bims-microg 2026-03-08 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–03–08
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Treponema pallidum Impairs Microglial Aβ1-42 Clearance by Hijacking TLR2/PI3K/AKT Immune Signaling.
Sfrp2 in Microglia Inhibited S100a8-Mediated Neuroinflammation and Protected Neural Damage Following Retinal Ischemia-Reperfusion.
Carnosine protects human microglia against Aβ oligomers through a multimodal mechanism of action: inhibition of oxidative stress, rescue of cellular energy status, and enhancement of phagocytosis.
Identification of plasma inflammatory biomarkers for Alzheimer's disease reveals IFN-γ as a regulator of ACSL1-mediated microglia phenotype.
Phagocytosis by retinal pigment epithelium and microglia does not affect vision restoration by P3HT nanoparticles in Retinitis pigmentosa.
HIV gp120 induces TREM1 expression through TLR-PGE₂ signalling in human monocyte-derived microglia.
Microglial CR3-mediated synaptic pruning in the dmPFC promotes the generation and maintenance of chronic muscle pain via glutamatergic dysfunction.
High-dose polystyrene nanoparticles trigger aberrant activation of the MAPK pathway in spinal cord and pain hypersensitivity.
Angiopep-2-engineered extracellular vesicles derived from spinal cord injury-responsive brown adipose tissue for targeted neuroinflammation modulation.
Phagocytes as plaque catalysts: Human macrophages generate seeding-competent Aβ42 fibrils with cross-seeding activity.
High-throughput phenotyping of microglial membrane Capacitance: Linking label-free dielectric signatures to polarization continuum and phospholipid remodeling.
Myelin sheaths persist for weeks following axon degeneration.
A strategy of microglia replacement alleviates microgliopathy in a CSF1R I794T hotspot mutation mouse model of CSF1R-related disorder.
Berbamine hydrochloride as a brain penetrant galectin 3 inhibitor in a model of Huntington's disease.
HDAC6 regulates BACE1 stability and NLRP3 inflammasome activation in Alzheimer's disease.
Lnc-USP28-6/ZBTB16 axis orchestrates NLRP3 inflammasome activation and α-synuclein SUMOylation to drive Parkinson's disease pathogenesis.
Ectopic B lymphocyte follicles exacerbate ischemic brain damage via MIF-CD74/CXCR4 and interferon signaling.
A genetic architect of opioid responses: Microglial Runx1.
MS4A4A and MS4A6A: New targets to enhance microglia protective function in Alzheimer's disease.
Targeting amyloid-β pathology by chimeric antigen receptor astrocyte (CAR-A) therapy.

ACS Infect Dis. 2026 Mar 06.

Treponema pallidum Impairs Microglial Aβ1-42 Clearance by Hijacking TLR2/PI3K/AKT Immune Signaling.

Lin Xie, Jian-Li Ke, Yun-Ting Hu, Feng-Qian Ma, Meng-Xue Zheng, Ruo-Ying Wang, Ya Yan, Yi-Yang Lin, Li-Li Liu.

  Neurosyphilis sharespathological features with neurodegenerative diseases, notably amyloid-β(Aβ) deposition. Given this association, we sought to elucidate how Treponemapallidum (Tp) mediates Aβ pathology by examining its effects onboth Aβ production and clearance using the integrated invivorabbit model and in vitro systems.Rabbits subjected to intracisternal Tp for two months exhibited elevatedAβ levels in the hippocampus relative to PBS controls. Focusing on the highlyamyloidogenic Aβ1-42 variant, we found that Tpexposure increased Aβ1-42secretion in iPSC-derived neurons byupregulating theexpression of β-site amyloid precursor proteincleaving enzyme 1 without altering amyloid precursor protein levels.Concurrently, impairedmicroglial function in HMC3 cells, markedly inhibiting both phagocytosis anddegradationof Aβ1-42, is quantified by flow cytometry and immunofluorescence. Mechanistic studies revealed that Tpactivates the TLR2/PI3K/AKT signaling pathway, which in turn impairedmicroglial Aβ uptake and clearance, a conclusion robustly supported by our finding thatpharmacological inhibition of this pathway restores clearance function.Our results establish adual mechanism whereby Tp promotes Aβ1-42 accumulation throughcoordinated enhancement of neuronal production and impairment of microglialclearance, an effect mediated via TLR2/PI3K/AKT activation, providing a crucialmechanistic insight into neurosyphilis-associated neurodegeneration.

Keywords:  Treponema pallidum; amyloid-β1−42; microglia; neuron; neurosyphilis

DOI:  https://doi.org/10.1021/acsinfecdis.5c00946
Invest Ophthalmol Vis Sci. 2026 Mar 02. 67(3): 8

Sfrp2 in Microglia Inhibited S100a8-Mediated Neuroinflammation and Protected Neural Damage Following Retinal Ischemia-Reperfusion.

Shuya Tao, Wen Hu, Yaguang Hu, Qiaochu Cheng, Zihao Lin, Hao Xu, Yuxun Shi, Dan Ye, Fan Xu, Yue Xu, Yantao Wei, Jingjing Huang.

