bims-micgli Biomed News
on Microglia
Issue of 2026–05–03
24 papers selected by
Matheus Garcia Fragas, Universidade de São Paulo
  1. TREM2 deficiency causes region-specific brain effects in a mouse model of cerebral amyloid angiopathy.
  2. Complement C3aR deletion does not attenuate degeneration in a tauopathy model or alter acute inflammation-induced gene expression changes.
  3. Lactate metabolism links reactive microglia, amyloid pathology, and Aβ dynamics.
  4. Investigating Glycolysis in Primary Microglia Using Extracellular Flux Assay.
  5. Short-chain fatty acids mitigate inflammation and associated metabolic programming of human stem cell-derived enteric glial cells.
  6. Functional interrogation of neuronal connections by chemoptogenetic presynaptic ablation.
  7. Sex differences in Alzheimer's.
  8. Inhibition of the Microglial cGAS-STING Pathway Improves Neurological Deficits and Long-Term Hydrocephalus Symptoms in Mice with Intraventricular Hemorrhage.
  9. Atomic structures of medin and Aβ fibrils reveal polymorphic remodeling in mixed amyloid systems.
  10. Low overlap of plasma and CSF protein quantitative trait loci affects protein discovery for neurological disease.
  11. Skin-resident Langerhans cells drive neuropathic pain via chemokine-dependent neuron-immune communication.
  12. Immunoproteasome Inhibition Modulates Microglial Polarization to Facilitate Anti-Inflammatory Responses and Hematoma Resolution After Intracerebral Hemorrhage.
  13. A causal role for the posterior corpus callosum in bimanual coordination.
  14. The hypoxia-inflammation cycle as a key mechanism of smoldering inflammation and progression in multiple sclerosis.
  15. A cell atlas charts the immune architecture of diabetic kidney disease.
  16. Glioblastoma radiomics can delineate systemic immune activity states like blood abundance of T cell populations or transcription factors.
  17. Tracking the turning point in Alzheimer's disease.
  18. Niacin promotes motor function recovery after spinal cord injury via Hcar2-dependent microglia immunometabolic regulation.
  19. IL-33/ST2 deficiency induces depression-like behaviors through neuroinflammation in the medial prefrontal cortex and hippocampus.
  20. TLR7 alters the maternal immune landscape during influenza A infection to increase maternal and fetal morbidity.
  21. Targeting Lipid Metabolism in Alzheimer's Disease: Emerging Insights and Future Directions.
  22. The PM20D1-OLE pathway induces microglia rewiring to ameliorate Alzheimer disease.
  23. SGK1 inhibition supports neuroprotection in spinal cord injury by suppressing oxidative stress and AIM2 activation via FoxO1 mediated mitophagy.
  24. CD33 Isoform Splicing Dysregulation: A Molecular Determinant of Microglial Dysfunction in Alzheimer's Disease Pathology.
  1. bioRxiv. 2026 Apr 19. pii: 2026.04.17.719285. [Epub ahead of print]
    TREM2 deficiency causes region-specific brain effects in a mouse model of cerebral amyloid angiopathy.
    Constanza Mercado, Armando Amaro, Jonathan Martinez-Pinto, Ruben Vidal, Nur Jury-Garfe, Cristian A Lasagna-Reeves.
      Cerebral amyloid angiopathy (CAA), a major vascular contributor to cognitive decline, is present in 85-95% of Alzheimer's disease (AD) patients. Despite its high prevalence, the mechanisms by which CAA contributes to neurodegeneration remain poorly understood. Triggering receptor expressed on myeloid cells 2 (TREM2), an innate immune receptor expressed exclusively by microglia, regulates activation, phagocytosis, and amyloid clearance, thereby shaping neuroinflammation. Loss-of-function mutations in TREM2 markedly increase AD risk, but its role in CAA pathology remains unknown. To investigate this, we crossed the Familial Danish Dementia (Tg-FDD) mouse model, which accumulates robust vascular amyloid, with TREM2 knockout (TREM2KO) mice to generate Tg-FDD/TREM2KO animals. Histological and transcriptomic analyses revealed region-specific effects of TREM2 deficiency. In the cortex, TREM2 loss markedly reduced vascular amyloid deposition, accompanied by decreased tau pathology. In contrast, in the cerebellum, TREM2 deletion exacerbated vascular amyloid accumulation, promoted astrogliosis, and enhanced tau pathology. Transcriptomic profiling further identified distinct neuroinflammatory signatures between cortex and cerebellum, particularly in cytokine signaling, matrix remodeling, and lipid metabolism. Together, these findings demonstrate that TREM2 deficiency leads to region-specific effects on CAA, revealing extensive regional variability in vascular amyloid pathology and underscoring the importance of considering these differences when developing TREM2-based therapies.
