bims-microg 2026-01-25 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–01–25
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Ageing promotes microglial accumulation of slow-degrading synaptic proteins.
The TREM2 T96K paradox: Stronger signaling in vitro, weaker microglia in vivo.
Midbrain microglial and macrophage mRNAs distinguish neuroinflammatory schizophrenia from bipolar disorder.
Inhibition of the NFATc2/FKBP5 axis alleviates microglial neuroinflammation by regulating arachidonic acid metabolism in Parkinson's disease.
Identification of Chlamydia pneumoniae and NLRP3 inflammasome activation in Alzheimer's disease retina.
Iron Oxide Nanozyme as Reactive Oxygen and Nitrogen Species Scavenger to Regulate Microglial Homeostasis in Stroke.
The Microbiota Shapes Central Nervous System Myelination in Early Life.
Compromised hepatic bilirubin clearance drives depressive symptoms via regulating microglial engulfment of dendritic spines.
Inducible deletion of DGAT1 and 2 from microglia exacerbates neurodegeneration and endolysosomal lipid accumulation in male PS19 mice.
Deficiency of Microglial-Derived Spp1 Exacerbates Age-Related Memory Decline by Impairing Mitochondrial Complex I Function.
TGFβ1 attenuates microglial IL1β release through inhibition of NLRP3 inflammasome priming.
Traumatic brain injury and post-injury sleep fragmentation differentially alter the microglial transcriptome.
APOE genotype differentially modulates prion pathology in a mouse model.
ZFP36-mediated ZBP1 degradation inhibits microglia pro-inflammatory and NLRP3 inflammasome activation in Alzheimer's disease.
Unmasking early microglial remodeling in an Alzheimer's disease mouse model.
Stage-Associated Microglial Subpopulations and Dynamics in Vascular Pathogenesis of Oxygen-Induced Retinopathy.
Silencing of Ifi27l2a Attenuates Inflammation After Spinal Cord Injury by Regulating Microglial Polarization via JAK2/STAT3 Signaling.
The emerging role of the paraventricular thalamic nucleus in bipolar disorder: Lessons from mitochondrial dysfunction.
Microglia and Retinal Vascularity: A Deeper Dive into Branching Dynamics.
Protocol for morphogen-guided differentiation of brain cell types using human induced pluripotent stem cells.

Nature. 2026 Jan 21.

Ageing promotes microglial accumulation of slow-degrading synaptic proteins.

Ian H Guldner, Viktoria P Wagner, Patricia Moran-Losada, Sophia M Shi, Sophia W Golub, Johannes F Hevler, Kelly Chen, Barbara T Meese, Ali Ghoochani, Ernst Pulido, Hamilton Se-Hwee Oh, Yann Le Guen, Nannan Lu, Pui Shuen Wong, Ning-Sum To, Dylan Garceau, Zimin Guo, Jian Luo, Carolyn R Bertozzi, Emma Lundberg, Monther Abu-Remaileh, Michael Sasner, Andreas Keller, Andrew C Yang, Tom H Cheung, Tony Wyss-Coray.

Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with ageing1,2. Here we engineered bioorthogonal tools3 that enabled us to tag the nascent neuronal proteome and study its turnover with ageing, its propensity to aggregate and its interaction with microglia. We show that neuronal protein half-life approximately doubles on average between 4-month-old and 24-month-old mice, with the stability of individual proteins differing among brain regions. Furthermore, we describe the aged neuronal 'aggregome', which encompasses 1,726 proteins, nearly half of which show reduced degradation with age. The aggregome includes well-known proteins linked to diseases and numerous proteins previously not associated with neurodegeneration. Notably, we demonstrate that neuronal proteins accumulate in aged microglia, with 54% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins are highly enriched, which suggests that there is a cascade of events that emerge from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly through microglial engulfment of synapses. These findings reveal the substantial loss of neuronal proteome maintenance with ageing, which could be causal for age-related synapse loss and cognitive decline.

DOI: https://doi.org/10.1038/s41586-025-09987-9
Neuron. 2026 Jan 21. pii: S0896-6273(25)00997-3. [Epub ahead of print]114(2): 193-195

The TREM2 T96K paradox: Stronger signaling in vitro, weaker microglia in vivo.

Silvia Penati, Marco Colonna.

Pilat, Le, and colleagues1 reveal that the Alzheimer's-linked TREM2 T96K variant, previously labeled gain of function based on in vitro assays, unexpectedly weakens microglial activation and disease-associated microglial responses in female mice in vivo, prompting a reassessment of what "functional gain" means for TREM2 in neurodegeneration.

DOI: https://doi.org/10.1016/j.neuron.2025.12.041
Brain Behav Immun. 2026 Jan 16. pii: S0889-1591(26)00024-3. [Epub ahead of print] 106276

Midbrain microglial and macrophage mRNAs distinguish neuroinflammatory schizophrenia from bipolar disorder.

Gerardo Mendez-Victoriano, Yunting Zhu, Yasmine Kostoglou, Adam K Walker, Frank Middleton, Paul T Massa, Bart J L Eggen, Maree J Webster, Iris E C Sommer, Cynthia S Weickert.