Purpose: The purpose of this study was to explore retinal Sfrp2 expression, functional roles, and underlying mechanism in retinal ischemia reperfusion (I/R).
Methods: We established an I/R mouse model in vivo and a lipopolysaccharide-stimulated BV2 model in vitro. Immunohistochemistry and Western blotting (WB) assessed Sfrp2 expression in human retinal tissue, and WB further evaluated its expression in I/R model. Immunofluorescence staining was used to define its localization. Sfrp2 expression was ablated by Cre-lox mediated conditional deletion in mouse retinal microglia and by siRNA-mediated knockdown in BV2 cells. Hematoxylin and eosin staining, immunofluorescence, and TUNEL staining were applied for evaluating retinal structure, survival of inner retinal neurons, and cell apoptosis, respectively. Retinal function was evaluated by electroretinography. RNA-sequencing, WB, and immunoprecipitation were used to elucidate the underlying mechanisms.
Results: Sfrp2 was highly expressed in the retina subjected to I/R injury. Sfrp2 was shown to localize in microglia in an I/R model. Correspondingly, microglial Sfrp2 deficiency exacerbated the retinal structural damage, inner retinal neuronal degeneration, visual dysfunction, and microglia-mediated inflammation in the I/R model. Mechanistically, Sfrp2 deficiency activated TRAF6-TAK1-NF-κB signaling cascade by promoting the TRAF6-TAK1 complex formation, subsequently increasing the expression of downstream inflammatory mediator S100a8. Importantly, S100a8 inhibitor could partially mitigate the retinal injury induced by microglial Sfrp2 deficiency following I/R.
Conclusions: Sfrp2 in microglia inhibits TRAF6-TAK1-NF-κB signaling pathway and downstream inflammatory mediator S100a8 thereby attenuating neuroinflammation and protecting the retina in I/R. Sfrp2 may represent a protective strategy for neuronal degeneration in ischemic retinopathy.

DOI: https://doi.org/10.1167/iovs.67.3.8
Front Immunol. 2026 ;17 1768094

Carnosine protects human microglia against Aβ oligomers through a multimodal mechanism of action: inhibition of oxidative stress, rescue of cellular energy status, and enhancement of phagocytosis.

Anna Privitera, Vincenzo Cardaci, Matthew C Zupan, Lucia Di Pietro, Giuseppe Carota, Jay Sibbitts, Renata Mangione, Andrea Graziani, Lucia Buccarello, Francesco Bellia, Valentina Di Pietro, Giuseppe Lazzarino, Susan M Lunte, Meredith D Hartley, Filippo Caraci, Barbara Tavazzi, Emiliano Maiani, Angela M Amorini, Giacomo Lazzarino, Giuseppe Caruso.

   Introduction: Carnosine is an endogenous dipeptide composed by β-alanine and L-histidine widely distributed in excitable tissues like muscles and brain. Carnosine participates in the cellular defenses against oxidative/nitrosative stress through a multimodal mechanism of action, including scavenging of the reactive oxygen and nitrogen species (ROS and RNS) and, in brain cells, the inhibition of amyloid-beta (Aβ) aggregation. Microglia play a central role in the pathophysiology of Alzheimer's disease (AD), maintaining the homeostasis of the brain microenvironment. However, its hyperactivation causes an increased secretion of inflammatory mediators and free radicals, leading to neuroinflammatory phenomena that exacerbate neurodegeneration. In the present work, carnosine was tested for its ability to protect human microglial cells (HMC3) against Aβ oligomers-induced oxidative stress and energy metabolism unbalance.
Methods: The effects of carnosine to modulate nitric oxide (NO) and ROS intracellular levels were evaluated by microchip electrophoresis coupled to laser-induced fluorescence (ME-LIF), while additional stress-related parameters and cellular energy metabolism were investigated through high-performance liquid chromatography (HPLC).
Results: Pre-treatment with carnosine counteracted the oxidative/nitrosative stress induced by Aβ1-42 oligomers by decreasing the intracellular levels of NO and ROS, and rescuing GSH levels. Carnosine preserved cellular mitochondrial-related energy metabolism, restoring concentrations of high-energy phosphates, nicotinic coenzymes and oxypurines, and normalizing UDP-derivatives homeostasis. Furthermore, carnosine strongly enhanced the phagocytic activity of HMC3 cells.
Discussion/Conclusion: These results demonstrate the protective effects of carnosine on human microglial cells against detrimental alterations induced by Aβ oligomers, underlining the multimodal mechanism of action of this dipeptide and supporting its promising potential in the context of AD pathology.

Keywords:  Alzheimer’s disease; carnosine; energy metabolism; human microglia; neurodegeneration; oxidative stress

DOI:  https://doi.org/10.3389/fimmu.2026.1768094
Front Immunol. 2026 ;17 1770509

Identification of plasma inflammatory biomarkers for Alzheimer's disease reveals IFN-γ as a regulator of ACSL1-mediated microglia phenotype.