    DOI:  https://doi.org/10.64898/2026.04.17.719285
  2. Cell Rep. 2026 Apr 24. pii: S2211-1247(26)00391-8. [Epub ahead of print]45(5): 117313
    Complement C3aR deletion does not attenuate degeneration in a tauopathy model or alter acute inflammation-induced gene expression changes.
    Yuanyuan Wang, Shristi Pandey, Martin Weber, Man Kin Choy, Tiffany Wu, Tania Chernov-Rogan, Max Adrian, Ming-Chi Tsai, Hai Ngu, Oded Foreman, Luke Xie, Jesse E Hanson.
      Aberrant activation of the classical complement pathway in the brain is implicated in contributing to synapse loss and neurodegeneration in various neurodegenerative conditions. Given that C3aR is a druggable target in the complement pathway, we evaluated the potential of C3aR knockout (KO) to rescue neurodegeneration in a tauopathy model and neuroinflammatory responses in an acute endotoxemia model. We found that C3aR KO did not rescue Tau pathology, microglia activation markers, neurodegeneration, or behavioral abnormalities in tauopathy model mice. While we found that endotoxemia resulted in numerous transcriptional changes, including distinct alterations in subpopulations of microglia, astrocytes, and oligodendrocytes, C3aR KO did not impact these alterations. Together, our results suggest that the beneficial effects of blocking the complement classical pathway in neurodegeneration models are likely independent of C3aR activation and raise questions about the rationale for therapeutically targeting C3aR for neurodegenerative disease.
    Keywords:  Alzheimer’s disease; C3aR; CP: neuroscience; complement; microglia; neurodegeneration; neuroinflammation; single-cell RNA-seq; tauopathy
    DOI:  https://doi.org/10.1016/j.celrep.2026.117313
  3. J Neuroinflammation. 2026 Apr 25.
    Lactate metabolism links reactive microglia, amyloid pathology, and Aβ dynamics.
    Clair C Ashley, Nicholas J Constantino, Ryan J Pettit-Mee, J Andy Snipes, Kai Saito, Riley E Irmen, Rui Zhang, Evan M Neary, Matthew J Lanning, Celeste M Karch, Lance A Johnson, Josh M Morganti, Shannon L Macauley.
      
    Keywords:  Amyloid plaques; Lactate; Metabolism; Microglia
    DOI:  https://doi.org/10.1186/s12974-026-03825-z
  4. J Vis Exp. 2026 Apr 10.
    Investigating Glycolysis in Primary Microglia Using Extracellular Flux Assay.
    Aysika Das, Deepak K Kaushik.
      Microglia, the resident macrophage cells of the central nervous system, dynamically alter their metabolic programs in response to physiological and pathological cues. Understanding these metabolic shifts is crucial for elucidating their roles in inflammation. Here, we present a detailed protocol for assessing the glycolytic profile of primary microglia isolated from neonatal mouse brain cortices using a glycolysis stress test on an extracellular flux analyzer. This assay enables real-time measurement of ECAR, an indicator of glycolytic activity associated with low pH, such as lactate. Our approach involves treating cultured microglia under different conditions to examine how metabolic pathways are altered in response to various stimuli, including pro-inflammatory stimuli. Uniquely, our lab prepares fresh stock solutions of different reagents, including glucose, oligomycin, and 2-deoxyglucose (2DG), to target the different aspects of the pathway, with careful adjustment of pH for each reagent to ensure experimental accuracy and reproducibility. This method provides a robust platform for investigating glycolysis in primary microglia and offers insight into their functional states under inflammatory or disease-relevant conditions.
    DOI:  https://doi.org/10.3791/69638
  5. J Neuroinflammation. 2026 Apr 28.
    Short-chain fatty acids mitigate inflammation and associated metabolic programming of human stem cell-derived enteric glial cells.
    Anastasia Markidi, Esther A Zaal, Lousanne H C de Wit, Maria Eleni Mavrogeni, Massimiliano Caiazzo, Aletta D Kraneveld, Paula Perez Pardo, Celia R Berkers.
      
    Keywords:  Enteric glial cells; Enteric nervous system; Human embryonic stem cells; Inflammation; Metabolism; Short-chain fatty acids
    DOI:  https://doi.org/10.1186/s12974-026-03818-y
  6. Sci Adv. 2026 May;12(18): eaeb6755
    Functional interrogation of neuronal connections by chemoptogenetic presynaptic ablation.
    Hariom Sharma, Jennifer M Panlilio, Madalina A Robea, Noel H McGrory, Daniel C Bazan, Edward A Burton, Harold A Burgess.
