bims-microg 2025-12-21 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–12–21
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

TREML2 Modulates Microglial Phagocytosis of Myelin Debris via TLR9 in Chronic Cerebral Ischemia.
Microglial Extracellular Vesicles Mediate C1q Deposition at the Pre-Synapse and Promote Synaptic Pruning.
Galectin-9 activates microglial asparagine endopeptidase and promotes α-synuclein pathology in Parkinson's disease.
Role of TREM1 in the sevoflurane-induced inflammatory activation of microglia in vitro.
Acetylation of fatty acid synthase regulates microglial lipid droplets accumulation and pro-inflammatory activity following traumatic brain injury.
Pioglitazone attenuates complement-mediated microglial synaptic engulfment in an Alzheimer's disease model.
Autophagy-Induced Microglial Death Contributes to Neuroinflammation in Acute Optic Nerve Injury.
The P2Y13 receptor-mediated microglial morphological transformation through the p38MAPK signaling pathway contributes to central sensitization in a murine model of chronic migraine.
Piezo1-Targeted Magnetoacoustic Nanobubbles Rescue Alzheimer's Pathology by Electromechanical Neuromodulation and Amyloid-β Clearance.
Ezetimibe mitigates microglial activation in Parkinson's disease via TLR4/JNK pathway inhibition: evidence from network pharmacology and experimental validation.
Stainless Steel-Synthesized gold Nanoparticles: Insights into Blood-Brain barrier permeability and microglial interaction.
Regulatory T cells promote microglia-mediated synapse engulfment and functional recovery via the OPN-CD74 axis after spinal cord injury in mice.
Tirzepatide reverses hypothalamic inflammation, cellular stress, and neuropeptide imbalance in metabolic-menopausal dysfunction.
Immuno-Regulation of Brain Region-Specific Organoids Containing Isogenic Microglia-Like Cells.
Lesion-remote astrocytes govern microglia-mediated white matter repair.
Anti-BCMA CAR-T cells attenuate microglial activation in progressive multiple sclerosis: indicating a plasma cell-microglia crosstalk.
Microglial clearance, neuroprotection and cognitive recovery via a novel synthetic sulfolipid in Alzheimer's disease.
Neurotrauma induced retinal basement membrane COL4A1 defects are restored by adipose tissue derived mesenchymal stem cell concentrated conditioned medium.
Single Cell RNAseq Analysis of Thyroid Hormone Effects on Retinal Glial Cells.
Quantitative assessment of hyperreflective dots in the outer nuclear layer over neovascular lesion components.

Inflammation. 2025 Dec 17. 49(1): 4

TREML2 Modulates Microglial Phagocytosis of Myelin Debris via TLR9 in Chronic Cerebral Ischemia.

Zhao-Han Xu, Jing-Wen Qi, Xin-Yu He, Shi-Yao Wang, Shuai-Yu Chen, Yu-Cheng Gu, Yi Xie, Ying-Dong Zhang, Teng Jiang.

  Demyelination is a significant pathological feature of chronic cerebral ischemia. Recent evidence suggested that microglia played a protective role in mitigating brain ischemic injury via phagocytosis of myelin debris resulting from demyelination. Triggering receptor expressed on myeloid cells-like 2 (TREML2) is a newly discovered inflammation-associated transmembrane receptor expressed by microglia. To date, whether microglial TREML2 contributes to the phagocytosis of myelin debris in chronic cerebral ischemia has not been fully clarified. In this study, employing a bilateral carotid artery stenosis animal model and a CoCl2-treated cellular model, we demonstrated for the first time that microglial TREML2 expression was upregulated in response to chronic cerebral ischemia. Utilizing Treml2-knockout mice, we provided the first evidence that Treml2 deficiency alleviated demyelination and cognitive deficits induced by chronic cerebral ischemia. Furthermore, this protective effect might be attributed to the microglial M2-type polarization and enhanced phagocytosis of myelin debris, both of which were induced by the Treml2 deficiency. Additionally, we showed that TREML2 regulated microglial phagocytosis of myelin debris via toll-like receptor 9 under ischemic conditions. These findings elucidated the mechanisms by which microglia modulated the phagocytosis of myelin debris in response to brain ischemic injury and suggested that inhibition of TREML2 might represent a novel therapeutic strategy for treating demyelination and cognitive decline induced by chronic cerebral ischemia.