Ronghua Huang, Bing-Biao Lin, Zhijie Lu, Yixuan Hao, Chenrui Li, Zixian Lin, Yingjie Zhang, Naili Wei, Jian Chen.

   Background: The identification of plasma biomarkers for the diagnosis of Alzheimer's disease (AD) has been a longstanding research priority; however, few plasma biomarkers have yet been implemented in routine clinical practice.
Methods: This study enrolled 141 participants, including 71 patients with AD, 44 individuals with mild cognitive impairment, and 28 cognitively healthy controls (HC). A total of 16 plasma inflammatory proteins were quantified using multiplex liquid-chip assays, and APOE genotyping was performed. The diagnostic utility of plasma proteins was assessed using the least absolute shrinkage and selection operator (LASSO) with nested cross-validation.
Results: Patients with AD exhibited marked alterations in plasma inflammatory profiles, with elevated levels of IFN-γ, IL-33, and IL-18, and reduced levels of IL-7 and CCL11. Integrating inflammatory markers with clinical variables and APOE genotype substantially improved discrimination between AD and HC, increasing the area under the ROC curve from 0.863 to 0.953. Among all biomarkers, IFN-γ emerged as the most informative predictor and was significantly elevated in AD patients carrying the APOE ϵ4 allele. Analyses of single-nucleus RNA sequencing data further revealed pronounced enrichment of IFN-γ signaling in APOE4/4 AD-associated lipid droplet-accumulating microglia (LDAM), defined by high ACSL1 expression. Notably, IFN-γ stimulation enhanced ACSL1 expression in ApoE4-overexpressing HMC3 microglial cells.
Conclusion: These findings provide a new perspective on the involvement of plasma inflammatory markers for AD diagnosis, and suggest a novel link between IFN-γ and APOE ϵ4-associated AD risk through modulating the ACSL1-driven pathogenic LDAM phenotype.

Keywords:  APOE; Alzheimer’s disease; IFN-gamma; biomarker; inflammation

DOI:  https://doi.org/10.3389/fimmu.2026.1770509
Cell Death Dis. 2026 Mar 03.

Phagocytosis by retinal pigment epithelium and microglia does not affect vision restoration by P3HT nanoparticles in Retinitis pigmentosa.

Giulia Mantero, Simona Francia, Filippo Galluzzi, Nikita Telitsyn, Dmytro Shmal, Sara Cupini, Edoardo Porzano, Alberto Perna, Matteo Vincenzi, Joao Filipe Ribeiro, Luca Berdondini, Guglielmo Lanzani, Grazia Pertile, Stefano Di Marco, Fabio Benfenati, Elisabetta Colombo.

Photoreceptor degeneration in Retinitis pigmentosa (RP) is the most prevalent cause of inherited legal blindness, for which effective visual restoration treatments are still missing. Injectable prosthetic strategies represent a promising tool for vision restoration. We demonstrated that injectable poly(3-hexylthiophene) nanoparticles (P3HT-NPs) promote a sustained visual restoration in Royal College of Surgeons rats, an RP model harboring a mutation that impairs the phagocytic activity of the retinal pigment epithelium (RPE) and microglia, leading to progressive and combined rod/cone degeneration. However, it is unclear whether the efficacy of P3HT-NPs in this model is enhanced by the impairment of RPE and microglial phagocytosis, and thus whether this prosthetic intervention will also be effective in more typical forms of RP that primarily affect rods. Here, we evaluated the efficacy of P3HT-NPs in the pigmented retinal degeneration 10 (rd10) mouse, which carries a recessive missense mutation in the rod phosphodiesterase-6B gene, while retaining a morphologically and functionally intact RPE. We demonstrate that, in this mouse model of RP, P3HT-NPs restore visually driven responses at both subcortical and cortical levels at the end stage of photoreceptor degeneration. Although partial phagocytosis of P3HT-NPs by the RPE occurs, the P3HT-NPs remaining in the outer retina were sufficient to mediate a significant recovery of visual function characterized by complex light-dependent reactivation of the primary visual cortex and formation of implicit visual memories. These results demonstrate that healthy RPE and microglial activities do not compromise the efficacy of the injectable nanotherapeutic strategy, underscoring the clinical potential of P3HT-NPs for visual restoration in late-stage retinal degeneration, which closely mimics the conditions of RP patients undergoing prosthetic interventions.

DOI: https://doi.org/10.1038/s41419-026-08510-w
J Neuroinflammation. 2026 Mar 05.

HIV gp120 induces TREM1 expression through TLR-PGE₂ signalling in human monocyte-derived microglia.

Ayisha Mahama, Pratima Rawat, Carmen Teodorof-Diedrich, Stephen A Spector, Grant R Campbell.



Keywords:  HIV; Microglia; Neuroinflammation; PGE₂; TREM1; Toll-like receptor; gp120

DOI:  https://doi.org/10.1186/s12974-026-03757-8
Exp Mol Med. 2026 Mar 02.

