of psychiatric and neurological disorders. Despite recent advances, major knowledge gaps persist in understanding the precise molecular intermediaries and mechanisms through which metabolite signaling to microglia shape neural function to influence susceptibility or resilience to brain-based disorders. Understanding both the bacterial metabolomic landscape and its collective impact on microglial programming holds substantial therapeutic promise, offering avenues to target microbial metabolite production or administer them directly to modulate brain health.

DOI: https://doi.org/10.1159/000545484
Glia. 2025 Apr 04.

The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia.

Swati Mishra, Nader Morshed, Sonia Beant Sidhu, Chizuru Kinoshita, Beth Stevens, Suman Jayadev, Jessica E Young.

  The SORL1 gene encodes the sortilin-related receptor protein SORLA, a sorting receptor that regulates endo-lysosomal trafficking of various substrates. Loss of function variants in SORL1 are causative for Alzheimer's disease (AD) and decreased expression of SORLA has been repeatedly observed in human AD brains. SORL1 is highly expressed in the central nervous system, including in microglia, the tissue-resident immune cells of the brain. Loss of SORLA leads to enlarged lysosomes in hiPSC-derived microglia-like cells (hMGLs). However, how SORLA deficiency contributes to lysosomal dysfunction in microglia and how this contributes to AD pathogenesis is not known. In this study, we show that loss of SORLA results in decreased lysosomal degradation and lysosomal enzyme activity due to altered trafficking of lysosomal enzymes in hMGLs. Phagocytic uptake of fibrillar amyloid beta 1-42 and synaptosomes is increased in SORLA-deficient hMGLs, but due to reduced lysosomal degradation, these substrates aberrantly accumulate in lysosomes. An alternative mechanism of lysosome clearance, lysosomal exocytosis, is also impaired in SORL1-deficient microglia, which may contribute to an altered immune response. Overall, these data suggest that SORLA has an important role in the proper trafficking of lysosomal hydrolases in hMGLs, which is critical for microglial function. This further substantiates the microglial endo-lysosomal network as a potential novel pathway through which SORL1 may increase AD risk and contribute to the development of AD. Additionally, our findings may inform the development of novel lysosome and microglia-associated drug targets for AD.

Keywords:   SORL1 ; Alzheimer's disease; hiPSC‐derived microglia; lysosomes; phagocytosis

DOI:  https://doi.org/10.1002/glia.70009
Stroke. 2025 Mar 31.

Transforming Growth Factor β1 Protects Against Ischemic Demyelination via Regulating Microglial Lipid Metabolism Pathway.

Yi Xie, Xin-Yue Wang, Shuai Liu, Zi-Yu He, Hang Zhang, Zhi-Yuan Yu, Min-Jie Xie, Wei Wang.

   BACKGROUND: Chronic cerebral hypoperfusion-induced white matter lesions are an important cause of vascular cognitive impairment in aging life. TGF-β1 (transforming growth factor β1) is widely recognized as a multifunctional cytokine participating in numerous pathophysiological processes in the central nervous system. In this study, we aimed to evaluate the neuroprotective potentials of TGF-β1 in ischemic white matter lesions.
METHODS: A mouse model of bilateral common carotid artery stenosis was established to imitate the ischemic white matter lesions. The agonist of the TGF-β1 pathway was continuously applied via intraperitoneal injection. The Morris water maze test and gait analysis system were used to assess the cognitive and gait disorders in modeling mice. The Luxol fast blue staining, immunofluorescence, and electron microscopy were conducted to determine the severity of demyelinating lesions, microglial activation, and dysfunction of the autophagy-lysosomal pathway in microglia. Furthermore, primary cultured microglia were exposed to extracted myelin debris and TGF-β1 in vitro to explore the underlying mechanisms.
RESULTS: As evaluated by behavioral tests, TGF-β1 significantly alleviated the cognitive dysfunction and gait disorder in bilateral common carotid artery stenosis-modeling mice. The demyelinating lesion and remyelination process were also found to be highly improved by activation of the TGF-β1 pathway. The results of immunostaining and electron microscopy showed that TGF-β1 could ameliorate microglial activation and the dysfunction of lipid metabolism in myelin-engulfed microglia. Mechanistically, in primary cultured microglia exposed to myelin debris, administration of TGF-β1 notably mitigated the inflammatory response and accumulation of intracellular lipid droplets via promoting the lipid droplets degradation in the autophagy-lysosomal pathway, as quantified by flow cytometry, immunostaining, Western blot, etc. Yet, the application of autophagy inhibitor (3-methyladenine) significantly reversed the above anti-inflammatory effects of TGF-β1.
CONCLUSIONS: TGF-β1 relieved cognitive deficit, demyelinating lesions, and microglia-mediated neuroinflammation in bilateral common carotid artery stenosis modeling by reducing abnormal lipid droplet accumulation and dysfunction of the autophagy-lysosomal pathway in microglia. Clinically, staged activation of the TGF-β1 pathway may become a potential target and promising treatment for ischemic white matter lesions and vascular cognitive impairment.

Keywords:  autophagy; lipid droplets; microglia; neuroinflammatory diseases; transforming growth factors

DOI:  https://doi.org/10.1161/STROKEAHA.124.048206
Nat Commun. 2025 Mar 31. 16(1): 3089

Repair-associated macrophages increase after early-phase microglia attenuation to promote ischemic stroke recovery.

Xiaotao Zhang, Huaming Li, Yichen Gu, An Ping, Jiarui Chen, Qia Zhang, Zhouhan Xu, Junjie Wang, Shenjie Tang, Rui Wang, Jianan Lu, Lingxiao Lu, Chenghao Jin, Ziyang Jin, Jianmin Zhang, Ligen Shi.