   BACKGROUND: Increased microglial/macrophage transcripts are found in the midbrains of cases with neuroinflammatory subtype of schizophrenia. However, it is unknown in which immune cell population these transcripts are mostly expressed, nor do we know if transcriptional changes in microglial/macrophage markers are also found in the midbrains of neuroinflammatory bipolar disorder subgroups.
METHODS: Here, we determined the extent of microglial/macrophage changes in the ventral midbrain (at the level of the oculomotor nerve exit) of a larger cohort of people with schizophrenia and bipolar disorder, defined as low or high-inflammation, compared to controls. We aimed to confirm in which cell cluster our transcripts were expressed (microglia vs macrophages). First, we mapped the cellular expression of putative microglial/macrophage markers via snRNA-seq. Then, mRNA levels of 11 microglial/macrophage markers were measured and compared via RT-PCR from human post-mortem midbrains of 61 healthy controls, 63 schizophrenia cases, and 33 bipolar disorder cases.
RESULTS: 7/11 mRNAs (IBA1, CD11B, CX3CR1, P2RY12, CD64, CD40, &TMEM119) were mainly expressed in microglial cell clusters; 2 mRNAs in the macrophage cell cluster (CD32C, CD86); 1 mRNA was broadly expressed (HEXB), and the CD68 mRNA cluster location appeared to vary according to diagnosis. Across groups, transcripts associated with microglia activation and motility were significantly increased in high-inflammation schizophrenia (IBA1, CD11B; all p ≤ 0.001) and significantly decreased in high-inflammation bipolar disorder (P2RY12, CX3CR1; all p ≤ 0.01) compared to low-inflammation controls. Transcripts associated with microglial and macrophage activation via FcγR-IgG/Immune complex antigen binding were significantly increased in high-inflammatory schizophrenia (CD64 &CD32C) and high-inflammatory bipolar disorder (CD32C) (all p ≤ 0.01). Transcripts associated with increased cytokine response (CD40 & CD86) and phagocytosis (CD68) were significantly increased in high-inflammatory schizophrenia and divergently changed in high-inflammatory bipolar disorder (CD40 increased/CD86 decreased) (all p ≤ 0.05). Overall, the number of CD68 + cells with reactive-like morphology was increased in high-inflammation schizophrenia compared to all the low-inflammation groups (all p ≤ 0.05).
CONCLUSION: Our findings strengthen the contention that microglia and macrophages are activated in schizophrenia and disrupted in bipolar disorder midbrains of high-inflammatory subgroups. This suggests that optimal immune-based treatments targeting schizophrenia and bipolar disorder patients may differ when restoring microglial function during inflammation.

Keywords:  Bipolar Disorder; Macrophage; Microglia; Midbrain; Schizophrenia; mRNA

DOI:  https://doi.org/10.1016/j.bbi.2026.106276
Brain Behav Immun. 2026 Jan 18. pii: S0889-1591(26)00044-9. [Epub ahead of print]134 106296

Inhibition of the NFATc2/FKBP5 axis alleviates microglial neuroinflammation by regulating arachidonic acid metabolism in Parkinson's disease.

Yao Si, Xue Zhao, Lei Wu, Xueying Li, Pusheng Quan, Shi Yan, Xinyu Zhang, Lige Han, Lifen Yao, Fan Yang.

  Microglia-induced neuroinflammation is among the core pathological hallmarks of Parkinson's disease (PD). FKBP5, which has been implicated in stress-related disorders, is recognized as a key regulator of inflammatory responses. However, the role and mechanism of FKBP5 in PD remain unclear. In the present study, we revealed that reducing FKBP5 levels via shRNA targeting microglia or pharmacological inhibition with SAFit2 could mitigate motor impairment and dopamine neuronal loss,as well as reducearachidonic acid (AA) and proinflammatory factors (IL-6, TNF-α, and iNOS) levels in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Conversely, FKBP5 knockdown in 1-methyl-4-phenylpyridinium (MPP+)-treated BV2 microglia reduced inflammatory marker expression and targeted the inhibition of AA synthesis. Moreover, we revealed that NFATc2, a transcription factor of FKBP5, was significantly involved in AA generation and proinflammatory cytokine expression both in vivo and in vitro. In the MPP+-treated microglia, FKBP5 upregulation reversed the inhibition of AA signaling pathways induced by NFATc2 silencing. Furthermore, PD patients presented elevated mRNA expression of NFATc2 and FKBP5 in the peripheral blood, which were positively correlated with disease severity and serum AA levels, respectively. These findings highlight the involvement of the NFATc2/FKBP5 signaling pathway in AA-induced microglial neuroinflammation, indicating that NFATc2/FKBP5 may serve as PD biomarkers and targets for therapeutic interventions.

Keywords:  Arachidonic acid; FKBP5; NFATc2; Neuroinflammation; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.bbi.2026.106296
Nat Commun. 2026 Jan 22. 17(1): 771

Identification of Chlamydia pneumoniae and NLRP3 inflammasome activation in Alzheimer's disease retina.