Microglial CR3-mediated synaptic pruning in the dmPFC promotes the generation and maintenance of chronic muscle pain via glutamatergic dysfunction.

Meiling Luo, Likai Wang, Yanan Liang, Qianxi Xu, Siqi Zhang, Xiangxin Xing, Shuangyang Niu, Yonghui Wang.

Chronic muscle pain (CMP) is highly prevalent, frequently comorbid with emotional disorders and characterized by a high risk of recurrence. Yet, the complex mechanisms underlying the generation and maintenance of CMP remain unclear, limiting the development of therapy. Here we identified suppressed glutamatergic neuronal excitability and reduced synaptic plasticity in the dorsomedial prefrontal cortex (dmPFC) of CMP rats using fiber photometry, patch-clamp, in vivo recording of field potentials and other techniques. The optochemical genetical activation of dmPFC glutamatergic neurons alleviated pain and anxiety-like behaviors. Single-cell RNA sequencing revealed a marked upregulation of proinflammatory microglia and complement receptor 3 (CR3) in the dmPFC, which correlated with reduced neuronal excitability and synaptic function. Flow cytometry and immunofluorescence further showed that hyperactive glutamatergic neurons induced microglial activation, proliferation, polarization and chemotaxis. Notably, the inhibition of microglia or knockdown of microglial CR3 restored dmPFC glutamatergic neuronal excitability and synaptic plasticity, thereby alleviating hyperalgesia and anxiety-like behaviors. This study demonstrates that microglial CR3-dependent synaptic pruning underlies suppressed glutamatergic neuronal excitability and reduced synaptic plasticity, playing a pivotal role in CMP generation and maintenance. These findings uncover novel microglia-neuron interactions and offer promising therapeutic targets for CMP and its emotional comorbid disorders. Microglial CR3-mediated synaptic pruning in the dmPFC suppresses glutamatergic neuronal excitability, contributing to chronic muscle pain generation and maintenance and represents a promising therapeutic target.

DOI: https://doi.org/10.1038/s12276-026-01666-7
J Nanobiotechnology. 2026 Mar 02.

High-dose polystyrene nanoparticles trigger aberrant activation of the MAPK pathway in spinal cord and pain hypersensitivity.

Yuan Yin, Panyang Gu, Hanyu Jiang, Yumei Yang, Shujun Wang, Fei Yuan, Wenrui Zhong, Miao Chen, Meichun Deng.

  The widespread use of plastic products has led to a serious environmental problem, with nanoplastics ubiquitously contaminating the environment and sustaining human exposure, yet the impacts of nanoplastics on human health remain poorly understood. In this study, based on preliminary epidemiological investigations, we found that abnormal pain perception exists in populations chronically exposed to manufacturing environments that mainly produce polystyrene plastics. Further mechanistic studies demonstrated that high-dose polystyrene nanoparticles (PS NPs) induce pain hypersensitivity and elucidated their molecular underpinnings. Upon high-dose PS NPs exposure, microglia in the spinal dorsal horn internalized a fraction of the PS NPs, which were subsequently found to bind to mitogen-activated-protein-kinases (MAPK) pathway components (ERK, JNK, and p38). Molecular dynamics simulations further suggested that this binding could induce conformational alterations in the MAPK components, potentially enhancing the flexibility of their phosphorylation sites (Thr-X-Tyr) and thereby facilitating activation by upstream kinases. As a canonical inflammatory and pain-associated pathway, MAPK activation elevates neuroinflammatory cascades in the spinal dorsal horn, driving neuronal hyperexcitability and, consequently, pain hypersensitivity. Notably, the PS NPs-induced hypersensitivity was reversed by microglial depletion (PLX5622) and inhibition of the MAPK pathway. Collectively, our findings delineate PS NPs-triggered sensory pathophysiology and establish a proof-of-concept mechanistic nexus between environmental pollutants and aberrant somatosensation.

Keywords:  Microglia; Mitogen-Activated protein kinase; PLX5622; Pain; Polystyrene nanoplastics

DOI:  https://doi.org/10.1186/s12951-026-04186-8
J Nanobiotechnology. 2026 Mar 05.

Angiopep-2-engineered extracellular vesicles derived from spinal cord injury-responsive brown adipose tissue for targeted neuroinflammation modulation.

Shijun Xiang, Tian Qin, Yiming Qin, Yi Sun, Ming Zhou, Yongxiang Tang, Peng Liu, Shuo Hu.

  Spinal cord injury (SCI) affects over 15 million people globally with no curative treatments available. While primary mechanical trauma initiates tissue damage, secondary pathological cascades including neuroinflammation and mitochondrial dysfunction expand the injury. Current clinical interventions focus only on symptom management without restoring neural function. This study investigates the role of brown adipose tissue (BAT) in SCI repair through extracellular vesicles (EVs). Using 18F-FDG PET/CT imaging, this study discovered significant BAT activation post-SCI, peaking at 7 days, which was confirmed by histological analysis. Activated BAT increased EV secretion, with secreted EVs being selectively taken up by spinal microglia. miRNA sequencing identified miR-692 as the key EV cargo that silenced pro-inflammatory Spp1 gene in microglia, promoting their anti-inflammatory polarization and enhancing neuronal survival. Further development of a targeted delivery system using Angiopep2-modified BAT-EVs encapsulated in GelMA hydrogel for sustained release at injury sites significantly reduced lesion volume and improved functional recovery. The research establishes the BAT-EV-microglia axis as crucial for SCI repair and presents a promising biomaterial-enhanced EV therapy for SCI treatment, marking a significant advancement in regenerative medicine.