Ischemic stroke recovery involves dynamic interactions between the central nervous system and infiltrating immune cells. Peripheral immune cells compete with resident microglia for spatial niches in the brain, but how modulating this balance affects recovery remains unclear. Here, we use PLX5622 to create spatial niches for peripheral immune cells, altering the competition between infiltrating immune cells and resident microglia in male mice following transient middle cerebral artery occlusion (tMCAO). We find that early-phase microglia attenuation promotes long-term functional recovery. This intervention amplifies a subset of monocyte-derived macrophages (RAMf) with reparative properties, characterized by high expression of GPNMB and CD63, enhanced lipid metabolism, and pro-angiogenic activity. Transplantation of RAMf into stroke-affected mice improves white matter integrity and vascular repair. We identify Mafb as the transcription factor regulating the reparative phenotype of RAMf. These findings highlight strategies to optimize immune cell dynamics for post-stroke rehabilitation.

DOI: https://doi.org/10.1038/s41467-025-58254-y
Front Psychiatry. 2025 ;16 1522128

Influence of antipsychotic drugs on microglia-mediated neuroinflammation in schizophrenia: perspectives in an astrocyte-microglia co-culture model.

Timo Jendrik Faustmann, Franco Corvace, Pedro M Faustmann, Fatme Seval Ismail.

  Schizophrenia is a severe mental disorder with a strong lifetime impact on patients' health and wellbeing. Usually, symptomatic treatment includes typical or atypical antipsychotics. Study findings show an involvement of low-grade inflammation (blood, brain parenchyma, and cerebrospinal fluid) in schizophrenia. Moreover, experimental and neuropathological evidence suggests that reactive microglia, which are the main resident immune cells of the central nervous system (CNS), have a negative impact on the differentiation and function of oligodendrocytes, glial progenitor cells, and astrocytes, which results in the disruption of neuronal networks and dysregulated synaptic transmission, contributing to the pathophysiology of schizophrenia. Here, the role of microglial cells related to neuroinflammation in schizophrenia was discussed to be essential. This review aims to summarize the evidence for the influence of antipsychotics on microglial inflammatory mechanisms in schizophrenia. Furthermore, we propose an established astrocyte-microglia co-culture model for testing regulatory mechanisms and examining the effects of antipsychotics on glia-mediated neuroinflammation. This could lead to a better understanding of how typical and atypical antipsychotics can be used to address positive and negative symptoms in schizophrenia and comorbidities like inflammatory diseases or the status of low-grade inflammation.

Keywords:  antipsychotic drugs; astrocyte-microglia co-culture model; glia; neuroinflammation; psychotic disorders; schizophrenia

DOI:  https://doi.org/10.3389/fpsyt.2025.1522128
Ann Clin Transl Neurol. 2025 Apr 01.

Phase 1, First-In-Human, Single-/Multiple-Ascending Dose Study of Iluzanebart in Healthy Volunteers.

Andreas Meier, Spyros Papapetropoulos, Andrew Marsh, Kelly Neelon, David Stiles, Ryan O'Mara, Evan A Thackaberry, Marco Colonna, Raj Rajagovindan.

   OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of iluzanebart, a fully human monoclonal antibody TREM2 (triggering receptor expressed on myeloid cells 2) agonist, after single- (SAD) and multiple-ascending-dose (MAD) administration.
METHODS: Healthy adult volunteers (N = 136) received intravenous placebo or iluzanebart 1-60 mg/kg (SAD) or 10-60 mg/kg (MAD) followed by serial pharmacokinetics and safety assessments. Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and clinical laboratory evaluations. Pharmacokinetics were assessed through noncompartmental analysis. The study also included open-label cohorts (3, 10, 20, 40, 60 mg/kg SAD; 10, 20, 40 mg/kg MAD) for cerebrospinal fluid (CSF) collection for exploratory pharmacodynamic biomarker analysis.
RESULTS: Iluzanebart was safe and well tolerated following single and multiple doses of up to 60 mg/kg. Most AEs were mild and resolved spontaneously. The most frequently reported AE was pruritus. No serious AEs or investigational product-related clinically meaningful changes in vital signs, electrocardiograms, or laboratory assessments were reported. Iluzanebart serum exposure was related to dose, with a 29-day half-life that is supportive of monthly dosing and confirmed central nervous system (CNS) exposure (≈0.15% CSF-to-serum ratio). Durable and dose-dependent target engagement, evidenced by marked reductions in soluble TREM2 and increased soluble CSF1R (colony-stimulating factor 1 receptor) and osteopontin/SPP1 (secreted phosphoprotein 1) levels in CSF, was observed, indicating that iluzanebart changes microglial activity following single and repeat dosing.
INTERPRETATION: Iluzanebart demonstrated favorable safety, tolerability, pharmacokinetics, and pharmacological activity in the CNS, supporting further clinical development for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.

Keywords:  CSF‐1 receptor; TREM2; adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia; iluzanebart; microglia

DOI:  https://doi.org/10.1002/acn3.70033
Neuroscience. 2025 Mar 30. pii: S0306-4522(25)00256-8. [Epub ahead of print]573 355-363

Spermidine attenuates microglial activation, neuroinflammation, and neuronal injury in rat model of vascular dementia.

Xinyuan Zhao, Dan Li, Zirui Zhu, Suzhen Li, Yaze Qin, Yi Yang.

  Spermidine has been implicated to provide beneficial effects on cognitive function in several model organisms as well as older adults with mild and moderate dementia. Nevertheless, the potential impact of spermidine on learning and memory deficits in vascular dementia (VaD) remains largely unknown. Here, bilateral common carotid artery occlusion (BCCAo) was applied to induce chronic cerebral hypoperfusion in rats. We demonstrated that spermidine therapy improved the spatial learning performance in model animals, accompanied with decreased cerebral histopathologic injury and increased restored myelin basic protein (MBP) expression. Moreover, spermidine suppressed abnormal microglia activation, inhibited the excessive generation of proinflammatory mediators, such as tumor necrosis factor (TNF)α and inducible nitric oxide synthase (iNOS), and increased the anti-inflammatory cytokine transforming growth factor (TGF)β expression in rodent brain following hypoperfusion. Our findings indicated that spermidine alleviated cognitive impairments of rats after VaD-like injury possibly via suppressing microglia-modulated neuroinflammation and neuronal injury. These data may shed light on understanding the pathogenesis of VaD and point to the promising value of spermidine supplementation for cognition improvement.

Keywords:  Chronic hypoperfusion; Microglia; Neuronal damage; Spermidine; Vascular dementia

DOI:  https://doi.org/10.1016/j.neuroscience.2025.03.054
Animal Model Exp Med. 2025 Mar 29.