Bhakta Prasad Gaire, Yosef Koronyo, Jean-Philippe Vit, Alexandre Hutton, Lalita Subedi, Dieu-Trang Fuchs, Natalie Swerdlow, Altan Rentsendorj, Saba Shahin, Daisy Martinon, Edward Robinson, Alexander V Ljubimov, Julie A Schneider, Lon S Schneider, Debra Hawes, Stuart L Graham, Vivek K Gupta, Mehdi Mirzaei, Keith L Black, Jesse G Meyer, Moshe Arditi, Timothy R Crother, Maya Koronyo-Hamaoui.

Chlamydia pneumoniae is an intracellular bacterium implicated in Alzheimer's disease (AD), but its role in retinal pathology and disease progression is unclear. Here we identify Chlamydia pneumoniae inclusions in the retina, showing higher burden in AD retina and brain, increasing with APOEε4, disease stage, and cognitive deficit. Retinal and cortical proteomics reveal bacterial-infection and related NLRP3-inflammasome pathways. Retinal NLRP3 is elevated in mild cognitive impairment and activated in AD dementia, evidenced by increased caspase-1, cleaved interleukin-1β, and cleaved N-terminal gasdermin-D. Chlamydia pneumoniae associates with amyloid-β42, inflammation, apoptosis, pyroptosis, and AD status. In neuronal cultures and APPSWE/PS1ΔE9 model mice, infection induces amyloid-β, inflammasome activation, neuroinflammation, and neurotoxicity, and chronic infection worsens cognition. Fewer pathogen-colocalized microglia are found in AD retinas, implying impaired clearance. Machine learning detects retinal Chlamydia pneumoniae or NLRP3, combined with amyloid-β42, as predictors of AD diagnosis and stage. These findings support a disease-amplifying role for Chlamydia pneumoniae and propose NLRP3-attenuation or antibiotic-based early interventions.

DOI: https://doi.org/10.1038/s41467-026-68580-4
Adv Sci (Weinh). 2026 Jan 20. e18191

Iron Oxide Nanozyme as Reactive Oxygen and Nitrogen Species Scavenger to Regulate Microglial Homeostasis in Stroke.

Yilin Qi, Chunxiao Wang, Yuqing Miao, Jiamin Li, Zengyu Xun, Di Sun, Fei Xu, Minrui Liu, Heping Wang, Galong Li, Xuyi Chen, Haiming Fan, Xue Xue.

  In ischemic stroke, microglia adopt a pro-inflammatory M1-like phenotype, which plays a pivotal role in the excessive production of nitric oxide radical (NO). The elevated levels of NO contribute to caspase-mediated apoptosis, resulting in significant disruption of cerebral tissue architecture and consequent loss of brain function. In this study, we demonstrate that iron oxide nanoparticles (IONPs) with intrinsic enzyme-like activities can effectively scavenge NO by forming a nitrosyl-metal complex. Specifically, 6 nm iron oxide nanoparticle (IONP6) exhibits enzyme-like activities, superoxide dismutase (SOD) and catalase (CAT), thus potentially possessing the ability to scavenge the Reactive Oxygen and Nitrogen Species (RONS), especially the ability to scavenge NO. Furthermore, we show that IONP6 promotes the polarization of microglia toward the M2 phenotype, thereby alleviating neuroinflammation in both in vitro oxygen and glucose deprivation (OGD) and in vivo permanent middle cerebral artery occlusion (pMCAO) stroke models. This is achieved through the modulation of the HIF-1α/TIM-3 signaling axis in stroke rats. Additionally, IONP6 administration significantly reduces infarct size and improves neurological outcomes in stroke rats. Our findings position IONP6 as a promising drug-free therapeutic agent for stroke, capable of regulating microglial polarization and mitigating secondary injury caused by the inflammatory cascade induced by NO.

Keywords:  RONS; iron oxide nanozyme; ischemic stroke; microglia; neuroinflammation

DOI:  https://doi.org/10.1002/advs.202518191
Adv Sci (Weinh). 2026 Jan 18. e15671

The Microbiota Shapes Central Nervous System Myelination in Early Life.

Caoimhe M K Lynch, Emily G Knox, Daniel Soong, Thomaz F S Bastiaanssen, Kalevi Trontti, Gabriel S S Tofani, Sophia Ivaschuk, Michael K Collins, Donia Arafa, Jatin Nagpal, Iiris Hovatta, David A Lyons, Gerard Clarke, John F Cryan.

  Maturation of the gut microbiota coincides with neurodevelopmental processes such as myelination, essential for efficient neural signal transmission. While a role for the microbiome in regulating adult prefrontal cortex (PFC) myelination is known, its effects on early-life myelin formation, growth, and integrity remain unclear. Using a cross-species approach in germ-free (GF) mice and zebrafish, we examined how the microbiota influences early myelination and neural development. Multi-system, multi-level analyses showed that the microbiota impacts glial maturation and myelination across species. In GF mice, we observed sex- and age-dependent alterations in pathways linked to neuronal activity and myelination, with myelin-related transcriptomic changes correlating with functional shifts in neurotransmission- and metabolism-related metabolites over time. Myelin growth and integrity were also affected in a sex- and time-dependent manner. As microglia regulate neuronal activity and engulf myelin, we examined microbiota-microglia interactions and found altered expression of genes involved in microglia maturation and synaptic pruning in both species. In zebrafish larvae, the microbiota influenced the spatial distribution of microglia and oligodendrocytes within the brain and spinal cord. These findings reveal conserved microbiota-mediated modulation of neuronal activity, myelination, and glial maturation in early life, providing a foundation for future studies into these mechanisms.