Keywords:  Angiopep-2; Brown adipose tissue; Extracellular vesicles; MiR-692; Neural inflammation; PET/CT; SPP1; Spinal cord injury

DOI:  https://doi.org/10.1186/s12951-026-04163-1
Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2516774123

Phagocytes as plaque catalysts: Human macrophages generate seeding-competent Aβ42 fibrils with cross-seeding activity.

Katerina Konstantoulea, Meine Ramakers, Sarah C Borrie, Dries T'Syen, Daan Moechars, Malgorzata A Sliwinska, Brajabandhu Pradhan, Giulia Albertini, Nóra Baligács, Grigoria Tsaka, Bert Houben, Mark Fiers, Rodrigo Gallardo, Maarten Dewilde, Dietmar Rudolf Thal, Michael Willem, Jonas J Neher, Bart De Strooper, Frederic Rousseau, Joost Schymkowitz.

  The prevailing view frames microglia and macrophages as guardians against amyloid beta (Aβ) accumulation in Alzheimer's disease (AD). Here, we overturn this paradigm by demonstrating that human phagocytic cells, including differentiated THP-1 macrophages and hESC-derived microglia, are not merely passive responders but active producers of extracellular, seeding-competent Aβ42 fibrils, the amyloid species most strongly linked to parenchymal plaque formation and neurodegeneration. These cell-generated aggregates differ structurally and functionally from synthetic fibrils, displaying enhanced seeding and tau cross-seeding activity in biosensor models. Notably, Aβ42 fibril formation in this system requires active cellular processes and is exacerbated by loss of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a major AD risk gene. Transcriptomic profiling reveals an early inflammatory response resembling microglial states observed in human AD models. Together, these findings support emerging evidence from in vivo studies that macrophages and microglia can influence amyloid seeding and introduce a human-relevant in vitro platform to explore how Aβ aggregation intersects with innate immune function and genetic risk. Our results reinforce the concept that microglia may play a dual role in AD, acting both as responders and inadvertent facilitators of amyloid assembly, with implications for early therapeutic intervention.

Keywords:  Ab42; Alzheimer’s disease; TREM2; microglia

DOI:  https://doi.org/10.1073/pnas.2516774123
J Adv Res. 2026 Mar 04. pii: S2090-1232(26)00187-6. [Epub ahead of print]

High-throughput phenotyping of microglial membrane Capacitance: Linking label-free dielectric signatures to polarization continuum and phospholipid remodeling.

Xiaofeng Luan, Xiaokun Geng, Yiwei Zhang, Qi Kong, Tian Zhi, Yifei Ye, Xue Li, Lingqian Zhang, Mingxiao Li, Hang Gao, Chengjun Huang, Yang Zhao, Haiping Zhao.

   INTRODUCTION: The dynamic monitoring of microglial polarization remains constrained by the static M1/M2 dichotomy and a lack of robust biomarkers, limiting therapeutic development for neurological disorders. Recent advances in bioelectrical characterization, however, have revealed that cellular processes correlate with distinct dielectric properties, suggesting a potential new approach for label-free cellular analysis.
OBJECTIVES: This study aimed to establish specific membrane capacitance (Csm) as a label-free, continuous metric for microglial polarization states and to elucidate the underlying biophysical mechanisms.
METHODS: We employed high-throughput single-cell dielectric phenotyping via a microfluidic impedance cytometry platform (54 cells/s) to characterize the ability of Csm to capture the continuous spectrum between M1/M2 phenotypes. Complementary lipidomic and proteomic analyses, alongside pharmacological interventions, were used to investigate the molecular basis of dielectric changes.
RESULTS: We demonstrate that M1-polarized microglia exhibit a significantly elevated Csm compared to M2 or resting (M0) states. This shift of Csm was continuous and dose-dependent to polarizing stimuli and was mechanistically linked to membrane lipid remodeling, specifically an increased lysophosphatidylcholine/phosphatidylcholine ratio (LPC/PC) regulated by Pla2g4a/Lpcat1. Furthermore, PPARγ/SIRT1 activators reversibly modulated these continuous changes of dielectric signatures. Pharmacological validation confirmed Csm's sensitivity to membrane reorganization.
CONCLUSION: Our results establish Csm as a real-time, single-cell functional metric for the continuum of microglial polarization, directly linking biophysical measurements to subcellular biochemistry. This work identifies Csm as a promising screening tool for neuroimmunomodulators and a predictive biomarker for therapeutic response, providing a scalable platform for neuroinflammation research.