The NLRP3 inflammasome pathway contributes to chronic inflammation in experimental autoimmune uveitis.

Avik Shome, Ilva D Rupenthal, Rachael L Niederer, Odunayo O Mugisho.

   BACKGROUND: Noninfectious uveitis, a chronic ocular inflammatory disease, is characterized by the activation of immune cells in the eye, with most studies focusing on the role of the adaptive immune system in the disease. However, limited data exist on the potential contribution of the innate immune system, specifically the nucleotide-binding oligomerization domain and leucine-rich repeat receptor-3 (NLRP3) inflammasome pathway. This pathway has previously been identified as a driver of inflammation in several low-grade, progressive inflammatory eye diseases such as diabetic retinopathy. The aim of this study was to determine whether the NLRP3 inflammasome pathway plays a role in the pathogenesis and chronicity of experimental autoimmune uveitis (EAU).
METHODS: EAU was induced in C57BL/6J mice via intraperitoneal pertussis toxin and subcutaneous interphotoreceptor retinoid-binding protein injections. After 12 weeks, eyes were enucleated, and whole eye sections were assessed for inflammasome, macrophage, and microglial markers in the retina, ciliary body, and cornea using immunohistochemistry.
RESULTS: Our study confirmed higher NLRP3 inflammasome activation (increased expression of NLRP3 and cleaved caspase 1 labeling) in EAU mouse retinas compared to controls. This correlated with increased astrogliosis and microglial activation throughout the eye. Migratory innate and adaptive peripheral immune cells (macrophages and leukocytes) were also found within the retina and ciliary body of EAU mice. Connexin43 proteins, which form hexameric hemichannels that can release adenosine triphosphate (ATP), an upstream inflammasome priming signal, were also found upregulated in the retina and cornea of EAU mice.
CONCLUSION: Overall, our findings support the idea that in the EAU model there is active inflammation, even 12 weeks post induction, and that it can be correlated to inflammasome activation. This contributes to the pathogenesis and chronicity of noninfectious uveitis, and our results emphasize that targeting the inflammasome pathway could be efficacious for noninfectious uveitis treatment.

Keywords:  experimental autoimmune uveitis; inflammation; nucleotide‐binding oligomerization domain and leucine‐rich repeat receptor‐3 (NLRP3) inflammasome; uveitis

DOI:  https://doi.org/10.1002/ame2.70011
Drug Des Devel Ther. 2025 ;19 2189-2203

Quercetin Improves Hippocampal Neurogenesis in Depression by Regulating the Level of Let-7e-5p in Microglia Exosomes.

Ying Xie, Tongxuan Ouyang, Anli Xu, Qinglai Bian, Biran Zhu, Min Zhao.

   Background: Adult hippocampal neurogenesis plays a beneficial role in the treatment of depression. The precise mechanism by which let-7e-5p functions as a potential marker for depression remains unclear. Quercetin, a flavonoid compound, exhibits antidepressant effects; however, further investigation is needed to elucidate its regulatory effect and mechanism on hippocampal neurogenesis.
Methods: Chronic unpredictable mild stress (CUMS) was employed to induce depressive-like signaling and cognitive impairment in mice, while quercetin was administered via oral gavage. The symptoms of the mice were evaluated using various signaling methods. The expression levels of microglia, neural stem cells, and let-7e-5p in the dentate gyrus (DG) area of hippocampus were assessed using pathological observation methods. The expression levels of let-7e-5p and the Wnt1/β-catenin signaling pathways in the hippocampal DG of mice were assessed using qRT-PCR and Western blotting, respectively. The exosomes from peripheral blood were isolated and identified, followed by the detection of expression levels for microglia markers CD11b and TMEM119. We isolated hippocampal neural stem cells (NSCs) and co-cultured them with exosomes secreted by BV2 cells under LPS stimulation to observe the proliferation of NSCs and the generation of new neurons. The targeting relationship between let-7e-5p and Wnt1 was ultimately confirmed through the utilization of a dual luciferase reporter assay.
Results: (1) Quercetin ameliorated depression-like behaviors in mice induced by CUMS and restored neurogenesis in the DG region of the hippocampus. (2) Quercetin suppressed the secretion of microglia-derived exosomes carrying let-7e-5p in the DG, which exerted effects on NSC. (3) let-7e-5p regulates depression-related neurogenesis through targeting the Wnt1/β-catenin signaling pathway.
Conclusion: The inhibitory effect of let-7e-5p in microglial exosomes on depression-associated neurogenesis is mediated through the blockade of the Wnt1/β-catenin signaling pathway, which can be effectively reversed by Quercetin treatment.

Keywords:  Wnt1/β-catenin; depression; exosome; let-7e-5p; microglia; neurogenesis; quercetin

DOI:  https://doi.org/10.2147/DDDT.S493779
J Transl Med. 2025 Apr 03. 23(1): 395

SOX4 accelerates intervertebral disc degeneration via EZH2/NRF2 pathway in response to mitochondrial ROS-dependent NLRP3 inflammasome activation in nucleus pulposus cells.

Wenzhi Zhao, Yadong Liu, Yunxiang Hu, Guiqi Zhang.

