bims-microg 2026-03-15 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–03–15
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

TLR3 as a PANoptosis-related gene: a potential diagnostic biomarker and therapeutic target for diabetic retinopathy.
Efavirenz treatment improves retinal vaso-obliteration and pathological neovascularization in a mouse model of retinopathy of prematurity.
Polyunsaturated Fatty Acid Balance Modulates Microglial State in a Murine Model of Oxygen-Induced Neovascularization.
Self-amplifying RNA therapy encoding CNTF with disulfiram co-delivery promotes optic nerve repair through microglial pyroptosis inhibition and RGC axonal regeneration.
Control of microglial dynamics by the Arp2/3 complex and the autism- and schizophrenia-associated protein CYFIP1.
Microglia Dld-K127 lactylation promotes Parkinson's disease via regulating the metabolism of lactate-pyruvate transformation.
Persistent microglial activation following neonatal CMV infection mediates neurodegeneration.
Dual association patterns between microglial activation and neuronal health in Alzheimer's disease: a whole-brain MRSI/PET study.
TDP-43 pathology triggers neuroinflammation and cognitive impairment by inducing microglial necroptosis.
Microglial morphology reflects cognitive status in the aging rat brain.
Endogenous progesterone deficiency impairs neonatal brain development via microglial dysregulation under chronic hypoxia.
Microglia Mitochondria Support Neuronal Maturation via Metabolic and Transcriptional Reprogramming in Human 3D In Vitro Brain Model.
Brain-engrafted monocyte-derived macrophages from blood and skull-bone marrow exhibit distinct properties.
Microglial cathepsin B is necessary for neuronal efferocytosis in zebrafish and mice during brain development.
Impaired α-Synuclein aggregate clearance in neuronal cells drive their spread to microglia through tunneling nanotubes.
scTWAS: a powerful statistical framework for single-cell transcriptome-wide association studies.
Simultaneous spatial transcriptomics and morphology profiling as tools to explore how microglia change with age.
Microglia protein profiles in CSF across Alzheimer's disease clinical stages.
Tumor-derived cystatin C enables amyloid clearance.
Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis.

3 Biotech. 2026 Apr;16(4): 133

TLR3 as a PANoptosis-related gene: a potential diagnostic biomarker and therapeutic target for diabetic retinopathy.

Juan Zhao, Mochi Yang, Yushan Shi, Dongmei Zhan, Xiaoyong Yuan.

  WGCNA was used to identify DR-related PANoptosis genes, and the LASSO, SVM-RFE, and Random Forest machine learning models were then employed to identify key PANoptosis-related genes. The lncRNA-miRNA-TLR3 networks were constructed, and the levels of hub lncRNAs, hub miRNAs and TLR3 were measured in a high-glucose cell model. The luciferase reporter assay was employed to validate the interactions between Gm12610 and miR-758-3p, as well as between miR-758-3p and Tlr3. In the GSE102485 and GSE185011 cohort, TLR3 expression was significantly elevated in the DR samples compared to controls. Data from the GSE236627 cohort indicated a marked upregulation of Tlr3 in retinal microglia of db/db mice relative to normal controls. GSEA results showed that AGE-RAGE signaling pathway in diabetic complications and NF-kappa B signaling pathway were enriched and activated in the high-TLR3 expression (H-TLR3) group. Additionally, M2 macrophage infiltration was reduced in this group. Through the ENCORI and TargetScan databases, two ceRNA networks were constructed: C15orf54/CDKN2B-AS1-hsa-miR-758-3p-TLR3 and CDKN2B-AS1-hsa-miR-374b-5p-TLR3. In vitro experiments validated that high glucose-stimulated microglia showed significantly increased levels of Tlr3 and Gm12610 (mouse CDKN2B-AS1), but decreased levels of miR-374b-5p and miR-758-3p compared to the control group. Luciferase assays confirmed direct binding between Gm12610 and miR-758-3p, and between miR-758-3p and Tlr3. Our study identifies TLR3 as a key PANoptosis-related gene in DR, suggesting it potential as a therapeutic target for DR.
Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-026-04720-3.

Keywords:  Complications; Diabetic retinopathy; PANoptosis; TLR3; lncRNA; miRNA

DOI:  https://doi.org/10.1007/s13205-026-04720-3
Front Med (Lausanne). 2026 ;13 1745351

Efavirenz treatment improves retinal vaso-obliteration and pathological neovascularization in a mouse model of retinopathy of prematurity.

Briah Bailey, Josephine Rudd Zhong Manis, Gayatri Seth, Shubhra Rajpurohit, Allston Oxenrider, Pamela M Martin, Ravirajsinh N Jadeja, Menaka C Thounaojam.