Keywords:  Bioelectrical marker; Flowcytometry; Microfluidic impedance; Microglia

DOI:  https://doi.org/10.1016/j.jare.2026.02.053
Sci Adv. 2026 Mar 06. 12(10): eaeb2628

Myelin sheaths persist for weeks following axon degeneration.

Megan E Doty, Edward C Tuckerman, Enrique T Piedra, Robert A Hill.

Axon degeneration underlies clinical deficits in traumatic injuries and neurodegenerative disease. It is not clear how myelinating oligodendrocytes are directly affected by or respond to axon injury and loss. Here, we combined intravital imaging with laser axotomy or single neuron ablation to determine the longitudinal responses by oligodendrocytes that myelinate the degenerating axon. We find that while axons rapidly degenerate, myelin sheaths devoid of axon can persist for weeks. These remaining myelin sheaths lose compaction and slowly shrink. Local to the injury, oligodendrocyte homeostasis is largely maintained, with only a brief change in myelin sheath structural plasticity. After neuron ablation and axotomy, clearance of axon debris is delayed if the axon is myelinated. However, longitudinal imaging of microglia revealed only rare microglial engagement with injured axons, regardless of myelination status. Likewise, microglia did not engage with de-axoned myelin sheaths. These findings highlight the stability of myelinating oligodendrocytes and provide insight into homeostatic neuroglia responses following injury.

DOI: https://doi.org/10.1126/sciadv.aeb2628
Cell Rep Med. 2026 Feb 27. pii: S2666-3791(26)00058-3. [Epub ahead of print] 102641

A strategy of microglia replacement alleviates microgliopathy in a CSF1R I794T hotspot mutation mouse model of CSF1R-related disorder.

Xin Li, Banglian Hu, Chujun Wu, Ziwei Wang, Hanzheng Fan, Xiaoyan Guan, Sulan Xie, Dadian Chen, Xiaohua Huang, Hao Sun, Yanfang Li, Xian Zhang, Guojun Bu, Zhanxiang Wang, Yun-Wu Zhang, Li Zhong, Zaiqiang Zhang, Honghua Zheng.

  The I794T hotspot mutation in the colony-stimulating factor 1 receptor (CSF1R) gene is associated with primary microgliopathy manifesting as leukoencephalopathy. In this study, we identify three Chinese probands harboring the CSF1R p.I794T variant and characterize their clinical and neuroimaging profiles. To elucidate disease mechanisms and explore therapeutic avenues, we generate a Csf1rI792T/+ knockin mouse model that carries this human mutation. These Csf1rI792T/+ mice exhibit hallmark features of CSF1R-related disorder (CSF1R-RD), including cognitive deficits, ventricular enlargement, reduced microglia, axonal spheroids, and demyelination. Transcriptomic analysis reveals that Csf1rI792T/+ microglia adopt an activated and disease-associated microglia (DAM)-like phenotype. Crucially, we develop and test a microglia replacement strategy, termed "duplicate-cyclic microglial depletion for transplantation" (DCMDT), which significantly ameliorates neuropathological deficits in Csf1rI792T/+ mice. Our findings highlight the pathological significance of the CSF1R p.I794T mutation and propose DCMDT as a promising therapeutic approach for neurodegenerative disorders driven by microglial dysfunction.

Keywords:  CSF1R; CSF1R-RD; leukoencephalopathy; microglia; microglia replacement

DOI:  https://doi.org/10.1016/j.xcrm.2026.102641
Brain. 2026 Mar 03. pii: awag069. [Epub ahead of print]

Berbamine hydrochloride as a brain penetrant galectin 3 inhibitor in a model of Huntington's disease.

Jian Jing Siew, Chia-Wei Lee, Hui-Mei Chen, Hsien-Ya Lin, Yi-Ling Liu, Yi-Hsuan Lee, Ying-Ta Wu, Hung-Lin Chen, Fu-Tong Liu, Chun-Hung Lin, Yijuang Chern.

  Galectin-3 (Gal3) acts as an intracellular sensor of lysosomal damage and a key driver of microglial activation and neuroinflammation in multiple neurodegenerative disorders. Despite its biological importance, no inhibitors have been identified that both modulate intracellular Gal3 activity and effectively cross the blood-brain barrier (BBB). Here, we established an innovative high-content imaging platform utilizing microglia expressing Gal3-GFP, allowing direct visualization of Gal3 puncta formation upon lysosomal damage as a phenotypic readout for compound screening. Through screening of approximately 24,000 small molecules, we identified berbamine hydrochloride as a potent inhibitor of Gal3 puncta formation with confirmed BBB permeability. Mechanistically, berbamine hydrochloride disrupts Gal3 oligomerization and Gal3-TREM2 interaction via a unique allosteric mechanism distinct from the canonical glycan-binding domain. It attenuated lipopolysaccharide-induced inflammation in vitro, and achieved sustained brain exposure in vivo. In the R6/2 mouse model of Huntington's disease (HD), berbamine hydrochloride effectively improved motor functions, reduced mutant huntingtin protein aggregation, and restored crucial dopaminergic and ciliary signaling pathways. Transcriptomic profiling further identified Gal3 as a central regulatory hub within HD-associated networks that were corrected upon treatment. Computational docking and molecular dynamics simulations further supported an allosteric binding mode distinct from Gal3's canonical glycan-binding domain. Together, these findings establish berbamine hydrochloride as the first BBB-penetrant small molecule inhibitor targeting intracellular Gal3 with therapeutic benefit in HD. Furthermore, the puncta-based screening strategy we developed provides a robust platform for discovering intracellular modulators of Gal3 relevant to a wide range of neurological diseases.