   OBJECTIVE: The transcription factor SRY-related HMG-box 4 (SOX4) has been implicated in intervertebral disc diseases. This study aimed to investigate the role of SOX4 in intervertebral disc degeneration (IDD) and explore the underlying molecular mechanisms.
METHODS: We established an IDD rat model via surgery and analyzed SOX4 expression using qRT-PCR and Western blotting. Histological evaluation, immunohistochemistry, and Safranin O staining assessed IDD progression. In vitro, an IDD cellular model was constructed using IL-1β-stimulated nucleus pulposus (NP) cells. SOX4 knockdown and overexpression experiments in NP cells examined SOX4 effects on ECM degradation, NLRP3-mediated pyroptosis, and mitochondrial ROS-dependent NLRP3 inflammasome activation. The involvement of the EZH2/NRF2 pathway in SOX4-mediated NLRP3 activation was also examined.
RESULTS: SOX4 expression was significantly increased in IDD rats and promoted IDD progression. Knockdown of SOX4 inhibited ECM degradation and NLRP3-mediated pyroptosis in NP cells. In vitro experiments showed that SOX4 promoted ECM degradation by upregulating MMPs and ADAMTS-5 expression, and suppressed collagen II and aggrecan synthesis. SOX4 knockdown inhibited NLRP3-mediated pyroptosis, while overexpression accelerated it in NP cells. Additionally, SOX4 was found to exacerbate mitochondrial ROS-dependent NLRP3 inflammasome activation in NP cells. Further investigation revealed that SOX4 enhanced NLRP3 inflammasome activation by upregulating EZH2 expression and modulating the EZH2/NRF2 pathway, with EZH2 inhibition attenuating SOX4-induced NLRP3 activation.
CONCLUSION: Our findings suggest that SOX4 accelerates IDD progression by promoting NLRP3 inflammasome activation via modulating the EZH2/NRF2 pathway, leading to NP cell pyroptosis and ECM degradation. Targeting SOX4 may represent a potential therapeutic strategy for treating IDD.

Keywords:  EZH2/NRF2 pathway; Extracellular matrix degradation; Intervertebral disc degeneration; NLRP3 inflammasome activation; Pyroptosis; SRY-related HMG-box 4

DOI:  https://doi.org/10.1186/s12967-024-05913-1
Exp Neurol. 2025 Mar 30. pii: S0014-4886(25)00096-2. [Epub ahead of print]389 115232

Narirutin reduces microglia-mediated neuroinflammation by inhibiting the JAK2/STAT3 pathway in MPP+/MPTP-induced Parkinson's disease models.

Ying Gao, Wenna Liu, Lei Shi, Peng Yang, Le Yang, Minggao Zhao, Li Luo.

  Parkinson's disease (PD) is one of the most common neurodegenerative disorders, characterized by the loss of dopaminergic neurons in the substantia nigra compacta (SNc). Although the detailed molecular mechanisms of PD remain unknown, microglia-mediated neuroinflammation undoubtedly plays a key role in disease progression. Narirutin (Nar), a major flavonoid naturally occurring in citrus fruits, has garnered considerable research attention due to its various therapeutic applications and low toxicity. However, its effects on PD remain unclear. In this study, we explored the protective effects of Nar in 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)-induced PD mouse model as well as in 1-methyl-4-phenyl-pyridinium (MPP+)-induced BV2 cells. Treatment with Nar (2.0, 10.0, and 50.0 mg/kg) reduced dopaminergic neuronal loss in a dose-dependent manner and ameliorated motor impairment in PD mice. Moreover, Nar administration inhibited microglia-mediated inflammation, evidenced by decreased microglial activation in SNc and BV2 cells, and lowered levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in the serum and cells. In addition, we found that Nar exerted anti-inflammatory effects by inhibiting the JAK2/STAT3 pathway. Importantly, using molecular docking and cellular thermal shift assay, we confirmed that JAK2 was a potential binding target of Nar. Overall, Nar attenuated MPTP/MPP+-induced neuroinflammation by inhibiting the JAK2/STAT3 pathway in activated microglia, thereby preventing dopaminergic neuron loss and improving motor disorders in PD mice. Our results provide new evidence supporting that Nar is promising for PD treatment and should be considered for further clinical development.

Keywords:  JAK2/STAT3 pathway; Microglia; Narirutin; Neuroinflammation; Parkinson's disease

DOI:  https://doi.org/10.1016/j.expneurol.2025.115232
Inflammation. 2025 Apr 02.

LRRK2 Mediates α-Synuclein-Induced Neuroinflammation and Ferroptosis through the p62-Keap1-Nrf2 Pathway in Parkinson's Disease.

Xinjie Liu, Zijian Zheng, Cheng Xue, Xiangrong Wang, Jianwei Li, Zheng Liu, Wenqiang Xin, Xinping Xu, Dongwei Zhou, Longping Yao, Guohui Lu.

  Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta and the abnormal aggregation of α-synuclein (α-syn). Despite extensive research, the mechanisms underlying microglial-mediated neuroinflammation and ferroptosis in PD remain inadequately understood. In particular, the role of leucine-rich repeat kinase 2 (LRRK2) in microglial cells and its modulation of the p62-Keap1-Nrf2 signaling pathway warrant further investigation.In this study, we present novel findings demonstrating that LRRK2 regulates microglial neuroinflammation and ferroptosis through the p62-Keap1-Nrf2 signaling axis in the context of PD. Using α-syn-stimulated BV2 microglial cells, we found that LRRK2 inhibition significantly reduced the production of pro-inflammatory cytokines and enhanced the activation of the p62-Keap1-Nrf2 pathway, thereby mitigating ferroptosis and oxidative stress. Furthermore, conditioned medium from LRRK2-inhibited microglia conferred neuroprotective effects on cultured neurons, highlighting the therapeutic potential of targeting LRRK2 in microglia.Importantly, these in vitro findings were corroborated in the MPTP-induced PD mouse model, where LRRK2 inhibition led to diminished microglial activation, decreased apoptosis of midbrain dopaminergic neurons, and upregulation of the p62-Keap1-Nrf2 pathway.Our study fills a critical gap in understanding the microglial mechanisms mediated by LRRK2 and provides novel insights into the pathogenesis of PD. These findings suggest that targeting LRRK2 in microglia may represent a promising therapeutic strategy for PD.

Keywords:  Ferroptosis; LRRK2; Neuroinflammation; Parkinson’s disease; p62-Keap1-Nrf2 pathway

DOI:  https://doi.org/10.1007/s10753-025-02291-8
Neuroreport. 2025 Apr 02. 36(6): 314-326

Hydrogen sulfide improves poststroke depression-induced inflammation in microglial cells by enhancing endoplasmic reticulum autophagy and inhibiting the cGAS-STING pathway.

Bang Luo, Yao Xie, Wending Kuang, Yuzheng Wang, Gang Chen, Yang Zhang, Mei Yuan.