      Most neurons are embedded in multiple circuits, with signaling to distinct postsynaptic partners playing functionally different roles. The function of specific connections can be interrogated using synaptically localized optogenetic effectors; however, these tools are often experimentally difficult to validate or produce paradoxical outcomes. We have developed a system for photoablation of synaptic connections originating from genetically defined neurons based on presynaptic localization of the fluorogen-activating protein dL5** that acts as a photosensitizer when bound to a cell-permeable fluorogen dye. Using the well-mapped zebrafish escape circuit as a readout, we first show that cytoplasmically expressed dL5** enables efficient spatially targeted neuronal ablation using near-infrared light. We then demonstrate that spatially patterned illumination of presynaptically localized dL5** (syp-dL5) can effectively disconnect neurons from selected downstream partners, suppressing postsynaptic responses and producing precise behavioral deficits. This technique should be applicable to almost any genetically tractable neuronal circuit, enabling refined manipulation of functional connectivity within the nervous system.
    DOI:  https://doi.org/10.1126/sciadv.aeb6755
  7. Nat Immunol. 2026 May;27(5): 885
    Sex differences in Alzheimer's.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-026-02519-1
  8. Mol Neurobiol. 2026 Apr 29. pii: 594. [Epub ahead of print]63(1):
    Inhibition of the Microglial cGAS-STING Pathway Improves Neurological Deficits and Long-Term Hydrocephalus Symptoms in Mice with Intraventricular Hemorrhage.
    Hao-Xiang Wang, Hua-Jiang Deng, Kun-Hong Zhong, Zi-Ang Deng, Bao-Cheng Gao, Xin Tang, Yuan-You Li, Ke-Ru Huang, Ai-Ping Tong, Da-Xiong Feng, Liang-Xue Zhou.
      Post-hemorrhagic hydrocephalus (PHH) represents a prevalent clinical form of hydrocephalus, where surgical interventions frequently fail or result in severe complications. While current research underscores the role of innate immunity and neuroinflammation in PHH pathogenesis, the precise mechanisms remain elusive. The cyclic guanylate adenylates synthase-stimulator of interferon genes (cGAS-STING) pathway, a pivotal component of innate immunity, has been implicated in various neuroinflammatory disorders. However, its mechanism of action in PHH has not yet been explored. Here, we propose that sustained activation of the cGAS-STING pathway in microglia following intraventricular hemorrhage (IVH) drives persistent neuroinflammation. Our results showed that dsDNA released from pyroptotic neurons and impaired mitochondrial autophagy in microglia can serve as substrates for cGAS detection, forming a cascade of interconnected pathways. Pharmacological inhibition or conditional knockout of cGAS attenuated global neuroinflammation, suppressed microglial activation, and reduced both pyroptosis-dependent (IL-1β and IL-18) and nonpyroptosis-dependent (TNF-α, IFN-β, and IL-6) cytokine release. Additionally, these interventions mitigated neuronal damage, apoptosis, and hydrocephalus-related neurological deficits after IVH Our results demonstrate that cGAS-STING pathway activation, mediated by neuronal pyroptosis and microglial mitophagy dysfunction, perpetuates post-IVH neuroinflammation. Our findings suggest that targeting cGAS may serve as a promising therapeutic approach for PHH.
    Keywords:  CGAS-STING pathways; Microglia; Mitophagy; Post-hemorrhagic hydrocephalus; Pyroptosis
    DOI:  https://doi.org/10.1007/s12035-026-05888-8
  9. Nat Commun. 2026 Apr 28.
    Atomic structures of medin and Aβ fibrils reveal polymorphic remodeling in mixed amyloid systems.
    Brajabandhu Pradhan, Senthil T Kumar, Jessica Wagner, Rodrigo Gallardo, Gabriele Orlando, Matthias De Vleeschouwer, Valentina Zorzini, Jillian Madine, Nikolaos Louros, Jonas J Neher, Frederic Rousseau, Joost Schymkowitz.
      Amyloid assembly in vivo occurs in complex environments where multiple aggregation-prone species coexist. Aβ and medin are prevalent amyloids in ageing humans that co-localize in cerebral amyloid angiopathy (CAA), yet their structural interactions remain poorly understood. Here, using cryo-electron microscopy, we determine high-resolution fibril structures from in vitro mixtures of Aβ40 and medin. From the same reaction, we resolve three distinct fibril populations: (i) a previously characterized Aβ40 polymorph that also forms in isolation, (ii) a Aβ40 polymorph with Aβ42-like features, including ordered N- and C-terminal regions, and (iii) the atomic structure of full-length medin fibrils. Biochemical and immunogold analyses demonstrate Aβ-medin association within mixed assemblies, though medin is not resolved within the ordered Aβ core. These findings support two non-exclusive mechanisms: transient heterotypic interactions redirecting Aβ folding, or partial medin incorporation into fibril architecture. Our data reveal how coexisting amyloids remodel each other's polymorphic landscapes.
    DOI:  https://doi.org/10.1038/s41467-026-72515-4
  10. Sci Transl Med. 2026 Apr 29. 18(847): eadz2016
    Low overlap of plasma and CSF protein quantitative trait loci affects protein discovery for neurological disease.