   Objectives: Previous studies have shown the metabolic and regulatory significance of CYP46A1 in the adult retina; however, its role in the developing retina is unknown. Here, we evaluate CYP46A1 expression and the impact of its activation in the developing mouse retina under normal and pathological conditions.
Methods: Seven-day-old (P7) C57BL/6 J mice maintained in room air (controls) or subjected to oxygen-induced retinopathy (OIR) were treated with/without 20 mg/kg efavirenz (EFV), a CYP46A1 activator administered intraperitoneally from P7 to P17.
Results: Retinal cross sections and flat mounts were prepared to study retinal vasculature morphology, Müller and microglia activation, and ganglion cell viability. EFV treatment significantly reduced pathological neovascularization and the size of avascular and hypoxic areas in OIR mice retinas. EFV treatment additionally limited reactive gliosis and microglia activation and improved retinal ganglion cell survival in OIR mice.
Conclusion: The current study demonstrates the developmental regulation of CYP46A1 and the dysregulated expression and levels of the downstream metabolite 24-Hydroxycholesterol (24HC) in OIR mice. The study further suggests that EFV treatment (in part via CYP46A1 activation) may improve key pathological features associated with pathological neovascularization in OIR mice.

Keywords:  CYP46A1; cholesterol metabolism; efavirenz; prematurity; retinopathy

DOI:  https://doi.org/10.3389/fmed.2026.1745351
Nutrients. 2026 Feb 26. pii: 749. [Epub ahead of print]18(5):

Polyunsaturated Fatty Acid Balance Modulates Microglial State in a Murine Model of Oxygen-Induced Neovascularization.

Esther S Kim, Meng-Chin Lin, Cheng-Hsiang Lu, David Casero, Brian Aguirre, Joanne Brown, Olawande Olagoke, Camilia R Martin, Madhuri Wadehra, Kara L Calkins, Alison Chu.

  Background/Objectives: The retina is enriched in polyunsaturated fatty acids (PUFAs) which are indispensable for normal vision, and recent clinical studies have shown that dietary supplementation of ω-6-and ω-3-polyunsaturated fatty acids (PUFAs) can provide a protective role against retinopathy of prematurity (ROP). Our study aims to understand the mechanisms by which altering ω-6-and ω-3-polyunsaturated fatty acids (PUFAs) in the eye can protect against pathologic retinal neovascularization (NV). Methods: We interrogated the effects of endogenous ω-3-PUFA enrichment using transgenic fat-1 mice which convert ω-6-PUFAs to ω-3-PUFAs in the oxygen-induced retinopathy (OIR) murine model. In the OIR model, mice are exposed to 75% oxygen from postnatal day 7 (P7) to P12, then returned to room air (RA). We used a combination of immunofluorescence, bulk retinal RNA sequencing, and lipid mediator profiling by UHPLC-MS/MS in P17 mouse retinas to identify mechanisms underlying the protective effect against NV seen in fat-1 mice exposed to OIR. Results:Fat-1 OIR mice were protected against the development of retinopathy, demonstrating 15.1% less vaso-obliteration (75.5% relative reduction) after OIR and a 6.1% reduction in neovascularization (71.8% relative reduction) at P17 (p < 0.0001 for both). We found a dampened transcriptional response to OIR in the retina of fat-1 mice as compared to WT mouse retinas (198 vs. 782 genes, adjusted p-value < 0.01). Pathway analyses confirmed these findings, with significant OIR-induced transcriptional shifts in angiogenesis (adjusted p-value < 10-27), inflammation (adjusted p-value < 10-25), and microglial activation pathways (adjusted p-value < 10-9) in WT mouse retina that were not observed in fat-1 mice. Enrichment scores obtained through the integration of our bulk transcriptomics data with cell-resolved retina data indicate that the protective phenotype observed in fat-1 mice could be associated with intrinsic differences in microglia cell subtypes between WT and fat-1 mice. In situ, WT OIR mice demonstrated an increase in Iba1+ microglia compared to WT RA mice, whereas fat-1 OIR mice showed no difference when compared to fat-1 RA mice. Three ARA-derived oxylipins, 12-hydroxyeicosatetraenoic acid (12-HETE), prostaglandin D2 (PGD2), and thromboxane B2 (TXB2) demonstrated a pattern of upregulation in WT OIR compared to WT RA, but no upregulation in fat-1 OIR mice compared to fat-1 RA. Two EPA-derived specialized pro-resolving mediators and two LA-derived oxylipins were also differentially expressed. Conclusions: These findings show that a lower ω-6:ω-3 protects against neovascularization and is associated with attenuation of hyperoxia-induced microglial recruitment and activation, as well as inflammation and angiogenic signaling.

Keywords:  angiogenesis; hypoxia; microglia; oxygen-induced retinopathy; polyunsaturated fatty acids; retina; retinopathy of prematurity

DOI:  https://doi.org/10.3390/nu18050749
J Nanobiotechnology. 2026 Mar 13.