Poststroke depression (PSD) affects approximately one-third of stroke survivors, contributing to poor outcomes and elevated mortality. This study aimed to investigate the therapeutic effects of hydrogen sulfide (H2S), administered as sodium hydrosulfide (NaHS), on PSD-induced inflammation, with a focus on the modulation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway and the enhancement of endoplasmic reticulum (ER) autophagy in microglial cells. An in-vivo rat model was established to evaluate the effects of NaHS on depression-like behaviors and inflammation. Mechanistic studies were conducted in vitro using BV2 microglia subjected to oxygen-glucose deprivation (OGD) and corticosterone. Key inflammatory markers, cGAS-STING pathway activity, and ER-autophagy-related proteins were analyzed using quantitative reverse transcription PCR, Western blotting, ELISA, transmission electron microscopy, and immunofluorescence staining. Depression-like behaviors in rats were assessed using the forced swimming and tail suspension tests. H2S treatment ameliorated depression-like symptoms, mitigated hippocampal damage, and reduced pro-inflammatory markers, including NOD-like receptor protein 3, interleukin-1β (IL-1β), and IL-18 by inhibiting the cGAS-STING pathway. Furthermore, H2S significantly upregulated autophagy-related proteins (LC3, Beclin-1, and FAM134B) and autophagic vesicles, indicating enhanced ER autophagy. Notably, silencing FAM134B reversed the inhibitory effects of H2S on the cGAS-STING pathway, underscoring the pivotal role of ER autophagy in H2S-mediated neuroprotection. These findings demonstrate that H2S mitigates PSD-induced microglial inflammation and depression-like behaviors by inhibiting the cGAS-STING pathway and promoting ER autophagy, suggesting its potential as a therapeutic strategy for PSD. Further investigation into H2S and autophagy-related pathways could reveal novel therapeutic avenues for neuroinflammatory conditions.

DOI: https://doi.org/10.1097/WNR.0000000000002152
STAR Protoc. 2025 Apr 03. pii: S2666-1667(25)00129-7. [Epub ahead of print]6(2): 103723

Protocol for observing tunneling nanotube formation and function in both fixed and live primary mouse neurons and microglia coculture system.

Vivian Baker, Dimitri Budinger, Sean-Patrick Riechers, Michael T Heneka.

  Microglia and neurons can connect via tunneling nanotubes (TNTs), facilitating the transfer of organelles, vesicles, and proteins. Here, we present a protocol for visualizing murine TNT formation and material transfer between neurons and microglia in both fixed samples and samples for live-cell imaging, as well as for flow cytometry. We describe steps for identifying and measuring TNTs and quantifying the transport of aggregated proteins, such as α-synuclein or tau, between these cells. For complete details on the use and execution of this protocol, please refer to Scheiblich et al.1.

Keywords:  Cell Biology; Flow Cytometry; Microscopy; Neuroscience

DOI:  https://doi.org/10.1016/j.xpro.2025.103723
Acta Pharm Sin B. 2025 Feb;15(2): 1098-1111

Enhanced BBB penetration and microglia-targeting nanomodulator for the two-pronged modulation of chronically activated microglia-mediated neuroinflammation in Alzheimer's disease.

Ya Wei, Xue Xia, Xiaorong Wang, Wenqin Yang, Siqin He, Lulu Wang, Yongke Chen, Yang Zhou, Feng Chen, Hanmei Li, Fu Peng, Guobo Li, Zheng Xu, Jintao Fu, Huile Gao.

  Intervention in chronically activated microglia-mediated neuroinflammation is a novel approach to treat Alzheimer's disease (AD). The low permeability of the blood‒brain barrier (BBB) and non-selective distribution in the brain severely restrict AD drugs' disease-modifying efficacy. Here, an immunosuppressant TREM2-lowing antisense oligonucleotides (ASOs) and resveratrol co-loaded cationic liposome is developed as an immune reprogramming nanomodulator modified by acid-cleavable BBB-targeting peptide and microglia-targeting peptide (Res@TcMNP/ASO) for AD management. Res@TcMNP/ASO can enter brain endothelial cells via D-T7 peptides. Then D-T7 undergoes an acid-responsive cleavage, facilitating the escape of Res@MNP/ASO from endo/lysosomes to cross the BBB. The detached Res@MNP/ASO specifically targets M1-phenotype microglia via exposed MG1 peptides to prompt the simultaneous delivery of two drugs into activated microglia. This nanomodulator can not only restore the immune function of microglia through TREM2-lowing ASO but also mitigate the immune stimulation to microglia caused by reactive oxygen species (ROS) through resveratrol, thereby synergistically inhibiting the chronic activation of microglia to alleviate neuroinflammation in AD. Our results indicate that this combination treatment can achieve significant behavioral and cognitive improvements in late APP/PS1 mice.

Keywords:  Alzheimer's disease; Blood‒brain barrier penetration; Chronic neuroinflammation; Immunotherapy; Microglial modulation; Microglial targeting; Resveratrol; TREM2

DOI:  https://doi.org/10.1016/j.apsb.2025.01.015
Inflamm Res. 2025 Apr 01. 74(1): 61

APOE4 impairs autophagy and Aβ clearance by microglial cells.

Rawan Bassal, Maria Rivkin-Natan, Alon Rabinovich, Daniel Moris Michaelson, Dan Frenkel, Ronit Pinkas-Kramarski.

  Alzheimer's disease (AD) is a predominant form of dementia in elderly. In sporadic AD and in families with higher risk of AD, correlation with apolipoprotein E4 (APOE) allele expression has been found. How APOE4 induces its pathological effects is still unclear. Several studies indicate that autophagy, a major degradation pathway trough the lysosome, may be compromised in AD. Here we studied, the effects of APOE isoforms expression in microglia cells. By using an in-situ model, the clearance of Aβ plaques from brain sections of transgenic 5xFAD mice by the APOE expressing microglia was examined. The results show that APOE4 microglia has Impairment In clearance of insoluble Aβ plaques as compared to APOE3 and APOE2 microglia. Furthermore, APOE4 affect the uptake of soluble Aβ. We found that microglia expressing APOE4 exhibit reduced autophagic flux as compared to those expressing APOE3. The autophagy inhibitor chloroquine also blocked Aβ plaque uptake in APOE3 expressing cells. Furthermore, we found that APOE4 expressing microglia have altered mitochondrial dynamics protein expression, mitochondrial morphology and mitochondrial activity compared to those expressing APOE2, and APOE3. Rapamycin treatment corrected Mitochondrial Membrane Potential in APOE4-expressing cells. Taken together, these findings suggest that APOE4 impairs the activation of autophagy, mitophagy, and Aβ clearance and that autophagy-inducing treatments, such as rapamycin, can enhance autophagy and mitochondrial functions in APOE4 expressing microglia. Our results reveal a direct link between APOE4 to autophagy activity in microglia, suggesting that the pathological effects of APOE4 could be counteracted by pharmacological treatments inducing autophagy, such as rapamycin.