    Daniel Western, Chengran Yang, Jigyasha Timsina, Menghan Liu, Ciyang Wang, Meghan C Campbell, Paul Kotzbauer, Joel S Perlmutter, Suzanne E Schindler, John C Morris, David M Holtzman, Ignacio Alvarez, Pau Pastor, Tony Wyss-Coray, Marta Marquié, Amanda Cano, Yun Ju Sung, Itziar de Rojas, Agustín Ruiz, John Budde, Maria Victoria Fernandez, Rawan Tarawneh, Laura Ibanez, Carlos Cruchaga.
      Plasma protein quantitative trait loci (pQTLs) have been integrated with genetic studies to prioritize proteins implicated in numerous human diseases. However, limited interaction between plasma and the central nervous system decreases the fluid's relevance for neurological disease. We compared the pQTL landscapes between plasma and cerebrospinal fluid (CSF), detecting widespread differences across fluids that translate to the identification and prioritization of proteins and pathways implicated in neurological disorders. Of almost 5000 CSF and plasma pQTLs, fewer than 30% were present in both fluids, demonstrating the importance of cross-context analyses to understand genetic regulation of protein abundance. We identified 427 associations between proteins and risk of 14 neurological traits, including 249 associations that were not found in previous studies. Only 69 of the associations were consistently detected in both fluids, demonstrating the information gained through the analysis of multiple bodily contexts. We further demonstrated that CSF proteogenomics captures more substantial disease overlap (for example, between Alzheimer's disease and dementia with Lewy bodies) and captures trait-relevant biology missed in plasma, including cell death and immune response signatures in Alzheimer's and multiple sclerosis. Through this work, we demonstrated the importance of analyzing less accessible but more trait-relevant contexts to fully understand human disease.
    DOI:  https://doi.org/10.1126/scitranslmed.adz2016
  11. J Clin Invest. 2026 Apr 30. pii: e192328. [Epub ahead of print]
    Skin-resident Langerhans cells drive neuropathic pain via chemokine-dependent neuron-immune communication.
    Paola Pacifico, Dale George, Nirupa D Jayaraj, Dongjun Ren, James S Coy-Dibley, Abdelhak A Belmadani, Sofia Veronesi, Mirna Andelic, Daniele Cartelli, Grazia Devigili, Raffaella Lombardi, Giuseppe Lauria Pinter, Amy S Paller, Richard J Miller, Daniela Menichella.
      Neuropathic pain affects over 20 million people in the United States, and painful diabetic neuropathy (PDN), a common complication of diabetes, is among its most prevalent and treatment-resistant forms. Although PDN is characterized by nociceptor dysfunction, the upstream peripheral mechanisms remain incompletely understood. While dorsal root ganglion (DRG) nociceptor hyperexcitability is a hallmark of PDN, emerging evidence suggests that non-neuronal skin cells may modulate nociceptor function. Here, we investigated whether epidermal Langerhans cells (LCs) contribute to neuropathic pain in PDN through neuroimmune signaling. Using a clinically relevant high-fat diet (HFD) mouse model, transgenic LC ablation, behavioral assays, human skin biopsies, and single-cell RNA sequencing of epidermis and DRG, we found that LC density increased in male diabetic mice in parallel with mechanical allodynia. In human PDN skin, LCs exhibited increased volume and dendritic complexity correlating with diabetes duration. Genetic depletion of LCs prevented mechanical allodynia and spontaneous pain-like behavior in male, but not female, HFD mice, revealing a sex-dependent contribution. Single-cell and interactome analyses identified male-specific inflammatory LC programs, including upregulation of chemokine signaling pathways. Consistently, LC secretome profiling showed increased CCL2 release, and local CCR2 blockade reversed allodynia. These findings identify epidermal LCs as peripheral regulators of PDN pain and highlight sex-dependent chemokine-mediated neuron-immune communication at the skin-nerve interface.
    Keywords:  Dermatology; Immunology; Neurodegeneration; Neuroscience; Pain; Skin
    DOI:  https://doi.org/10.1172/JCI192328
  12. Cells. 2026 Apr 09. pii: 664. [Epub ahead of print]15(8):
    Immunoproteasome Inhibition Modulates Microglial Polarization to Facilitate Anti-Inflammatory Responses and Hematoma Resolution After Intracerebral Hemorrhage.
    Wei-Fen Hu, Chien-Hui Lee, Hsin-Yi Huang, Cheng-Yoong Pang, Yi-Feng Wu, Tsung-Jen Lin, Peter Bor-Chian Lin, Sheng-Tzung Tsai, Chia-Ho Lin, Hock-Kean Liew.