Keywords:  Chronic cerebral ischemia; Demyelination; Microglia; Phagocytosis; TLR9; TREML2

DOI:  https://doi.org/10.1007/s10753-025-02397-z
J Extracell Vesicles. 2025 Dec;14(12): e70173

Microglial Extracellular Vesicles Mediate C1q Deposition at the Pre-Synapse and Promote Synaptic Pruning.

Giulia D'Arrigo, Giulia Cutugno, Maria Teresa Golia, Francesca Sironi, Marta Lombardi, Sara Francesca Colombo, Roberto Frigerio, Marina Cretich, Paola Gagni, Elisabetta Battocchio, Cristiana Barone, Emanuele Azzoni, Sonia Bellini, Claudia Saraceno, Roberta Ghidoni, Caterina Bendotti, Rosa Chiara Paolicelli, Martina Gabrielli, Claudia Verderio.

  C1q is released by microglia, localizes on weak synapses and acts as a tag for microglial synaptic pruning. However, how C1q tags synapses during the pruning period remains to be fully elucidated. Here, we report that C1q is delivered via extracellular vesicles by microglia to pre-synaptic sites that externalize phosphatidylserine. Using approaches to increase or reduce vesicles production in microglia, by C9orf72 knock out or pharmacological inhibition, respectively, we provided mechanistic evidence linking extracellular vesicle release to pre-synaptic remodelling in neuron-microglia cultures. In C9orf72 knockout mice, we confirmed larger production of microglial extracellular vesicles and showed augmented C1q presynaptic deposition associated with enhanced engulfment by microglia in the early postnatal hippocampus. Finally, we provide evidence that microglia physiologically release more vesicles during the period of postnatal circuit refinement. These findings implicate abnormal release of microglial extracellular vesicles in both neurodevelopmental and age-related disorders characterized by dysregulated microglia-mediated synaptic pruning.

Keywords:  C1q; C9orf72 knock out; extracellular vesicles; microglia; synaptic pruning

DOI:  https://doi.org/10.1002/jev2.70173
Cell Death Differ. 2025 Dec 14.

Galectin-9 activates microglial asparagine endopeptidase and promotes α-synuclein pathology in Parkinson's disease.

Qinyu Peng, Guoxin Zhang, Xiaodi Guo, Xu Xu, Yiming Li, Lina Pan, Lanxia Meng, Jing Xiong, Sheng Li, Zhentao Zhang.

Parkinson's disease (PD) is characterized by the aggregation of misfolded α-synuclein (α-syn) and microglial activation. Galectin-9 (Gal-9) is an immunoregulatory mediator generated by microglia. Here, we found that α-syn fibrils are internalized by microglia and processed by microglial protease AEP, generating α-syn species with enhanced seeding activity and neurotoxicity. Notably, the uptake of α-syn fibrils by microglia leads to increased expression of Gal-9, which further promotes the production of toxic α-syn species via activation of the C/EBPβ/AEP axis. Knockout of Gal-9 attenuates α-syn pathology, dopaminergic neuronal loss, and motor impairments in a mouse model induced by intrastriatal injection of α-syn PFFs. Intrastriatal injection of Gal-9 promoted PD-like phenotypes induced by α-syn PFFs. Furthermore, the detrimental effect of Gal-9 was attenuated by the knockout of AEP. These observations illustrate the key role of Gal-9 in promoting α-syn pathology and neurodegeneration via the C/EBPβ/AEP axis in PD.

DOI: https://doi.org/10.1038/s41418-025-01640-2
Ibrain. 2025 ;11(4): 512-523

Role of TREM1 in the sevoflurane-induced inflammatory activation of microglia in vitro.

Chunchun Tang, Yuhang Zhu, Dexing Liu, Xue Zheng, Junli Jiang, Wanqiu Yu, Yinan Zhang, Dongqin Chen, Zhaoqiong Zhu.