Keywords:  development; germ‐free; microbiota‐gut‐brain axis; microglia; myelination; neurodevelopment; neuronal activity; zebrafish

DOI:  https://doi.org/10.1002/advs.202515671
J Neuroinflammation. 2026 Jan 20.

Compromised hepatic bilirubin clearance drives depressive symptoms via regulating microglial engulfment of dendritic spines.

Shuaijie Sun, Mengyu Li, Jun Ma, Keqiang He, Li Wang, Chunliu Li, Xiangru Liu, Shiyuan Zhang, Tianyue Yin, Mengmeng Yang, Xinlu Yang, Jiaming Zhang, Chengjun Xu, Zhong Li, Sheng Wang, Hongrui Zhu.

   BACKGROUND: Major depressive disorder (MDD) remains a debilitating global health issue with limited treatment efficacy. Liver qi stagnation (or called liver depression) has been associated with MDD, but the underlying mechanisms are poorly understood. This study investigates whether impaired hepatic function contributes to depressive symptomatology.
METHODS: Using retrospective clinical data, chronic unpredictable stress (CUMS) models, orthotopic liver transplantation, and microglia-specific genetic tools (including TRPM2 and SYK conditional knockouts), we combined behavioral assays, multi-omics, electrophysiology, and optogenetics to explore the liver-brain axis in depression.
RESULTS: Compromised hepatic bilirubin clearance in depressive subjects drives depressive symptoms by enhancing microglial engulfment of dendritic spines in the anterior cingulate cortex (ACC). Clinical evidence highly reveals a correlation between hyperbilirubinemia and MDD severity, mirrored in chronic stress mouse models. Liver transplantation from stressed to non-stressed mice impaired bilirubin clearance and induced depressive behaviors, accompanied by ACC glutamatergic neuronal hypoactivity (ACCGlu) and microglial overactivation. Conversely, transplanting healthy livers into stressed mice alleviated these symptoms. Mechanistically, hyperbilirubinemia activates the bilirubin-TRPM2-SYK axis in microglia, promoting excessive spine pruning and synaptic loss in ACCGlu by employing transcriptional pause-release mechanisms to prioritize protein synthesis of pro-phagocytosis machines. Pharmacological inhibition or genetic ablation of microglial TRPM2 rescues spine density and depressive behaviors. And the maladaptation of ACCGlu neurons in hyperbilirubinemic mice was reversible by TRPM2 blockade, either.
CONCLUSION: Our results reveal a novel liver-brain pathway whereby impaired bilirubin clearance drives depression via microglial synaptic pruning. Targeting microglial TRPM2 offers a promising therapeutic strategy for MDD.

Keywords:  Bilirubin; Depression; Liver-brain axis; Microglia; Neuroinflammation; Pause-release; TRPM2

DOI:  https://doi.org/10.1186/s12974-025-03685-z
Cell Rep. 2026 Jan 16. pii: S2211-1247(25)01613-4. [Epub ahead of print]45(1): 116841

Inducible deletion of DGAT1 and 2 from microglia exacerbates neurodegeneration and endolysosomal lipid accumulation in male PS19 mice.

G Travis Tabor, Alexandra Litvinchuk, Yun Chen, Austin Allison, Elizabeth W Sun, Bettina van Lengerich, Sonnet S Davis, Elizabeth West, Johannes C M Schlachetzki, Carisa Zeng, Hao Hu, Peter B Lin, Prabal Sharma, Xiaoying Chen, Samira Parhizkar, Sihui Song, Xin Bao, Lakshita Senthil, Abhirami K Iyer, Shih Feng You, Javier Remolina Serrano, Melissa Manis, Emily Franke, Anil G Cashikar, Carla M Yuede, Jung H Suh, Celeste M Karch, Andrew Folick, Suneil K Koliwad, Robert V Farese, Tobias Walther, Eric J Huang, Maxim Artyomov, Christopher K Glass, Gilbert Di Paolo, Jason D Ulrich, David M Holtzman.

  Brain myeloid cells accumulate neutral lipids in multiple human neurodegenerative disorders and relevant mouse models. These lipids are often assumed to be contained in lipid droplets (LDs). While studies have been performed in cell culture and Drosophila models to characterize glial LDs, the roles of microglial LD biogenesis in mammalian tauopathy are unclear. To address this issue, we induced the deletion of diacylglycerol acyltransferases (DGATs) 1 and 2, enzymes critical for LD formation, from microglia in the PS19 mouse model of tauopathy. Microglial DGAT double knockout (KO) exacerbated neurodegeneration and increased the abundance of brain cholesteryl esters in male PS19 mice. Myeloid cell lipid accumulations appeared to largely localize to endosomes/lysosomes, not LDs, at baseline and were exacerbated upon DGAT KO. Our results suggest that microglial DGAT-dependent TAG/LD biogenesis is adaptive in advanced tauopathy. Most lipid accumulation in brain myeloid cells does not appear to correspond to LDs in this tauopathy model, which has implications for the development of lipid-modulating therapies for neurodegenerative diseases.