Self-amplifying RNA therapy encoding CNTF with disulfiram co-delivery promotes optic nerve repair through microglial pyroptosis inhibition and RGC axonal regeneration.

Qianyue Zhang, Yusha Liu, Qin Wei, Mingyang Song, Siwei Liu, Haiyang Zhang, Tingyu Deng, Chutong Zhang, Kexin Tan, Rui Huang, Ni Ni, Jun Zhang, Ping Gu, Gang Du, Jipeng Li, Yingzhi Chen, Huifang Zhou, Xianqun Fan.

   BACKGROUND: Traumatic optic neuropathy (TON) is a devastating cause of irreversible vision loss for which no effective treatment currently exists. Its poor prognosis stems from two major challenges: the limited regenerative capacity of retinal ganglion cells (RGCs) and the hostile, inflammation-driven environment that follows injury.
RESULTS: In this work, using transcriptomic bioinformatic and histopathological analysis, we discovered that mechanical trauma and subsequent neuroinflammation trigger microglial pyroptosis through the NLRP3/CASP1/GSDMD pathway. This process amplifies inflammatory cascades and exacerbates RGC degeneration via microglia-neuron interactions. To overcome these dual barriers, we engineered a microglia-targeted lipid nanoparticle (LNP) platform co-delivering disulfiram (DSF), a selective GSDMD inhibitor, together with self-amplifying mRNA (saRNA) encoding ciliary neurotrophic factor (CNTF). We found that this combinatorial strategy concurrently suppresses pyroptosis-driven neuroinflammation while providing sustained neurotrophic support. Through comprehensive in vitro and in vivo evaluations, the co-delivery system showed enhanced RGC survival, remarkable axonal regeneration, and eventually significant restoration of visual function.
CONCLUSIONS: In summary, our results demonstrate that a coordinated strategy targeting both neuroinflammatory mechanisms and regenerative pathways yields superior therapeutic outcomes in TON. This work underscores the potential of integrated RNA-small molecule therapies as a promising multi-target treatment paradigm, with broad applicability for other neuroinflammatory and neurodegenerative diseases.

Keywords:  Axon regeneration; Co-delivery LNP; Disulfiram; Microglial pyroptosis; Self-amplifying RNA therapy; Traumatic optic neuropathy

DOI:  https://doi.org/10.1186/s12951-026-04272-x
Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2532488123

Control of microglial dynamics by the Arp2/3 complex and the autism- and schizophrenia-associated protein CYFIP1.

James Scott-Solache, Jiaxin Pei, James Drew, Guillermo López-Doménech, Renaud B Jolivet, Manuela Nieto-Rostro, Elizabeth C Davenport, I Lorena Arancibia-Cárcamo, David Attwell, Josef T Kittler.

  Microglia use a highly complex and dynamic network of branched processes to sense and respond to their surroundings. Despite emerging evidence that microglial motility plays important roles in brain development, neurodegeneration, and neuropsychiatric disease, little is known about the intracellular machinery orchestrating microglial process dynamics. Here, we identify roles for regulators of the actin cytoskeleton in controlling microglial behavior. We show that the actin branching Arp2/3 complex is critical for maintaining microglial morphology and is required for surveillance but not chemotactic motility. Neuropsychiatric disease-associated CYFIP1, a core component of the WAVE regulatory complex linking upstream signaling pathways to activation of the Arp2/3 complex, is highly expressed in microglia but has an unknown function. We report that conditional deletion of Cyfip1 in mouse microglia reduces their morphological complexity and surveillance of the brain parenchyma, with no effect on chemotaxis. Deletion of Cyfip1 also increased microglial CD68 positive lysosome volume and engulfment of presynapses. Thus, actin remodeling by CYFIP1 and the Arp2/3 complex controls microglial dynamics and shifts microglia away from a homeostatic state with potential implications for neuropsychiatric disease.

Keywords:  15q11.2; WRC; glia; neuroinflammation; phagocytosis

DOI:  https://doi.org/10.1073/pnas.2532488123
J Adv Res. 2026 Mar 09. pii: S2090-1232(26)00235-3. [Epub ahead of print]

Microglia Dld-K127 lactylation promotes Parkinson's disease via regulating the metabolism of lactate-pyruvate transformation.

Guoqing Wang, Guichun Gong, Xinxing Yang, Yanran Qian, Yujia Zhao, Daidi Li, Mei Liu, Zucai Xu, Feng Zhang.