Keywords:  Alzheimer's disease (AD); Amyloid β; Apolipoprotein E4 (apoE4); Autophagy

DOI:  https://doi.org/10.1007/s00011-025-02016-5
Neurochem Res. 2025 Mar 29. 50(2): 131

SAM Alleviates Neuroinflammation by Regulating M1/M2 Polarization of Microglia Through α7nAChR/Nrf2/HO-1 Signaling Pathway.

Kang Ma, Jiandong Niu, Liang Zeng, Jianying Tian, Yawen Zhang.

  Microglia are the drivers of neuroinflammation. Microglia activation plays a critical role in the pathogenesis of aging. However, the mechanisms underlying microglial activation during aging are still not fully understood. Here, we investigated the role of S-adenosylmethionine (SAM) and its interplay with microglial activation in aging. In this study, we investigated the effect of SAM on BV2 cells treated with D-galactose (D-gal) and its molecular mechanism by Cell Counting Kit-8 (CCK8) assay, Senescence-associated β-Galactosidase (SA-β-gal) staining, western blot and immunofluorescence. We found that D-gal could induce microglia senescence. SAM intervention induced a significant decrease in the levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and increased arginase-1 (Arg1), α7 nicotinic acetylcholine receptor (α7nAChR), nuclear factor erythrocyte 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) expression. Moreover, after administration of α7nAChR selective antagonist methyllycaconitine citrate (MLA), our results showed that SAM enhanced expression of α7nAChR, Nrf2 and HO-1, promoted the transformation of microglia from M1 to M2 subtype, and decreased the proinflammatory cytokines compared with MLA + D-gal group. These results suggest that SAM attenuates neuroinflammation by inhibiting microglia polarization through the α7nAChR/Nrf2/HO-1 pathway.

Keywords:  Aging; Microglia polarization; Neuroinflammation; SAM

DOI:  https://doi.org/10.1007/s11064-025-04373-3
Sci Rep. 2025 Apr 03. 15(1): 11368

Microglial TLR4-Lyn kinase is a critical regulator of neuroinflammation, Aβ phagocytosis, neuronal damage, and cell survival in Alzheimer's disease.

Rezwanul Islam, Hadi Hasan Choudhary, Feng Zhang, Hritik Mehta, Jun Yoshida, Ajith J Thomas, Khalid Hanafy.

  Disease-Associated Microglia (DAM) are a focus in Alzheimer's disease (AD) research due to their central involvement in the response to amyloid-beta plaques. Microglial Toll-like receptor 4 (TLR4) is instrumental in the binding of fibrillary amyloid proteins, while Lyn kinase (Lyn) is a member of the Src family of non-receptor tyrosine kinases involved in immune signaling. Lyn is a novel, non-canonical, intracellular adaptor with diverse roles in cell-specific signaling which directly binds to TLR4 to modify its function. Lyn can be activated in response to TLR4 stimulation, leading to phosphorylation of various substrates and modulation of inflammatory and phagocytosis signaling pathways. Here, we investigated the TLR4-Lyn interaction in neuroinflammation using WT, 5XFAD, and 5XFAD x Lyn-/- mouse models by western blotting (WB), co-immunoprecipitation (co-IP), immunohistochemistry (IHC) and flow cytometric (FC) analysis. A spatial transcriptomic analysis of microglia in WT, 5XFAD, and 5XFAD x Lyn-/- mice revealed essential genes involved in neuroinflammation, Aβ phagocytosis, and neuronal damage. Finally, we explored the effects of a synthetic, TLR4-Lyn modulator protein (TLIM) through an in vitro AD model using primary murine microglia. Our WB, co-IP, IHC, and FC data show an increased, novel, direct protein-protein interaction between TLR4 and Lyn kinase in the brains of 5XFAD mice compared to WT. Furthermore, in the absence of Lyn (5XFAD x Lyn-/- mice); increased expression of protective Syk kinase was observed, enhanced microglial Aβ phagocytosis, increased astrocyte activity, decreased neuronal dystrophy, and a further increase in the cell survival signaling and protective DAM population was noted. The DAM population in 5XFAD mice which produce more inflammatory cytokines and phagocytose more Aβ were observed to express greater levels of TLR4 and Lyn. Pathway analysis comparison between WT, 5XFAD, and 5XFAD x Lyn-/- mice supported these findings via our microglial spatial transcriptomic analysis. Finally, we created an in vitro co-culture system with primary murine microglial and primary murine hippocampal cells exposed to Aβ as a model of AD. When these co-cultures were treated with our TLR4-Lyn Interaction Modulators (TLIMs), an increase in Aβ phagocytosis and a decrease in neuronal dystrophy was seen. Lyn kinase has a central role in modulating TLR4-induced inflammation and Syk-induced protection in a 5XFAD mouse model. Our TLIMs ameliorate AD sequalae in an in vitro model of AD and could be a promising therapeutic strategy to treat AD.

Keywords:  5XFAD; Alzheimer’s disease; Disease-Associated Microglia; Lyn kinase; TLR4; TLR4-Lyn modulator protein

DOI:  https://doi.org/10.1038/s41598-025-96456-y
Eur J Pharmacol. 2025 Apr 01. pii: S0014-2999(25)00339-5. [Epub ahead of print] 177585

Microglia modulate integrity of myelin and proliferation of oligodendrocyte precursor cells in murine model of bone cancer pain.