Keywords:  CD68; CP: metabolism; CP: neuroscience; PS19; cholesteryl ester; diacylglycerol acyltransferase; lipid droplet; lysosome; microglia; neurodegeneration; tauopathy; triglyceride

DOI:  https://doi.org/10.1016/j.celrep.2025.116841
Aging Cell. 2026 Feb;25(2): e70378

Deficiency of Microglial-Derived Spp1 Exacerbates Age-Related Memory Decline by Impairing Mitochondrial Complex I Function.

Meiling Wang, Yumin Chang, Aojie He, Jing Yang, Ang Li, Hongqin Wang, Kah-Leong Lim, Xing Guo, Chengwu Zhang, Li Lu.

  Age-related memory decline is a hallmark of brain aging and a primary risk factor for neurodegenerative disorders. Microglia play a crucial role in preserving memory function by maintaining brain homeostasis through phagocytosis, yet the specific mechanisms governing this protective function remain elusive. In the present study, we identified a population of Secreted Phosphoprotein 1 (Spp1)-positive microglia in both aged mouse and human brains. To investigate the role of microglial Spp1 in aging, we generated microglia-specific Spp1 knockout (Spp1-cKO) mice. We demonstrate that Spp1 deficiency selectively precipitates memory deficits in aged mice, without affecting memory function in young mice, indicating an age-dependent reliance on Spp1 signaling. Microglial phagocytic capacity positively correlates with Spp1 levels and is diminished by Spp1 deficiency. Mechanistically, Spp1 deficiency leads to the downregulation of the AKT/mitochondrial complex I pathway, thereby compromising microglial oxidative phosphorylation and function. Notably, microglia-specific overexpression of Spp1 partially ameliorates the age-related phenotypes induced by Spp1 deficiency. In conclusion, this study is the first to reveal the crucial role of microglial Spp1 in brain aging and to uncover its underlying mechanism, providing novel insights into age-related memory decline.

Keywords:  ATP; Spp1; age‐related memory decline; microglia; mitochondrial complex I

DOI:  https://doi.org/10.1111/acel.70378
Front Immunol. 2025 ;16 1623643

TGFβ1 attenuates microglial IL1β release through inhibition of NLRP3 inflammasome priming.

Christopher Kalischer, Phani Sankar Potru, Nele Lehmann, Jannik Jahn, Nikolai Leander Rupp, Natascha Vidovic, Tamara Russ, Susanne Wiemann, Björn Spittau.

   Introduction: Microglia reactivity has been described as a driver of brain tissue damage in multiple neurodegenerative pathologies. One of the key features of reactive microglia is the transcriptional upregulation of in ammatory markers, including components of the NLRP3 inflammasome such as Nlrp3, Casp1, and Il1b. The NLRP3 inflammasome is a multiprotein complex that plays an important role in several neurodegenerative diseases, being essential for cleavage and subsequent release of IL1b from activated microglia. Transforming growth factor β1 (TGFβ1) is a potent immunoregulatory cytokine with fundamental roles in microglial development, maintenance, and regulation of microglia reactivity.
Methods: Using BV2 cells, primary microglia, qPCR, and western blotting the effect of TGFβ1 on LPS-induced inflammasome priming and activation was addressed. Cx3cr1CreERT2:R26-YFP: Tgfbr2flox/flox mice were used to elucidate priming in the absence of microglial TGFβ signalling.
Results: In the present study, we demonstrate that TGFβ1 is able to abrogate LPS-induced transcriptional upregulation of the inflammasome-associated genes Nlrp3, Casp1, and Il1b in microglia. Moreover, we provide evidence that TGFβ1 attenuates microglial IL1b release after nigericin-triggered NLRP3 inflammasome activation as a consequence of reduced priming.Finally, we demonstrate that silencing of microglial TGFβ signalling in vivo results in upregulation of Casp1, Il18, and Il1b.
Discussion: Together, our data enhance the understanding of how TGFβ1 and microglial TGFβ signaling regulate microglial reactivity, further highlighting the essential functions of TGFβ1 as a potentimmunoregulatory factor for microglia.

Keywords:  IL1b; LPS; NLRP3; TGFβ1; inflammasome; microglia

DOI:  https://doi.org/10.3389/fimmu.2025.1623643
Front Immunol. 2025 ;16 1689773

Traumatic brain injury and post-injury sleep fragmentation differentially alter the microglial transcriptome.

Morgan A Taylor, Rebecca Boland, Samuel Houle, Zoe M Tapp, Amara C Davis, Christopher Cotter, John F Sheridan, Jonathan Godbout, Olga N Kokiko-Cochran.