   INTRODUCTION: Microglial activation represents a central pathological hallmark of Parkinson's disease (PD), characterized by a distinct metabolic reprogramming from oxidative phosphorylation toward glycolysis during pro-inflammatory activation. This metabolic shift drives lactate accumulation and subsequent protein lactylation, which has been increasingly implicated in PD development. However, the molecular mechanisms through which protein lactylation exerts its pathological effects remain largely unknown.
OBJECTIVES: This study aimed to elucidate the mechanism by which lactate-derived protein lactylation contributes to PD pathogenesis. We sought to identify key protein targets of lactylation in PD models, elucidate the functional consequences of these modifications on cellular metabolism, and ultimately establish a comprehensive mechanism linking lactylation to dopamine (DA) neuronal degeneration.
METHODS: We employed an integrated approach including comprehensive lactylome screening to identify modified proteins, functional enzymatic assays to determine the influence of specific lactylation events, and clinical correlation studies in human PD specimens to validate the pathological relevance of our findings across species.
RESULTS: Following our initial observation of elevated lactate in PD mice, a subsequent finding revealed that up-regulation of lactylation was paralleled by enhanced microglial activation. Furthermore, endogenous lactate-derived lactylation was ultimately involved in the pathological process of PD. In addition, global lactylome revealed significant hyperlactylation of dihydrolipoyl dehydrogenase (Dld) at residues Lys127, Lys277, and Lys410. Mechanistically, Dld-K127 hyperlactylation inhibited pyruvate dehydrogenase (PDH) enzyme activity and promoted the metabolism of lactate-pyruvate transition, thereby accelerating DA neuronal degeneration. Meanwhile, Dld-K127 lactylation participate PD progression in p300 (lactylation writer)-dependent manner. Notably, clinical human specimens reveled that Dld-K127 lactylation, lactate and pyruvate production were increased in PD patients, accompanied with reduced PDH activity.
CONCLUSION: Our finding defined a lactate-Dld-K127-pyruvate positive feedback loop that drove DA neuronal loss in "metabolism-epigenetic" level, positioning the disruption of this self-amplifying cycle as a viable therapeutic strategy for PD.

Keywords:  Dihydrolipoyl dehydrogenase; Lactylation; Microglia; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.jare.2026.03.016
Sci Adv. 2026 Mar 13. 12(11): eadz1686

Persistent microglial activation following neonatal CMV infection mediates neurodegeneration.

Jessica L McCord, Debotri Chatterjee, John Y S Han, Drew Scoles, Richard J Smeyne, Nancy J Philp, Christopher M Snyder.

Human cytomegalovirus (HCMV) causes the most common congenital viral infection in the United States, with well-known acute and late-onset neurological pathologies. Moreover, HCMV, like multiple herpesviruses, has been associated with neuroinflammation and neurodegeneration. Using a well-established neonatal murine (M)CMV infection model, we found that early-life infection drove adult-onset neuron loss and neuropathology in the retina and brain, without evident viral reactivation. Pathology was associated with the persistence of highly activated and inflammatory damage-associated microglia. Transient depletion of these microglia before the development of pathology resulted in repopulation of the tissue by microglia with a more reparative profile, which was then sustained over time. Transient microglia depletion alone was sufficient to preserve retinal structure and photoreceptor neurons, promote healing of some existing retinal damage, and preserve brain neuron density in adult infected mice. Thus, early-life infection by MCMV promoted dysfunctional and pathogenic microglia that drove adult-onset neurodegeneration in the eye and brain.

DOI: https://doi.org/10.1126/sciadv.adz1686
Alzheimers Dement. 2026 Mar;22(3): e71229

Dual association patterns between microglial activation and neuronal health in Alzheimer's disease: a whole-brain MRSI/PET study.

Yaoyu Zhang, Xiao-Hang Qian, Huixiang Zhuang, Wenqi Zhang, Jialin Hu, Yibo Zhao, Yudu Li, Wen Jin, Chang Xu, Ziyu Meng, Wenli Li, Siyue Chen, Xu-Feng Jiang, Tengfei Guo, Ya-Dong Li, Jian Ye, Zhi-Pei Liang, Biao Li, Miao Zhang, Huidong Tang, Yao Li.

   INTRODUCTION: Microglial activation can either support neuronal function or exacerbate damage, contributing to Alzheimer's disease (AD) progression. We investigated spatial relationships among microglial activation, neuronal health, and amyloid beta (Aβ) in the AD spectrum.
METHODS: Forty healthy controls, 37 patients with mild cognitive impairment (MCI), and 62 patients with AD underwent whole-brain high-resolution 1H-magnetic resonance spectroscopic imaging (MRSI), [1 8F]DPA-714, and [1 8F]AV-45 positron emission tomography (PET). Regional and voxel-wise analyses assessed changes and associations of microglial activation with N-acetylaspartate (NAA) and Aβ.
RESULTS: MCI and AD patients showed higher microglial activation and lower NAA, correlating with cognitive decline. In controls and MCI, microglial activation correlated positively with NAA and Aβ in early amyloid-accumulating regions. Conversely, negative correlations with NAA emerged in the hippocampus in MCI and extended to temporal and occipital regions in AD.
DISCUSSION: For the first time, we identified two distinct spatial association patterns between [1 8F]DPA-714 PET and NAA, shedding light on the complex interplay between neuroinflammation and neuronal health in AD.