      Intracerebral hemorrhage induces severe secondary brain injury characterized by excessive neuroinflammation and inefficient hematoma clearance, processes largely governed by microglial polarization and phagocytic activity. The immunoproteasome, an inducible proteasome isoform involved in immune regulation, has been implicated in inflammatory neurological disorders, but its role in microglial responses after ICH remains unclear. In this study, rat models of common hemorrhage, severe hemorrhage, and severe hemorrhage with hematoma aspiration were used to represent graded injury severity and post-evacuation recovery. Transcriptomic profiling at day 3 post-injury identified immunoproteasome-associated gene networks, while expression of the catalytic subunits LMP2 and LMP7, microglial polarization markers, and phagocytic receptors was analyzed by Western blotting and immunofluorescence. Severe hemorrhage markedly induced LMP2 and LMP7 expression, predominantly in Iba1+ microglia, accompanied by enhanced ER stress, NF-κB signaling, and M1-like polarization and reduced phagocytic marker expression. Hematoma aspiration attenuated immunoproteasome expression and restored M2-associated and phagocytic signatures. Consistently, pharmacological inhibition of immunoproteasomes in primary microglia enhanced erythrophagocytosis and promoted a reparative phenotype in vitro. These findings indicate that immunoproteasome activation links hemorrhagic severity to maladaptive microglial polarization and impaired hematoma clearance after ICH, and that reducing immunoproteasome expression may help rebalance inflammatory and phagocytic microglial functions.
    Keywords:  hematoma clearance; immunoproteasome; intracerebral hemorrhage (ICH); microglial polarization; phagocytosis
    DOI:  https://doi.org/10.3390/cells15080664
  13. Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2516541123
    A causal role for the posterior corpus callosum in bimanual coordination.
    Jung Uk Kang, Lawrence H Snyder, Eric Mooshagian.
      Interareal communication is crucial for coordinated brain function. Given the largely contralateral organization of the brain, bimanual coordination likely depends on interactions across the two cerebral hemispheres for motor planning and execution. The parietal reach region (PRR) is an early node in the sensorimotor transformation stream. Here, we examined the contributions of direct callosal connections between left and right PRR to bimanual coordination. Using manganese-enhanced MRI, we traced callosal pathways crossing the midline and found that PRR-PRR connections are restricted to the splenium. We then temporarily blocked these fibers with lidocaine while measuring behavioral performance and interhemispheric coherence. Blockade selectively reduced PRR-PRR coherence during bimanual movements to a common target, but not during movements to separate targets. Behaviorally, blockade sped movement initiation across tasks, consistent with a functionally inhibitory influence of interhemispheric communication, reduced the temporal synchrony of bimanual movements to a common target, and reduced errors for bimanual movements to separate targets. These findings provide causal evidence that posterior callosal communication supports the temporal precision of spatially coordinated bimanual actions, while potentially constraining independent limb control.
    Keywords:  bimanual coordination; callosal blockade; corpus callosum; interhemispheric communication; parietal cortex
    DOI:  https://doi.org/10.1073/pnas.2516541123
  14. Acta Neuropathol. 2026 Apr 28. pii: 49. [Epub ahead of print]151(1):
    The hypoxia-inflammation cycle as a key mechanism of smoldering inflammation and progression in multiple sclerosis.
    M Missaglia, M Filippi, F Esposito, A Giordano.
      Disease progression in multiple sclerosis (MS) remains a major unmet clinical challenge, as it is driven by pathogenic mechanisms that are poorly targeted by currently available disease-modifying treatments. Whereas acute focal inflammation characterizes the relapsing-remitting phase, converging neuropathological, imaging and experimental evidence identifies a chronic low-grade compartmentalized inflammatory process, the so-called "smoldering" inflammation, as a central driver of disease progression in MS. Recent findings suggest that both tissue hypoxia (primarily resulting from vascular dysfunction) and virtual hypoxia (a state of metabolic supply-demand mismatch culminating in bioenergetic failure) may critically contribute to the onset, persistence and compartmentalization of smoldering inflammation. In this review, we first delineate the pathological mechanisms underlying smoldering inflammation, distinguishing between lesional and extra-lesional features. We then examine the processes leading to tissue and virtual hypoxia in MS. As a key link between smoldering inflammation and hypoxia, we focused on the Hypoxia-Inducible Factor (HIF) signaling, the master regulator of cellular responses to hypoxia. Particularly, we reviewed recent evidence supporting its role as a central immunometabolic hub shaping immune and glial cell function within the hypoxic microenvironment of smoldering inflammation in MS. Finally, we critically evaluate the potential of the HIF signaling as a therapeutic target to hamper smoldering inflammation and disease progression in MS.
    Keywords:  HIF1A; Hypoxia; Multiple sclerosis; Progression; Review; Smoldering inflammation
    DOI:  https://doi.org/10.1007/s00401-026-03021-6
  15. Nature. 2026 Apr 29.
    A cell atlas charts the immune architecture of diabetic kidney disease.