   Introduction: Traumatic brain injury (TBI) is a global source of injury-related death and disability, and survivors often suffer functional and psychiatric consequences that persist for years. Neuroinflammation, mediated in part by microglia, perpetuates chronic dysfunction after TBI and leaves survivors vulnerable to the effects of secondary immune challenges. Previous data from our lab shows that 30 days of mechanical sleep fragmentation (SF) aggravates microglia- associated neuroinflammation in C57BL/6 mice, impairing recovery after TBI.
Methods: To better understand the mechanisms through which microglia contribute to impairment following post-TBI SF, we used flow cytometry to analyze multiple cell types from brain and peripheral tissues of C57BL/6 mice who received a TBI or sham injury followed by 7 or 30 days of SF or control housing. Next, bulk RNA sequencing was used to analyze gene expression in microglia and coronal slice from the ipsilateral brain. We analyzed differentially expressed genes (DEGs) within each tissue type to determine how ipsilateral brain and microglia are independently influenced by TBI and SF. We also compared microglial DEGS directly to those of coronal slice, gaining novel insight into how microglia contribute to dysfunction in the ipsilateral brain after TBI and post-injury SF.
Results: Flow cytometry revealed transient increases in monocyte infiltration to the brain 7 days post-injury (DPI) that resolved by 30 DPI. SF did not exacerbate the immune response to injury within peripheral tissues or the brain at either of these time points. From our transcriptomic analysis, we identified distinct sets of DEGs which are uniquely dysregulated by TBI, SF, and the combination of TBI and SF. Notably, we found distinct subsets of olfactory genes that are differentially dysregulated by TBI and SF in the ipsilateral brain, as well as significant enrichment of cell-cell communication and steroidogenesis pathways that are specifically disrupted in microglia compared to the rest of the brain.
Discussion: Through in-depth transcriptional analysis we identify potential molecular targets that shed light on the mechanisms of TBI-induced microglial activity and reveal how SF after TBI alters this response. Together, these data could inform therapeutic strategies that target neuroinflammation to improve chronic recovery after brain injury.

Keywords:  RNA-sequencing; TBI; microglia; monocytes; neuroinflammation; sleep fragmentation

DOI:  https://doi.org/10.3389/fimmu.2025.1689773
Acta Neuropathol Commun. 2026 Jan 21.

APOE genotype differentially modulates prion pathology in a mouse model.

Anita M Lizińczyk, Joanna E Pankiewicz, William L Cullina, Leor A Franco, Patrick M Sullivan, Martin J Sadowski.



Keywords:  Alzheimer’s disease; Apolipoprotein E; Astrocytes; Microglia; Neurodegeneration; Neuroinflammation; Prion diseases; Prion protein

DOI:  https://doi.org/10.1186/s40478-025-02207-5
Cell Biol Toxicol. 2026 Jan 20.

ZFP36-mediated ZBP1 degradation inhibits microglia pro-inflammatory and NLRP3 inflammasome activation in Alzheimer's disease.

Ting Liu, Dan Chen, Fengjie Liu, Yun Sun.

  Alzheimer's disease (AD) is a heterogeneous disease with limited treatment efficacy. Identifying novel molecular targets and mechanisms is therefore crucial for developing therapeutic strategies. Zinc finger protein 36 (ZFP36) has not been reported in AD. This study found that the hippocampus of APP/PS1 mice showed ZFP36 upregulation. Using recombinant adeno-associated virus to overexpress ZFP36 improved the cognitive function of APP/PS1 mice, as assessed by Morris maze and Y maze tests. Furthermore, ZFP36 overexpression reduced Aβ deposition, expression of pro-inflammatory markers, and inhibited NLRP3 inflammasome activation in the hippocampus. These inhibitory effects of ZFP36 overexpression on the aforementioned proteins were also observed in Aβ₁₋₄₂-treated BV-2 cells. mRNA sequencing identified Z-DNA Binding Protein 1 (ZBP1) as a target of ZFP36. After ZFP36 overexpression, ZBP1 was downregulated in the hippocampus and Aβ1-42-treated BV-2 cells. The interaction between ZFP36 and ZBP1 RNA was verified by RIP-PCR, and ZFP36 was shown to promote the degradation of ZBP1 mRNA. The inhibitory effects of ZFP36 on the NLRP3 inflammasome activation and microglial pro-inflammatory activation was reversed by ZBP1 overexpression. In summary, ZFP36 inhibits microglia pro-inflammatory and NLRP3 inflammasome activation through promoting the degradation of ZBP1 mRNA, thereby ameliorating cognitive deficits of APP/PS1 mice.

Keywords:  APP/PS1 mice; Alzheimer's disease; Microglia; NLRP3 inflammasome; ZFP36

DOI:  https://doi.org/10.1007/s10565-026-10139-6
Front Cell Neurosci. 2025 ;19 1720382

Unmasking early microglial remodeling in an Alzheimer's disease mouse model.

Priyanka Saminathan, Sara McArdle, Maija Corey, Namratha Nadig, Camille Fang, Alicia Gibbons, Mahati Rayadurgam, Sonia Sharma.