Keywords:  Alzheimer's disease; N‐acetylaspartate; amyloid beta; magnetic resonance spectroscopic imaging; microglial activation; neuroinflammation

DOI:  https://doi.org/10.1002/alz.71229
EMBO Mol Med. 2026 Mar 10.

TDP-43 pathology triggers neuroinflammation and cognitive impairment by inducing microglial necroptosis.

Shenrui Guo, Hongfu Jin, Hui Sun, Shuo Huang, Yuanyuan Chen, Yuge Chang, Yu Zhang, Lin Ding, Suyun Chen, Chenglai Fu, Yafu Yin, Weiwei Cheng.

  Pathological TAR DNA-binding protein-43 (TDP-43) is a defining feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). However, the mechanism by which TDP-43 pathology disrupts microglial function and drives neuroinflammation remains unclear. In this study, we demonstrated that cytoplasmically mis-localized TDP-43 exacerbated neuroinflammation, induced cell death, and impaired phagocytic function in microglial cells, primarily through receptor interacting serine/threonine kinase 3 (RIPK3)-dependent necroptosis. Pharmacological inhibition of RIPK3 with GSK872 markedly attenuated these pathological effects in vitro. These findings were further corroborated in a murine model with cytoplasmic TDP-43 mis-localization, where GSK872 treatment remarkably alleviated neuroinflammation and restored cognitive deficits. Mechanistically, our findings indicate that the nuclear depletion of TDP-43, resulted from its cytoplasmic mis-localization, impairs its ability to transcriptionally repress the Ripk3 gene, subsequently leading to RIPK3 upregulation and activation of RIPK3-dependent necroptosis. Collectively, our findings establish RIPK3-dependent necroptosis as a critical driver of TDP-43 pathology-mediated neuroinflammation and identified necroptosis as a promising therapeutic target in TDP-43-associated neurodegenerative disorders.

Keywords:  Microglia; Necroptosis; Neuroinflammation; RIPK3; TDP-43

DOI:  https://doi.org/10.1038/s44321-026-00394-9
Brain Behav Immun. 2026 Mar 10. pii: S0889-1591(26)00281-3. [Epub ahead of print] 106533

Microglial morphology reflects cognitive status in the aging rat brain.

Sarah J Myers, Austyn D Roseborough, Cristian X Bayona, Carlangelo Carrese, Brian L Allman, Shawn N Whitehead.

  Age-related cognitive decline affects millions of individuals worldwide, but the cellular mechanisms underlying this decline remain incompletely understood. Microglia undergo significant changes with aging, including alterations in morphology, that may reflect or contribute to cognitive dysfunction. However, the relationship between specific microglial morphologies and cognitive performance in relevant brain regions remains poorly understood. To address this, we evaluated the relationship between morphology-based microglial phenotypes and cognitive performance across domains affected by aging. Microglial morphology was analyzed in four cognitive brain regions of male and female 3-, 9-, and 15-month-old rats and features were subjected to hierarchical clustering on principal components to identify microglial subtypes. Rats underwent cognitive testing using a radial arm water maze and a T-maze set-shifting task to assess spatial working and reference memory, striatal-based learning, and cognitive flexibility. We observed age-related cognitive impairments alongside region-specific changes in microglial morphotype abundance. Importantly, the relative abundance of distinct microglial clusters correlated with cognitive performance in functionally relevant brain regions including the prefrontal cortex, the orbitofrontal cortex, and the hippocampus. Taken together, these findings highlight the utility of morphological profiling in capturing microglial heterogeneity and suggest that morphological changes may reflect or contribute to cognitive decline during aging.

Keywords:  Aging; Cognition; Executive function; Hierarchical clustering; Microglia; Morphology; Principal components

DOI:  https://doi.org/10.1016/j.bbi.2026.106533
Brain Behav Immun. 2026 Mar 11. pii: S0889-1591(26)00279-5. [Epub ahead of print] 106531

Endogenous progesterone deficiency impairs neonatal brain development via microglial dysregulation under chronic hypoxia.

Yichen Yan, Gang Liu, Yue Cui, Cong Li, Huiwen Chen, Zhongqun Zhu.