      
    Keywords:  Diabetes; Diseases; Immunology; Transcriptomics
    DOI:  https://doi.org/10.1038/d41586-026-01177-5
  16. J Neuroinflammation. 2026 Apr 28.
    Glioblastoma radiomics can delineate systemic immune activity states like blood abundance of T cell populations or transcription factors.
    Johanna Heugenhauser, Carmen Visus, Johanna Buchroithner, Christine Marosi, Karl Rössler, Thomas Felzmann, Georg Widhalm, Sarah Iglseder, Martha Nowosielski, Friedrich Erhart.
      
    DOI:  https://doi.org/10.1186/s12974-026-03806-2
  17. Science. 2026 Apr 30. 392(6797): 468-469
    Tracking the turning point in Alzheimer's disease.
    Bart De Strooper, Henrik Zetterberg.
      A blood biomarker reveals the mechanistic shift from amyloid to tau pathology.
    DOI:  https://doi.org/10.1126/science.aeb6987
  18. Clin Transl Med. 2026 May;16(5): e70683
    Niacin promotes motor function recovery after spinal cord injury via Hcar2-dependent microglia immunometabolic regulation.
    Hua Du, Lingnian Zeng, Chan Liu, Huyao Zhou, Xia Wang, Qing Ai, Jinpiao Zhu, Nong Xiao.
       BACKGROUND: Traumatic spinal cord injury (SCI) induces a robust local inflammatory response that can both facilitate repair and exacerbate pathology. Hydroxycarboxylic acid receptor 2 (Hcar2) is known to exert immunomodulatory effects; however, its role in SCI and its potential for targeting Hcar2 to alleviate motor deficits remain unclear.
    METHODS: The spinal cord transcriptome following SCI, with a focus on Hcar2, was analysed via publicly available single-cell RNA sequencing datasets from mice and rhesus macaques. Additionally, an in vivo SCI mouse model with Hcar2 knockout and an in vitro LPS-induced BV2 microglial model were established to assess Hcar2 gene and protein expression, microglial activation and inflammatory responses via bulk RNA sequencing, immunofluorescence staining, Western blotting, and real-time polymerase chain reaction. To evaluate the protective effects of Hcar2 activation, niacin, a known Hcar2 agonist, was administered to mice or BV2 cells, followed by assessments of the inflammatory response and motor function.
    RESULTS: Hcar2 gene expression, which was enriched predominantly in spinal cord microglia, was upregulated following SCl, peaking at 7 days post-SCl. Genetic knockout of Hcar2 decreased the percentage of impaired anti-inflammatory polarized microglia and increased the inflammatory response. In contrast, Hcar2 activation with niacin in LPS-stimulated microglia BV cell models reversed mitochondrial dysfunction, increased the oxygen consumption rate and reduced the expression of the cytokines IL-6 and IL-1β. The administration of niacin to SCl mice upregulated anti-inflammatory microglia, reduced the expression of multiple proinflammatory cytokines, increased the number of motor neurons and improved motor function recovery. Notably, all these protective effects were abolished by genetic loss of Hcar2.
    CONCLUSIONS: Hcar2 serves as a critical regulator of microglial polarization, promoting the switch from a proinflammatory phenotype to an anti-inflammatory phenotype through immunometabolic reprogramming. Targeting Hcar2 with niacin may offer a translatable therapeutic strategy to improve functional recovery after SCl.
    KEY POINTS: Hcar2 is identified as a conserved, injury-induced metabolic checkpoint specifically enriched in microglia following spinal cord injury. Hcar2 activation reprogrammes microglial metabolism from glycolysis to oxidative phosphorylation to drive reparative anti-inflammatory polarization. Pharmacological targeting of Hcar2 with niacin resolves neuroinflammation and promotes functional motor recovery in an Hcar2-dependent manner.
    Keywords:  hydroxycarboxylic acid receptor 2; immunometabolism; metabolic reprogramming; microglia; neuroinflammation; niacin; spinal cord injury
    DOI:  https://doi.org/10.1002/ctm2.70683
  19. Neurochem Int. 2026 Apr 28. pii: S0197-0186(26)00056-2. [Epub ahead of print] 106165
    IL-33/ST2 deficiency induces depression-like behaviors through neuroinflammation in the medial prefrontal cortex and hippocampus.
    Haoyu Wang, Siyu Yang, Jiapei Dai, Fang Zheng, Yi Luo, Jiachen Zhao, E Du, Ke Lei, Jiawen Lei, Jinpeng Liu, Yifan Xiao, Huoying Chen, Yan Sun.