  Early neuroimmune remodeling is a critical yet understudied component of Alzheimer's disease (AD) pathogenesis. To investigate microglial contributions to AD development prior to overt plaque deposition, we developed an open-source morphometric pipeline to systematically quantify hippocampal microglial structure and activation states in pre-plaque 5xFAD mice. Across ∼11,000 cells, we extracted multidimensional parameters including area, circularity, convex hull, branch points, nearest-neighbor distance, and nuclear features, alongside Iba1 and CD68 intensity measurements. While no significant overt gliosis was observed at this early stage, microglia from 5xFAD mice exhibited subtle trends toward increased structural complexity compared to wild-type controls. Importantly, significant sex-specific differences were detected within the CA1 subregion: male 5xFAD microglia displayed hyper-ramified morphologies consistent with enhanced surveillance states, whereas female microglia demonstrated greater density and a more reactive phenotype. Correlation analyses revealed a conserved association between microglial complexity and Iba1/CD68 expression, independent of sex or genotype, underscoring a fundamental link between cytoskeletal remodeling and phagolysosomal activity. These findings highlight the capacity of morphometric profiling to sensitively detect early, region-specific, and sex-dependent shifts in microglial phenotype before amyloid deposition. By integrating quantitative morphology with canonical molecular markers, this framework provides a robust and unbiased approach for characterizing microglial activation trajectories. Such early readouts may inform biomarker discovery and therapeutic strategies aimed at modulating microglial responses to delay or prevent AD progression.

Keywords:  Alzheimer’s disease; Iba1 and CD68 quantification; QuPath; hippocampus; image segmentation; microglia morphometry; morphological remodeling; neuroinflammation

DOI:  https://doi.org/10.3389/fncel.2025.1720382
Cell Prolif. 2026 Jan 22. e70165

Stage-Associated Microglial Subpopulations and Dynamics in Vascular Pathogenesis of Oxygen-Induced Retinopathy.

Yuan Ma, Ziye Chen, Baoyi Liu, Wen Ding, Runping Duan, Kangjie Kong, Zhuojun Xu, Jizhu Li, Jiali Ru, Dianlei Guo, Xiaoyue Wei, Yaping Liu, Zhuangling Lin, Yang Meng, Yuan Liu, Lan Jiang, Zitong Chen, Rebiya Tuxun, Chinling Tsai, Chunqiao Liu, Tao Li.

  Retinal neovascularisation (RNV) is manifested in various retinal pathological conditions, often leading to irreversible blindness. The oxygen-induced retinopathy (OIR) mouse model proves to be a useful tool for understanding RNV pathogenesis. In this model, retinal vascular phenotype undergoes two distinct stages: neovascular formation, followed by spontaneous regression. While microglial functions in the neovascular formation stage have been extensively studied, their behaviors and roles during regression remain unclear. In this study, we characterise the spatiotemporal dynamics and molecular heterogeneity of retinal microglia across both stages. During RNV formation, microglia exhibit an outer-to-inner and central-to-midperipheral migration pattern, whereas a reversed migration trend is observed during regression. We confirm a highly glycolytic microglia (HGM) subpopulation during RNV formation and demonstrate its pro-angiogenic role by targeting a highly expressed pyruvate kinase M2 (Pkm2), a crucial enzyme for glycolysis. Importantly, we find that microglia exhibit enhanced phagocytic activity during regression, constituting a distinct phagocytosis-associated microglia (PAM) subtype, expressing mannose receptor C-type 1 (Mrc1/CD206). Altogether, our findings reveal stage-specific microglial functional dynamics, providing novel insights into RNV pathogenesis and intervention.

Keywords:  Pkm2; microglia; oxygen‐induced retinopathy; phagocytosis; retinal neovascularisation

DOI:  https://doi.org/10.1111/cpr.70165
Mol Neurobiol. 2026 Jan 23. 63(1): 390

Silencing of Ifi27l2a Attenuates Inflammation After Spinal Cord Injury by Regulating Microglial Polarization via JAK2/STAT3 Signaling.

Wenhao Chen, Xingkun Wang, Qian Xu, Heng Duan, Di Pan, Xinyu Wang, Yuwei Su, Hao Li.

  Microglial polarization toward M1/M2 phenotypes is crucial in modulating neuroinflammation following spinal cord injury (SCI). This study aimed to investigate the role of interferon alpha-inducible protein 27-like 2A (Ifi27l2a) in regulating microglial polarization in SCI. The expression of Ifi27l2a were analyzed using single-cell RNA sequencing. C57BL/6 mice that underwent SCI were pretreated with adeno-associated virus (AAV) carrying sh-Ifi27l2a. In vitro, BV-2 cells were transfected with si-Ifi27l2a and stimulated with lipopolysaccharide (LPS). The effects of Ifi27l2a silencing were assessed through Basso Mouse Scale (BMS) scoring, inclined plane testing, hematoxylin and eosin (H&E) and Nissl staining, quantitative real-time PCR (qRT-PCR), western blotting, and immunofluorescence. Ifi27l2a expression was markedly upregulated in microglia of mice with SCI. AAV delivery of sh-Ifi27l2a in SCI mice improved motor function and decreased neuronal death, as evidenced by increased BMS score, greater inclined plane angles, and increased Nissl bodies. sh-Ifi27l2a downregulated the expression of the M1-type marker inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines TNF-α, IL-1β, and IL-6, while upregulating the M2 marker Arginase-1 and the anti-inflammatory cytokine IL-10. The effects of Ifi27l2a silencing on the M1/M2 polarization balance were confirmed in LPS-stimulated BV-2 cells. Bioinformatic prediction identified JAK2/STAT3 as a potential downstream signaling of Ifi27l2a. The modulatory effects of Ifi27l2a silencing on microglial polarization were partially mediated by JAK2/STAT3 signaling. Ifi27l2a expression was upregulated in the microglia of SCI mice. Silencing Ifi27l2a at the injury site suppressed M1 polarization while promoting M2 polarization, primarily through inhibition of the JAK2/STAT3 signaling pathway.