   BACKGROUND: Several studies have confirmed the important role of progesterone in fetal and neonatal brain development. Chronic hypoxia in the fetal period may mediate neurodevelopmental and cognitive impairment in offspring by interfering with placental steroid hormone synthesis, but the mechanism is unclear.
METHODS: We systematically evaluated the effects of hypoxia on placental endocrine-fetal neuro-cognitive function by constructing a model of chronic hypoxia from fetal to early childhood, combined with progesterone supplementation, multi-omics of placenta and brain samples, microglial morphological analysis, and behavioral testing.
RESULTS: Chronic hypoxia significantly inhibited placental steroid synthase, leading to a concurrent decrease of progesterone levels in the fetal circulation and brain. Progesterone deficiency in the brain activates microglia, which in turn drives excessive inflammation under chronic hypoxic conditions, thereby interrupting oligodendrocyte differentiation and causing myelination deficits. Chronic hypoxia could also lead to impairment of spatial memory and learning ability shown by behavioral tests. During hypoxic pregnancy, administration of exogenous progesterone restored the progesterone gradient between the placenta and brain, inhibited abnormal activation of microglia, promoted myelination, and reversed cognitive deficits.
CONCLUSION: Chronic hypoxia downregulates placenta-derived progesterone through the "placenta-neural axis", which in turn leads to cognitive impairment through the microglia-myelin pathway. Progesterone supplementation during pregnancy can provide a theoretical basis for clinical intervention.

Keywords:  Chronic fetal hypoxia; Microglial activation; Myelination; Neurodevelopmental impairment; Placental progesterone; Progesterone supplementation

DOI:  https://doi.org/10.1016/j.bbi.2026.106531
Adv Sci (Weinh). 2026 Mar 13. e08815

Microglia Mitochondria Support Neuronal Maturation via Metabolic and Transcriptional Reprogramming in Human 3D In Vitro Brain Model.

Sydney P Sterben, Charitha C Anamala, Sahan B S Kansakar, Vaishnavi Koduri, Volha Liaudanskaya.

  Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by disrupted neuronal circuit maturation. Emerging evidence implicates microglial function and mitochondrial regulation as contributors to ASD-associated biology, yet the mechanisms linking these processes to neuronal development remain poorly defined. Neuronal maturation requires tightly coordinated metabolic and transcriptional remodeling, in which mitochondria play a central role in regulating the developmental tempo and metabolic identity, while microglia modulate neuronal synaptic network maturation; however, whether microglia influence neuronal development through direct mitochondrial contributions remains unknown. Here, using a 3D human in vitro brain model, it is shown that microglial mitochondria can act as transferable cues that promote metabolic, mitochondria-dynamic, and transcriptional aspects of neuronal maturation. Neurons treated with microglial mitochondria exhibited enhanced oxidative metabolism, improved mitochondrial dynamics, and activation of gene programs associated with nervous system development and neurogenesis. These effects are accompanied by increased expression of dendritic maturation markers, supporting the view that transferred mitochondria can contribute to the regulation of neuronal state. However, full structural and synaptic maturation required the combined action of microglia-derived mitochondria and secreted signaling factors. Together, this study identified microglial mitochondrial transfer as a contributor to neuronal maturation with potential relevance to developmental trajectories disrupted in ASD.

Keywords:  autism spectrum disorder; microglia; mitochondria; neurodevelopment; transcriptional reprogramming

DOI:  https://doi.org/10.1002/advs.202508815
Neuron. 2026 Mar 11. pii: S0896-6273(26)00057-7. [Epub ahead of print]

Brain-engrafted monocyte-derived macrophages from blood and skull-bone marrow exhibit distinct properties.

Siling Du, Feiya Ou, Antoine Drieu, Eric Z Xu, Yumeng Cheng, Steffen E Storck, Tornike Mamuladze, Jay Cao, Nora Abduljawad, Bishan Bhattarai, Justin Rustenhoven, Niall Mortimer, Simone Brioschi, Khai Nguyen, Patrick Fernandes Rodrigues, Igor Smirnov, Daniel Gibson, J Michael White, Wandy Beatty, David DeNardo, Qingyun Li, Michael Meers, Claudia Z Han, Na Sun, Florent Ginhoux, Marina Cella, Marco Colonna, Jonathan Kipnis.

  Microglia arise from yolk sac progenitors and are thought to persist throughout life with minimal input from adult hematopoiesis. However, whether brain-engrafted monocyte-derived macrophages (MDMs) exist at homeostasis and during turnover and how they function relative to yolk-sac-derived microglia (YSMs) remain unsettled. Here, we combine lineage tracing, pharmacological microglia depletion, and multi-omics profiling to define the ontogeny, identity, and function of brain parenchymal macrophages. Despite sharing the parenchymal milieu, MDMs display transcriptional and epigenetic landscapes distinct from YSMs. Fate-mapping reveals that brain-engrafted MDMs transiently express CD206, echoing a developmental stage of microglial precursors. MDM engraftment and polarization are modulated by interleukin (IL)-34 and C-C chemokine receptor 2 (CCR2). Furthermore, parabiosis and skull-flap transplantation reveal that both blood and skull marrow supply the niche, yielding origin-biased MDM states. Functionally, MDM engraftment enhances cuprizone-mediated demyelination. Together, our study defines the origins, molecular features, and context-dependent roles of brain parenchymal macrophages across homeostasis, turnover, and central nervous system (CNS) pathology.