Li Jiang, Yu Wang, Qing-Zi Wu, Jia-Cheng Yu, Yu-Lin Huang, Rui Xu, Kun Ni, Xiao-Ping Gu, Zheng-Liang Ma.

  Cancer pain, a frequent complication in patients with cancer, adversely affects quality of life and survival rates. Microglia promote nociceptive information transmission by modulating myelin integrity during pain perception. However, the specific mechanisms by which microglia regulate myelin in the context of cancer pain remain poorly understood. In this study, we developed a bone cancer pain model to examine the interactions among microglia, myelin, and oligodendrocyte precursor cells and their roles in cancer pain. Our study found that mice with bone cancer pain had oligodendrocyte differentiation defects and myelin loss, and that promoting myelination did not relieve pain. In addition, we observed that reactive microglia and inflammatory cytokines increased and microglia phagocytosed myelin in mice with bone cancer pain. Inhibition of microglia not only alleviated pain behaviors in mice with bone cancer but also mitigated myelin phagocytosis and the proliferation of oligodendrocyte precursor cells. Our study suggests that microglia-mediated myelin loss and oligodendrocyte precursor cell proliferation may be one of the pathological mechanisms underlying pain in mice with bone cancer.

Keywords:  bone cancer pain; microglia; myelin; neuroinflammation; oligodendrocyte precursor cells

DOI:  https://doi.org/10.1016/j.ejphar.2025.177585
Acta Pharm Sin B. 2025 Feb;15(2): 1056-1069

Synthesis, preclinical evaluation and pilot clinical study of a P2Y12 receptor targeting radiotracer [18F]QTFT for imaging brain disorders by visualizing anti-inflammatory microglia.

Bolin Yao, Yanyan Kong, Jianing Li, Fulin Xu, Yan Deng, Yuncan Chen, Yixiu Chen, Jian Chen, Minhua Xu, Xiao Zhu, Liang Chen, Fang Xie, Xin Zhang, Cong Wang, Cong Li.

  As the brain's resident immune cells, microglia perform crucial functions such as phagocytosis, neuronal network maintenance, and injury restoration by adopting various phenotypes. Dynamic imaging of these phenotypes is essential for accessing brain diseases and therapeutic responses. Although numerous probes are available for imaging pro-inflammatory microglia, no PET tracers have been developed specifically to visualize anti-inflammatory microglia. In this study, we present an 18F-labeled PET tracer (QTFT) that targets the P2Y12, a receptor highly expressed on anti-inflammatory microglia. [18F]QTFT exhibited high binding affinity to the P2Y12 (14.43 nmol/L) and superior blood-brain barrier permeability compared to other candidates. Micro-PET imaging in IL-4-induced neuroinflammation models showed higher [18F]QTFT uptake in lesions compared to the contralateral normal brain tissues. Importantly, this specific uptake could be blocked by QTFT or a P2Y12 antagonist. Furthermore, [18F]QTFT visualized brain lesions in mouse models of epilepsy, glioma, and aging by targeting the aberrantly expressed P2Y12 in anti-inflammatory microglia. In a pilot clinical study, [18F]QTFT successfully located epileptic foci, showing enhanced radioactive signals in a patient with epilepsy. Collectively, these studies suggest that [18F]QTFT could serve as a valuable diagnostic tool for imaging various brain disorders by targeting P2Y12 overexpressed in anti-inflammatory microglia.

Keywords:  Aging; Brain diseases; Epilepsy; Glioma; Microglia; Neuroinflammation; P2Y12 receptor; Positron emission tomography (PET)

DOI:  https://doi.org/10.1016/j.apsb.2025.01.009
Front Aging Neurosci. 2025 ;17 1535094

Strategic delivery of omega-3 fatty acids for modulating inflammatory neurodegenerative diseases.

Yixin Chen, Roni Touboul, Yao Chen, Chuchun L Chang.

   Objectives: Early-life inflammatory events like infections and injuries may predispose the brain to Alzheimer's disease (AD) by disrupting neurodevelopment and raising vulnerability. The association between early neuroinflammation and subsequent neurodegeneration leading to dementia remains unclear. We hypothesize that omega-3 (n-3) fatty acids (FA), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), positively regulate neuro-immune cells, preserving their cell membrane structure and metabolic homeostasis. Our study examined whether strategic delivery of n-3 FA via injectable n-3 triglycerides (TG) can influence microglial lipid metabolism to prevent or delay AD progression.
Methods and results: We characterized n-3 treatment effects on modulating lipid and metabolic homeostasis in microglia during the critical window of brain development. Our preliminary studies on determining the effects of early n-3 treatment on brain cell homeostasis indicate that perinatal bolus n-3 TG injections suppressed activation of gliosis-associated markers in young mice predisposed to AD (5xFAD) and yielded sustained regulatory effects on the expression of inflammatory molecules, such as interleukin-6 (Il6) and tumor necrosis factor-alpha (Tnfα), in adult brains. A significant increase in high-frequency ultrasonic vocalizations (USV) was observed in P6 5xFAD mice that received perinatal n-3 compared to vehicle control, implicating enhanced active communication patterns. Improvement in behavior deficits was observed in n-3-treated adult AD mice. Perinatal n-3 TG treatment modified brain lipid composition in young offspring, increasing key membrane lipid species, such as phospholipids (PL) and lysophospholipids (lysoPL). Pro-inflammatory sphingolipids associated with neurodegeneration, including lactosylceramide, were significantly lower in mice treated with n-3 than those in saline-treated AD mice.
Conclusion: Our study establishes a proof of principle for targeting brain immune cell metabolism with injectable n-3 TG to mitigate neuroinflammation in AD pathogenesis, paving the way for future research into early treatments for related central nervous system (CNS) disorders.

Keywords:  5xFAD; Alzheimer’s disease; fatty acids; microglia; neuroinflammation; omega-3

DOI:  https://doi.org/10.3389/fnagi.2025.1535094
Addict Biol. 2025 Feb;30(4): e70024

Effects of Cigarette Smoking and 3-Day Smoking Abstinence on Translocator Protein 18 kDa Availability: A [18F]FEPPA Positron Emission Tomography Study.