Keywords:   Ifi27l2a ; JAK/STAT signaling; Microglial polarization; Spinal cord injury

DOI:  https://doi.org/10.1007/s12035-026-05701-6
Psychiatry Clin Neurosci. 2026 Jan 19.

The emerging role of the paraventricular thalamic nucleus in bipolar disorder: Lessons from mitochondrial dysfunction.

Tadafumi Kato, Mie Kubota-Sakashita, Yasuyuki Shima, Masaki Nishioka.

  Bipolar disorder is a psychiatric disorder marked by recurrent mood episodes and a strong genetic component. Despite widespread use of mood stabilizers and atypical antipsychotics, effective treatments remain limited, highlighting the need for mechanistic insights. Early studies revealed decreased phosphocreatine and increased mitochondrial DNA (mtDNA) deletions in the brains of bipolar disorder patients, leading to the mitochondrial dysfunction hypothesis. This framework proposes that mtDNA mutations impair Ca2+ buffering, producing neuronal dysfunction and mood instability. Supporting evidence spans neuroimaging, postmortem, genetic, and cellular studies, as well as therapeutic responses to mitochondrial modulators. Large-scale genomic analyses implicate both rare and common variants affecting Ca2+ signaling and mitochondrial-endoplasmic reticulum function, while somatic mtDNA mutations further link mitochondrial pathology to bipolar disorder. Animal and induced pluripotent stem cell models converge on neuronal hyperexcitability as a downstream effect of impaired Ca2+ regulation. Recent work highlights the paraventricular thalamic nucleus (PVT) as a critical site of pathology. The PVT integrates serotonergic and limbic circuits, regulates salience, and exhibits the highest burden of mtDNA deletions in mutant Polg (mtDNA polymerase) mice. In humans, single-nucleus RNA sequencing reveals a ~50% reduction of PVT neurons in bipolar disorder, with marked transcriptional dysregulation enriched for bipolar disorder risk loci in PVT, with additional changes in microglia. Neuropathological studies further suggest neurodegenerative changes in PVT, particularly in late-onset bipolar disorder. Collectively, these findings position PVT pathology at the core of bipolar disorder pathophysiology, offering a framework that integrates genetic risk, neuronal hyperexcitability, and circuit-level dysregulation and guiding future therapeutic strategies.

Keywords:  bipolar disorder; intracellular calcium signaling; microglia; paraventricular nucleus of the thalamus; serotonin

DOI:  https://doi.org/10.1111/pcn.70015
Curr Eye Res. 2026 Jan 22. 1-9

Microglia and Retinal Vascularity: A Deeper Dive into Branching Dynamics.

Ting Xu, Jingjing Ding, Jiawei Zhang, Dongwei Liu, Liming Tao.

   PURPOSE: This study explored the regulatory role of microglia in retinal vascular development, particularly their effects on vascular bifurcation and maturation. The study aimed to elucidate how microglia influence retinal vascular complexity and maturation.
METHODS: Using CX3CR1GFP/+ reporter and pharmacological depletion mouse model, retinas were analyzed at P42 via immunofluorescence staining and confocal microscopy. Primary brain-derived microglia and brain microvascular endothelial cells were used for in vitro co-culture experiments. Quantitative assessments of vascular bifurcation points were performed via ImageJ software. Tangential frozen sections were used to analyze spatial relationships.
RESULTS: The results revealed an increase in vascular bifurcation complexity, which was correlated with microglia density. Conversely, microglial depletion led to a significant reduction in vascular bifurcation, particularly in the peripheral retina, impairing the formation of the vascular network. In vitro, co-culture with microglia enhanced endothelial cell tube formation and sprouting.
CONCLUSION: Our findings reveal a strong association between microglial distribution and vascular patterning, supporting the role of microglia in normal retinal vascular development and offering perspectives for future research.

Keywords:  Microglia; PLX5622; branch; retinal imaging; retinal vascularity

DOI:  https://doi.org/10.1080/02713683.2025.2601172
STAR Protoc. 2026 Jan 16. pii: S2666-1667(25)00745-2. [Epub ahead of print]7(1): 104339

Protocol for morphogen-guided differentiation of brain cell types using human induced pluripotent stem cells.

Lu Qian, Juao-Guilherme Rosa, Julia Tcw.

  Modeling neurological disorders is challenging due to differing functional genomics and phenotypes among species. Here, we present a protocol for morphogen-guided differentiation of human induced pluripotent stem cells (hiPSCs) into microglia, astrocytes, and mixed cortical cultures (MCCs) for studying human brain disorders. We describe steps for enhancing microglial production using hypoxia and implementing quality-control measures for astrocyte and MCC differentiations. We detail knockout serum replacement procedures for serum-free astrocytes. This protocol enables cell-type-specific investigation of disease mechanisms and drug screening.

Keywords:  Cell culture; Cell differentiation; Neuroscience; Stem cells

DOI:  https://doi.org/10.1016/j.xpro.2025.104339