Keywords:  Huntington’s disease; drug screening; galectin; microglia; neurodegeneration

DOI:  https://doi.org/10.1093/brain/awag069
Brain. 2026 Mar 06. pii: awag089. [Epub ahead of print]

HDAC6 regulates BACE1 stability and NLRP3 inflammasome activation in Alzheimer's disease.

Jeongmi Lee, Yongeun Cho, Bo Youn Choi, Hark Kyun Kim, Yeongyeong Lee, Eunae Kim, Jihoon Han, Jae Hoon Sul, Jun-Sik Kim, Seung Hyun Baek, Yoonsuk Cho, Jinsu Park, Gahee Bahn, Han-Gyu Bae, Jae Hyun Jun, Mitchell K P Lai, Thiruma V Arumugam, Dong-Gyu Jo.

  Alzheimer's disease (AD) is marked by amyloid-β (Aβ) accumulation, tau pathology, and neuroinflammation. The β-site APP cleaving enzyme 1 (BACE1) is a key driver of Aβ production, while the NLRP3 inflammasome mediates microglial inflammatory responses. Histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase, is upregulated in AD, yet its role in disease mechanisms remains unclear. Here, we show that HDAC6 promotes BACE1 protein stability through direct deacetylation of its C-terminal lysine (K501), thereby increasing Aβ production. HDAC6 also facilitated NLRP3 inflammasome activation in microglia, increasing IL-1β production in a catalytic domain-dependent manner. HDAC6 deficiency in 5xFAD mice reduced BACE1 accumulation, Aβ deposition, ASC speck formation, and IL-1β levels, accompanied by improved cognitive performance. Transcriptomic profiling further revealed downregulation of disease-associated microglial and neurotoxic astrocyte signatures alongside enrichment of synaptic pathways. These findings establish HDAC6 as a dual regulator of Aβ production and neuroinflammation, highlighting it as a promising therapeutic target in AD.

Keywords:  Alzheimer’s disease (AD); BACE1; HDAC6; NLRP3 inflammasome

DOI:  https://doi.org/10.1093/brain/awag089
Brain Behav Immun. 2026 Mar 01. pii: S0889-1591(26)00258-8. [Epub ahead of print]135 106510

Lnc-USP28-6/ZBTB16 axis orchestrates NLRP3 inflammasome activation and α-synuclein SUMOylation to drive Parkinson's disease pathogenesis.

Nan Wang, Man Wang, Yifei You, Jiajia An, Rui Jia, Bin Zhao, Zhang Cao, Xianzhi Wang, Ruli Ge, Chen Li, Hongcai Wang.

  Parkinson's disease (PD) is a neurodegenerative disorder characterized by neuroinflammation and the aggregation of α-synuclein (α-syn), which lead to progressive neuronal loss, yet regulatory mechanisms remain elusive. Zinc finger and BTB domain-containing protein 16 (ZBTB16) has been implicated as a critical nexus integrating proteostatic dysregulation with neuroimmune axis activation in neuropathogenesis. However, its specific role and molecular mechanisms in PD remain poorly understood. Building upon the initial RNA sequencing analysis showing ZBTB16 upregulation in peripheral blood mononuclear cells (PBMCs) of PD patients, we further analyzed its expression in PBMCs from 57 PD patients and postmortem striatal tissues, revealing significant upregulation relative to controls. In rotenone (ROT)-induced PD models, elevated ZBTB16 correlated with increased apoptotic activity. Mechanistic investigations in SH-SY5Y dopaminergic neurons and BV2 microglia-like cells (BV2 cells) showed that ZBTB16 overexpression enhanced α-syn expression through transcriptional activation and post-translational modifications, promoting aggregation independent of mutation status. Confocal microscopy confirmed α-syn/SUMO1 colocalization in PD striatal tissues, with microglial models demonstrating ZBTB16-dependent UBC9 upregulation that increased SUMO1+/α-syn+ cells; knockdown reversed this effect. Additionally, in BV2 cells co-expressing mutant LRRK2 and α-syn, ZBTB16 amplified pathogenicity by boosting NLRP3 inflammasome activation, Gasdermin D (GSDMD) expression, and IL-1β/IL-18 secretion, with significant GSDMD/α-syn co-localization in PD tissues. Based on initial RNA sequencing analysis indicating that lnc-USP28-6 regulates ZBTB16 expression, systematic analysis of the ZBTB16 promoter identified lnc-USP28-6. Clinical data identified elevated lnc-USP28-6 in PD peripheral blood, which transcriptionally upregulated ZBTB16 and α-syn in SH-SY5Y cells independently of ROT. These findings unveil a novel lnc-USP28-6/ZBTB16 axis driving PD pathogenesis via dual mechanisms: exacerbating neuroinflammation through inflammasome activation and promoting α-syn aggregation via SUMOylation, indicating promising therapeutic targets.