Keywords:  macrophage ontogeny; microglia; monocyte; monocyte-derived macrophages; skull-bone marrow

DOI:  https://doi.org/10.1016/j.neuron.2026.01.032
Nat Commun. 2026 Mar 13.

Microglial cathepsin B is necessary for neuronal efferocytosis in zebrafish and mice during brain development.

Nicholas J Silva, Sarah R Anderson, Supriya A Mula, Caroline C Escoubas, Haruna Nakajo, Anna V Molofsky.

Half of all newborn neurons in the developing brain are removed via efferocytosis - the phagocytic clearance of apoptotic cells. Microglia are brain-resident professional phagocytes that play important roles in neural circuit development including as primary effectors of efferocytosis. While the mechanisms through which microglia recognize potential phagocytic cargo are widely studied, the lysosomal mechanisms that are necessary for efficient digestion are less well defined. Here we show that the lysosomal protease cathepsin B is enriched in microglia located in brain regions where neuronal turnover is high in both zebrafish and mouse. Genetic disruption of cathepsin B in zebrafish and mice had an accumulation of microglia containing undigested dead cells. Live imaging studies in zebrafish and in cultured mouse microglia revealed fewer phagocytic events and reduced overall phagocytosis. We also observed behavioral impairments in both models. These data reveal a role for microglial cathepsin B in vertebrate brain development.

DOI: https://doi.org/10.1038/s41467-026-70350-1
Nat Commun. 2026 Mar 12.

Impaired α-Synuclein aggregate clearance in neuronal cells drive their spread to microglia through tunneling nanotubes.

Ranabir Chakraborty, Francesca Palese, Philippa Samella, Veronica Testa, Jara Montero-Muñoz, Sylvie Syan, Takashi Nonaka, Masato Hasegawa, Antonella Consiglio, Chiara Zurzolo.

Tunneling nanotubes (TNTs) play a crucial role in intercellular communication, enabling transfer of molecular cargoes over long distances between connected cells. Previous studies have demonstrated efficient, directional transfer of α-Synuclein (α-Syn) aggregates from neurons to microglia, with endosomal trafficking and lysosomal processing identified as the primary events following α-Syn internalization. Using human neuronal and microglial cell lines, we show that microglia exhibit higher lysosomal turnover, particularly through lysophagy, whereas neuronal lysosomes display compromised degradative capacity and impaired autophagic flux upon α-Syn exposure, resulting in compromised aggregate clearance. Such a response to α-Syn aggregates is also conserved in human iPSC-derived neurons and microglia. Moreover, perturbing aggregate clearance via autophagy inhibition enhances TNT-mediated transfer of α-Syn from neuronal cells to microglia. Microglia co-cultured with α-Syn-containing neurons upregulate autophagy flux, enabling efficient degradation of the transferred aggregates. These results highlight dysfunctional autophagy in neurons as a key driver outsourcing α-Syn aggregates to microglia.

DOI: https://doi.org/10.1038/s41467-026-69930-y
Nat Commun. 2026 Mar 12.

scTWAS: a powerful statistical framework for single-cell transcriptome-wide association studies.

Zhaotong Lin, Chang Su.

Transcriptome-wide association studies (TWAS) have successfully identified genes associated with complex traits and diseases, but most have been performed using bulk gene expression data, which aggregate signals across heterogeneous cell types. Population-scale single-cell RNA sequencing data now make it possible to perform TWAS at the cell-type resolution, but present unique challenges due to strong noises, technical variations, and high sparsity. Here, we propose scTWAS, a statistical method to conduct cell-type-specific TWAS using single-cell data. Leveraging a latent-variable model and moment-based estimation to address the challenges of single-cell data, scTWAS consistently improves the prediction of genetically regulated gene expression across cell types in both blood and brain tissues. Compared to existing methods, scTWAS identifies substantially more gene-trait associations across 29 hematological traits and three immune-related diseases in immune cell types. An application to Alzheimer's disease also reveals cell-subtype-specific associations, including MS4A6A in the disease-associated microglial subtype and PPP1R37 in the inflammatory microglial subtype.

DOI: https://doi.org/10.1038/s41467-026-70374-7
Nat Aging. 2026 Mar 10.

Simultaneous spatial transcriptomics and morphology profiling as tools to explore how microglia change with age.

Douglas E Henze, Andy P Tsai, Tony Wyss-Coray, Stephen R Quake.