      Depression remains a leading cause of global disability, yet its precise neurobiological underpinnings are incompletely understood. While inflammatory cytokines have been implicated in depressive pathology, the specific role of Interleukin-33 (IL-33) and its receptor ST2 in modulating microglial-mediated neuroinflammation has remained elusive. In this study, we reveal that deficiency of the IL-33/ST2 signaling axis in naive adult male mice selectively induces depression-like behaviors without impairing memory, motor coordination, or balance. This behavioral phenotype is mechanistically linked to heightened microglial activation, increased branching complexity, and exacerbated neuronal loss within the medial prefrontal cortex (mPFC) and dentate gyrus (DG). Furthermore, we demonstrate that IL-33 counteract LPS-induced microglial activation, nuclear translocation, and subsequent neuroinflammatory responses in vitro. Collectively, these findings delineate a novel neuroimmune pathway wherein IL-33/ST2 deficiency precipitates microglia-driven neuroinflammation, thereby contributing to depressive phenotypes.
    Keywords:  Depression; IL-33 and ST2; Microglia; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.neuint.2026.106165
  20. Sci Adv. 2026 May;12(18): eady2382
    TLR7 alters the maternal immune landscape during influenza A infection to increase maternal and fetal morbidity.
    Gemma S Trollope, Mark A Miles, Madison Coward-Smith, Felicia Liong, Doug A Brooks, John J O'Leary, Stavros Selemidis, Stella Liong.
      Pregnant women infected with influenza A virus (IAV) are at increased risk of severe disease, leading to maternal and fetal complications. Toll-like receptor 7 (TLR7) recognizes single-stranded RNA viruses, including IAV, yet its role in maternal immune responses and pregnancy outcomes during IAV infection is poorly understood. Here, we demonstrate that TLR7-knockout (TLR7-/-) pregnant mice showed reduced disease severity, despite similar pulmonary viral titers to wild-type (WT) mice. TLR7-/- dams exhibited distinct pulmonary responses, including reduced lymphocyte infiltration, enhanced neutrophil response, and a shift from type I to type II interferon activity. TLR7 signaling was found to be essential for the development of IAV-induced vascular dysfunction during pregnancy. Offspring from TLR7-/- mice showed improved body weight and reduced placental and fetal brain inflammation compared to WT counterparts. We provide evidence that TLR7 is a critical mediator of adverse pregnancy outcomes during IAV infection and a potential therapeutic target to reduce maternal and fetal morbidity.
    DOI:  https://doi.org/10.1126/sciadv.ady2382
  21. J Integr Neurosci. 2026 Apr 21. 25(4): 48436
    Targeting Lipid Metabolism in Alzheimer's Disease: Emerging Insights and Future Directions.
    Jeyakumar Balakrishnan, Suganya Kannan, Kathiresan Shanmugam, Dhavamani Sugasini.
      Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that is conventionally characterized by amyloid-β and tau pathology. There is growing evidence, however, that lipid metabolic disturbances are part of the biology of the disease, and not a secondary phenomenon. Lipid signaling controls membrane organization, amyloid precursor protein, tau phosphorylation, mitochondrial energetics, neuroinflammatory signaling, and synaptic stability. The accumulating genetic evidence, including risk variants in the APOE (apolipoprotein E), ABCA1 (ATP-binding cassette subfamily A member 1), ABCA7 (ATP-binding cassette subfamily A member 7), and TREM2 (Triggering receptor expressed on myeloid cells 2) genes, further makes lipid transport and lipid-sensing pathways central to late-onset AD vulnerability. Recent developments in lipidomics based on mass spectrometry have revealed concerted changes in phospholipids, sphingolipids, sterols, and oxidized lipid derivatives in brain tissue and peripheral biofluids. Instead of single abnormalities, directional metabolic imbalance is indicated by pathway changes, including decreased sphingomyelin-to-ceramide ratios and decreased polyunsaturated phospholipids. Co-analysis of lipidomic, genomic, and proteomic data has shown the existence of metabolically different subgroups, which aids genotype stratified risk evaluation and the lipid responder phenotype concept. Protein-centered therapies are complemented by therapeutic strategies that focus on lipid homeostasis, such as the regulation of cholesterol efflux, sphingolipid metabolism, pro-resolving lipid mediators, and metabolic reprogramming. There is also emerging evidence that implicates peroxisomal dysfunction and compromised glymphatic clearance in interfering with lipid balance. Although this field of research has come a long way, the issues of proving causality, standardizing lipidomic techniques, and converting pathway signatures into clinically useful resources persist. Restructuring AD as a lipid network instability disorder offers a systems level model of earlier diagnosis and targeted treatment.
    Keywords:  Alzheimer’s disease; apolipoprotein E; lipid metabolism; lipidomics; mitochondria; neuroinflammation; precision medicine
    DOI:  https://doi.org/10.31083/JIN48436
  22. Cell Death Dis. 2026 Apr 27.
    The PM20D1-OLE pathway induces microglia rewiring to ameliorate Alzheimer disease.