Keywords:  Inflammasome; Neuroinflammation; RNA sequencing; SUMOylation; ZBTB16; lnc-USP28-6; α-synuclein (α-syn)

DOI:  https://doi.org/10.1016/j.bbi.2026.106510
J Clin Invest. 2026 Mar 02. pii: e196905. [Epub ahead of print]136(5):

Ectopic B lymphocyte follicles exacerbate ischemic brain damage via MIF-CD74/CXCR4 and interferon signaling.

Sheng Yang, Hang Zhang, Lu-Lu Xu, Luo-Qi Zhou, Yun-Hui Chu, Lian Chen, Xiao-Wei Pang, Lu-Yang Zhang, Li-Fang Zhu, Ming-Hao Dong, Ke Shang, Jun Xiao, Long-Jun Wu, Wei Wang, Dai-Shi Tian, Chuan Qin.

  Neuroinflammation, encompassing both innate and adaptive immune responses, plays a crucial role in ischemic stroke. Although B lymphocytes are central to adaptive immunity, their contributions to ischemic stroke remain poorly understood. Here, we demonstrated that B lymphocytes accumulate in ischemic lesions, forming germinal center-like structures at the later stage after stroke, which mainly depended on in situ proliferation. This accumulation correlated with worsened neuroinflammation and ischemic injury, whereas B cell depletion reduced chronic brain damage during stroke. Mechanistically, microglia recruited B cells into ischemic lesions through MIF-CD74/CXCR4 signaling during the early phase of stroke, while IFN-related pathways in B cells further drove neuroinflammation and brain injury. Targeting these pathways markedly alleviated cerebral ischemia and inflammation. Our findings shed light on the role of B lymphocytes in stroke pathology and suggest promising new avenues for therapeutic intervention.

Keywords:  B cells; Immunology; Neuroscience

DOI:  https://doi.org/10.1172/JCI196905
Neuron. 2026 Mar 04. pii: S0896-6273(26)00008-5. [Epub ahead of print]114(5): 795-797

A genetic architect of opioid responses: Microglial Runx1.

Dong Dong, Longzhen Cheng.

Why do opioid responses vary greatly among individuals? Leduc-Pessah et al.1 show that the Runx1 transcription factor is a genetic determinant of opioid analgesia and adverse effects across species, presumably operating by governing microglial reactivity.

DOI: https://doi.org/10.1016/j.neuron.2026.01.008
Neuron. 2026 Mar 04. pii: S0896-6273(26)00088-7. [Epub ahead of print]114(5): 791-794

MS4A4A and MS4A6A: New targets to enhance microglia protective function in Alzheimer's disease.

David V Hansen, Celeste M Karch, Drishya Mainali, Laura Piccio.

MS4A4A and MS4A6A are microglia-expressed genes linked to Alzheimer's disease risk. In this issue of Neuron, Rosner et al.1 show that these proteins cooperatively restrain TREM2 signaling, dampening protective microglial responses and highlighting MS4A inhibition as a potential strategy to rejuvenate the brain's innate immune system in Alzheimer's disease.

DOI: https://doi.org/10.1016/j.neuron.2026.02.005
Science. 2026 Mar 05. 391(6789): eads3972

Targeting amyloid-β pathology by chimeric antigen receptor astrocyte (CAR-A) therapy.

Yun Chen, Yizhou Liu, Khai Nguyen, Junjie Wu, Sihui Song, Kent Lin, Patrick F Rodrigues, Siling Du, Charles Zhou, Kyle Xiong, Megan Bosch, Peter Bor-Chian Lin, Darya Khantakova, Shitong Wu, May Wu, Carla Yuede, David M Holtzman, Marco Colonna.

Alzheimer's disease (AD) is the leading cause of dementia and is characterized by progressive amyloid accumulation followed by tau-mediated neurodegeneration. Despite advances in anti-amyloid immunotherapies, important limitations remain, highlighting the need for new therapeutic strategies. Here, we introduce anti-amyloid chimeric antigen receptors expressed in astrocytes (CAR-A) and validate their function in vitro. We show that two CAR-A designs reduce amyloid and associated pathology after plaque formation and prevent early plaque deposition in vivo. Single-nucleus RNA sequencing shows that CAR-A treatment induces a distinct glial response to amyloid pathology involving coordinated activity of astrocytes and microglia. Each construct additionally elicits distinctive, receptor-specific effects in astrocytes or microglia. Together, these findings support the therapeutic potential of CAR-A as a disease-modifying strategy for AD.

DOI: https://doi.org/10.1126/science.ads3972