Cellular morphology is tightly linked to function, but how subcellular transcript localization contributes remains unclear. Using microglia, the brain's resident macrophages, as a model, we combined multiplexed error-robust fluorescence in situ hybridization with immunohistochemistry to map how morphology and subcellular mRNA localization interact with function in young and aged mouse brains. We show that mRNA spatial organization varies across microglial states and defines distinct localization patterns within their processes, revealing morphological heterogeneity within transcriptomically defined populations. Notably, we found a subpopulation of disease-associated-like microglia with a ramified morphology (that is, displaying numerous processes), challenging the conventional assumption between morphology and microglial states. Finally, we found that aging may reshape mRNA distributions and their co-localization networks, shifting microglial programs from intracellular signaling and regulation of phagocytosis toward migration and catabolic regulation. Our findings highlight the role of subcellular transcript organization in shaping microglial morphology and function, offering new avenues for studying and modulating microglial states in health, disease and aging.

DOI: https://doi.org/10.1038/s43587-026-01089-z
Nat Aging. 2026 Mar 11.

Microglia protein profiles in CSF across Alzheimer's disease clinical stages.

DELCODE Consortium

Microglia are implicated in the progression of Alzheimer's disease (AD) pathology from its earliest stages, suggesting that cerebrospinal fluid (CSF) microglia profiling across clinical AD stages can aid in treatment development and monitoring. We analyzed two CSF cohorts (n = 834) that span from unimpaired controls to preclinical and dementia AD stages, identifying 109 dysregulated microglia-related proteins. Enrichment analyses revealed innate immune processes and cellular recruitment in preclinical AD, whereas AD dementia revealed adaptive immunity and macrophage responses. Next, we aligned the in vivo microglia protein profiles with ex vivo-derived microglial transcriptomic signatures, such as disease-associated microglia phenotypes. Transcriptomic signatures were not specific to either clinical stage but spanned both. We classified an 18-protein panel highlighting distinct changes between the preclinical and dementia stages. Our findings underscore the potential of microglia-based biomarker research for AD staging, offering insights into microglia dynamics in clinical AD stages and how transcriptomic signatures translate to proteomic profiles.

DOI: https://doi.org/10.1038/s43587-026-01088-0
Trends Immunol. 2026 Mar 11. pii: S1471-4906(26)00038-4. [Epub ahead of print]

Tumor-derived cystatin C enables amyloid clearance.

Joseph Zambelas, Yun Huang, Hong Zhao, Stephen T C Wong.

  Li et al. described a tumor-derived neuroimmune mechanism that promotes clearance of established amyloid pathology in Alzheimer's disease. secreted cystatin C activates TREM2-dependent microglial phagocytosis, reducing plaques and improving cognition. This work introduces a context-dependent neuroimmune-modulatory strategy that shifts Alzheimer's therapy from broad immune activation toward substrate-coupled amyloid clearance.

Keywords:  Alzheimer’s disease; TREM2; amyloid clearance; cancer–brain interaction; cystatin C; microglia

DOI:  https://doi.org/10.1016/j.it.2026.02.007
Science. 2026 Mar 12. eaeb6999

Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis.

Alejandro Collado-Sole, Nozha Borjini, Jing Zhai, Francisco Ruiz-Pino, Gonzalo Soria-Alcaide, Cintia Folgueira, Celia García-Vilela, Beatriz Romero-de la Rosa, Victor Lopez, Yassine Zouaghi, An Jacobs, Bella Mora-Romero, Alexandra Barranco, Guillermo Yoldi, Karine Rizzoti, Guadalupe Sabio, Gema Perez-Chacon, Patricia G Santamaria, Jose Antonio Esteban, Nathalie Journiac, Vincent Prevot, Alberto Pascual, Rafael Fernández-Chacón, Manuel Tena-Sempere, Nelly Pitteloud, Eva Gonzalez-Suarez.

The hypothalamic-pituitary-gonadal axis (HPG) controls pubertal development, sexual maturation, and fertility. We identified a role of hypothalamic microglia in controlling the HPG axis through receptor activator of nuclear factor κβ (Rank) signaling. Whole-body and microglia Rank depletion led to hypogonadotropic hypogonadism (HH) resulting from an alteration in gonadotropin-releasing hormone (GnRH) neuron function. In addition, we identified rare gene variants of RANK in patients with HH. Transcriptional profiling upon Rank loss revealed defective microglia activation and morphological alterations in the median eminence, decreasing the contacts and engulfment of GnRH terminal projections and impairing GnRH neuronal responses to kisspeptin. Overall, our data uncover the microglia as regulator of GnRH neuronal function through Rank signaling, with potential implications for reproductive maturation and fertility.

DOI: https://doi.org/10.1126/science.aeb6999