    Victoria Pozzi-Ruiz, Aida Giner de Gracia, Liliane Glauser, Mario Romani, Fatima Gunter-Rahman, Alejandro González-Ramón, Mahmood Haj-Yahya, Rajasekhar Kolla, Allison M Burns, Hilal A Lashuel, Johan Auwerx, Johannes Gräff, Jose V Sanchez-Mut.
      There is increasing evidence of microglia participation in Alzheimer's disease (AD), which incentives their modulation to intercept the disease. Here, we describe a new mechanism by which the recently AD-associated Peptidase M20 Domain Containing 1 (PM20D1) instructs microglia to tackle AD. We show that the PM20D1-derived N-oleoyl-Leucine (OLE) improves AD pathologies in two animal models of AD. OLE induces microglia association with amyloid beta (Aβ) plaques, reduce their size, number and toxicity, and leads to enhanced neuroprotection and cognition. Furthermore, OLE also increases Aβ chemotaxis and clearance in microglia cultures and enhances cell viability in neurons subjected to AD-related stressors. Finally, we also find evidence for a PM20D1- and OLE-mediated microglia association with amyloid plaques and neuroprotection in human AD brains. In sum, our results provide further insight into the protective role of PM20D1 in AD and support the use of OLE as a microglia-modifying treatment for AD.
    DOI:  https://doi.org/10.1038/s41419-026-08791-1
  23. J Neuroinflammation. 2026 May 02.
    SGK1 inhibition supports neuroprotection in spinal cord injury by suppressing oxidative stress and AIM2 activation via FoxO1 mediated mitophagy.
    Yige Chen, Yikang Wang, Nongtao Fang, Jiawei Xu, Yiwei Teng, Ke Wang, Longze Huang, Haifen Ni, Yongli Wang, Kailiang Zhou, Yan Lin, Yao Li.
      Spinal cord injury (SCI) is accompanied by a significant microglia-associated inflammatory response that is associated with secondary tissue damage and poorer functional outcomes. Serum and glucocorticoid-regulated kinase 1 (SGK1) has been implicated in the regulation of cell survival and neuronal excitability in various diseases. However, the role and cell-specific mechanism of SGK1 in SCI remain to be elucidated. In this study, we observed that SGK1 was predominantly expressed in microglia located at the lesion margin during the early phase of SCI in a mouse contusion model. Inhibition of SGK1 by GSK650394 has been shown to promote neural repair while simultaneously suppressing neuroinflammation and mitochondrial oxidative stress. Mechanistically, the inhibition of SGK1 results in a reduction of FoxO1 phosphorylation and the promotion of nuclear import, consequently inducing microglial mitophagy and promoting mitochondrial homeostasis, leading to the suppression of absent in melanoma 2 (AIM2) related pyroptosis and the conversion of microglia into a neuroprotective M2 phenotype. In particular, AIM2 overexpression or deletion effectively interfered with the influence of SGK1-FoxO1 on the modulation of SCI. In conclusion, the present findings provide a potential therapeutic strategy for the treatment of SCI.
    Keywords:  Absent in melanoma 2; Inflammasome; Mitochondria; Serum and glucocorticoid-regulated kinase 1; Spinal cord injury
    DOI:  https://doi.org/10.1186/s12974-026-03844-w
  24. Mol Neurobiol. 2026 Apr 29. pii: 593. [Epub ahead of print]63(1):
    CD33 Isoform Splicing Dysregulation: A Molecular Determinant of Microglial Dysfunction in Alzheimer's Disease Pathology.
    Xiao-Yan Li, Yu Zhang, Zhao Ran, Jia-Xin Luo, Xiao-Qin Yu, Mei-Hong Lu.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation. Genome-wide association studies (GWAS) have identified microglial dysfunction as central to AD pathogenesis, with CD33 emerging as a critical genetic risk factor. This review explores the dual roles of CD33 isoforms, CD33M (pro-pathogenic) and CD33m (protective), in modulating microglial activity, Aβ clearance, and neuroinflammatory responses. We dissect the molecular mechanisms underlying isoform formation, including genetic polymorphisms (e.g., rs3865444, rs12459419) and splicing regulation by hnRNPA/B, PTBP1, and SRSF1. Additionally, we highlight the antagonistic interplay between CD33 and TREM2, emphasizing their convergence on DAP12 signaling and downstream pathways. Emerging therapeutic strategies targeting CD33, such as isoform-specific immunotherapies, small-molecule splicing modulators, and Siglec-glycan interactions, are critically evaluated for their potential to mitigate AD pathology. By integrating recent preclinical and clinical advancements, this review underscores the necessity of precision approaches to harness CD33's therapeutic potential while addressing challenges like blood-brain barrier penetration and species-specific discrepancies.
    Keywords:  Alzheimer’s disease; CD33 isoforms; Microglia; TREM2
    DOI:  https://doi.org/10.1007/s12035-026-05886-w
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