Arthur L Brody, Andre Y Sanavi, Renee Beverly-Aylwin, Natalie Guggino, Anna K Mischel, Alvin Wong, Ji Hye Bahn, Mark G Myers, Brinda Rana, David Vera, Kishore K Kotta, Jeffrey H Meyer, Jared W Young, Carl K Hoh.

  With the many negative health consequences of cigarette smoking, quitting is known to improve health in multiple domains. Using positron emission tomography/computed tomography (PET/CT) scanning, our group previously demonstrated that smokers have lower levels than nonsmokers of translocator protein binding both acutely and following overnight abstinence. Here, we sought to determine the effects of longer smoking abstinence on this marker of gliosis for microglia and astroglia, as well as explore associations between the marker and smoking-related symptoms. This observational study was performed in an academic VA medical centre. Fifty-nine generally healthy Veterans who were either nonsmokers (n = 15) or smokers (n = 44) participated in the study. Participants completed an intake visit to evaluate for inclusion/exclusion criteria, [18F]FEPPA PET/CT scanning and a structural magnetic resonance imaging scan. Smokers were alternately assigned either to smoke to satiety (n = 24) before scanning or undergo three nights of continuous abstinence prior to scanning using contingency management (n = 20 completed this protocol and scanning). The smoker satiety group had a significantly lower mean whole brain (WB) standardized uptake value (SUV) for [18F]FEPPA binding than both the nonsmoking (-15.3%) and abstinent smoker (-12.3%) groups. The nonsmoking control and abstinent smoker groups had mean WB SUVs that were not significantly different from one another (3.0% group difference). In an exploratory analysis, a significant inverse relationship was found between WB SUVs and mood ratings for smokers, indicating that higher levels of TSPO binding were associated with worse mood. The central findings here support previous studies demonstrating lower levels of the marker for gliosis in satiated smokers and imply normalization with elimination of cigarette smoke constituents from the body, although other explanations for study results (e.g., alterations in radioligand delivery or clearance of radioligand by cigarette smoke constituents) are possible. These findings may represent a previously unknown health benefit of quitting smoking.

Keywords:  Neuroinflammation; Positron Emission Tomography; Tobacco Dependence

DOI:  https://doi.org/10.1111/adb.70024
PLoS One. 2025 ;20(4): e0320561

Depression as a risk factor for Alzheimer's disease: A human post-mortem study.

Mizuki Morisaki, Farnoosh Rezaali, Laurie C Lau, Delphine Boche, Golam M Khandaker, Gustavo Turecki, Lindsey I Sinclair.

Depression is associated with persistent low mood. In mid to late life, it has been identified as a risk factor for Alzheimer's disease (AD) with evidence that depression might be an early manifestation of AD. Although the underlying mechanisms by which depression enhances AD development remain unknown, there are several features commonly seen in both diseases such as the presence of neuroinflammation. In this study, we aimed to identify whether neuroinflammation is increased in depression as observed in the early stages of AD by examining post-mortem human brain tissue. Post-mortem human brain tissue from 54 cases with depression and 37 controls without depression were retrieved from the Douglas Bell Canada Brain Bank. Sixteen early-stage AD cases defined as a Braak stage III-IV and 15 controls were sourced from the South West Dementia Brain Bank. Frozen tissue from the dorsal prefrontal cortex was obtained for all cases in order to measure inflammatory proteins (IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and TNF-α) and endothelial markers (ICAM-1, VCAM) using ELISA and MesoScale Multiplex Assays. In the depression group, increase of IL-6 and IL-10, and decrease of IL-1β were observed compared to controls, with no changes detected for the other cytokines and the endothelial markers. In early-stage AD cases, only increased ICAM-1 expression was found compared to controls, indicating endothelial activation as an early feature of AD. None of the cytokines measured showed alteration of their expression in early-stage AD cases. Depression, but not AD, was associated with evidence of neuroinflammation. Depression may increase AD risk through different mechanism(s) than inflammation.

DOI: https://doi.org/10.1371/journal.pone.0320561
bioRxiv. 2025 Mar 14. pii: 2025.03.12.642624. [Epub ahead of print]

Multi-omic landscape of human gliomas from diagnosis to treatment and recurrence.

Hadeesha Piyadasa, Benjamin Oberlton, Mikaela Ribi, Jolene S Ranek, Inna Averbukh, Ke Leow, Meelad Amouzgar, Candace C Liu, Noah F Greenwald, Erin F McCaffrey, Rashmi Kumar, Selena Ferrian, Albert G Tsai, Ferda Filiz, Christine Camacho Fullaway, Marc Bosse, Sricharan Reddy Varra, Alex Kong, Cameron Sowers, Melanie Hayden Gephart, Pablo Nuñez-Perez, EnJun Yang, Mike Travers, Michael J Schachter, Samantha Liang, Maria R Santi, Samantha Bucktrout, Pier Federico Gherardini, Kristina Cole, Michael E Barish, Christine E Brown, Derek A Oldridge, Richard R Drake, Joanna J Phillips, Hideho Okada, Robert Prins, Sean C Bendall, Michael Angelo.

Gliomas are among the most lethal cancers, with limited treatment options. To uncover hallmarks of therapeutic escape and tumor microenvironment (TME) evolution, we applied spatial proteomics, transcriptomics, and glycomics to 670 lesions from 310 adult and pediatric patients. Single-cell analysis shows high B7H3+ tumor cell prevalence in glioblastoma (GBM) and pleomorphic xanthoastrocytoma (PXA), while most gliomas, including pediatric cases, express targetable tumor antigens in less than 50% of tumor cells, potentially explaining trial failures. Longitudinal samples of isocitrate dehydrogenase (IDH)-mutant gliomas reveal recurrence driven by tumor-immune spatial reorganization, shifting from T-cell and vasculature-associated myeloid cell-enriched niches to microglia and CD206+ macrophage-dominated tumors. Multi-omic integration identified N-glycosylation as the best classifier of grade, while the immune transcriptome best predicted GBM survival. Provided as a community resource, this study opens new avenues for glioma targeting, classification, outcome prediction, and a baseline of TME composition across all stages.

DOI: https://doi.org/10.1101/2025.03.12.642624