  Perioperative neurocognitive disorders (PNDs) are one of the most common complications in perioperative patients, and neuroinflammatory reaction mediated by microglia plays a key role in their formation, but the underlying mechanism remains unknown. Given that the triggering receptor expressed on myeloid cells 1 (TREM1) is a key regulator of inflammation, this study aimed to observe the role of TREM1 on the sevoflurane-induced inflammatory activation in microglia. BV2 microglia were subjected to varying sevoflurane concentrations and durations to assess their viability using CCK8 and the expression of TREM1, iNOS, and ARG using enzyme-linked immunosorbent assays. Additionally, TREM1 knockdown lentivirus was employed to examine its impacts on microglia response to sevoflurane and altered expression of inflammatory markers, IL-1β, TNF-α, TGF-β, IL-10, iNOS, and ARG, as detected using qRT-PCR and immunofluorescence for INOS/Iba-1 and ARG/Iba-1. Our findings underscore the potent inflammatory activation induced by prolonged, high-concentration sevoflurane exposure on microglia. We highlight the potential role of TREM1 as a modulator of microglial polarization and a potential target for the treatment and prevention of sevoflurane-induced PNDs.

Keywords:  TREM1; inflammatory activation; microglia; polarization phenotype; sevoflurane

DOI:  https://doi.org/10.1002/ibra.12182
Redox Biol. 2025 Dec 15. pii: S2213-2317(25)00491-4. [Epub ahead of print]89 103978

Acetylation of fatty acid synthase regulates microglial lipid droplets accumulation and pro-inflammatory activity following traumatic brain injury.

Fengchen Zhang, Tao Lv, Tianqi Xu, Jie Li, Jie Lian, Siyu Lin, Qin Hu, Yichao Jin, Feng Jia, Xiaohua Zhang.

  Lipid droplet accumulation in microglia has been implicated in inflammatory functions associated with aging and demyelinating diseases. However, the molecular mechanisms driving lipid droplet formation under pathological conditions remain unrevealed. It is demonstrated herein that the acetylation of fatty acid synthase (FASN) plays a key regulatory role in the accumulation of lipid droplets in microglia following traumatic brain injury (TBI). Through mass spectrometry analysis, we identified hyperacetylation at lysine K673 of FASN as a critical driver of lipid droplet formation in microglia. Notably, this acetylation event not only promotes lipid droplet accumulation but also enhances pro-inflammatory cytokine production and phagocytic activity in microglia. Additionally, we found that HDAC3 may be the enzyme responsible for deacetylation of FASN K673. Importantly, observation of a mouse model carrying the FASN K673R mutation revealed a reduction in microglial lipid droplet accumulation and neuroinflammatory responses following TBI relative to wild-type mice. Thus, FASN acetylation is a pivotal regulator of post-TBI microglial lipid droplet formation and neuroinflammation. This positions the targeting of deacetylation pathways as a novel therapeutic strategy for TBI.

Keywords:  Acetylation; Fatty acid synthase; Microglia; Neuroinflammation; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.redox.2025.103978
Brain. 2025 Dec 15. pii: awaf462. [Epub ahead of print]

Pioglitazone attenuates complement-mediated microglial synaptic engulfment in an Alzheimer's disease model.

Juan Zu, Cong Li, Mochen Cui, Xinwu Liu, Zhouyang Pan, Xiaohe Li, Fang Zhang, Johanna Gentz, Gerda Mitteregger-Kretzschmar, Jochen Herms, Yuan Shi.

  Synaptic loss is an early hallmark of Alzheimer's disease (AD), predominantly driven by aberrant microglial reactivity. Pioglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist with anti-diabetic properties, has been shown to suppress microglial activity and improve cognitive performance in both AD models and clinical studies. However, whether its neuroprotective effects involve direct modulation of synaptic architecture remains unclear. Here, using longitudinal in vivo two-photon imaging, multi-channel immunohistochemistry, super-resolution confocal microscopy, and 3D reconstruction techniques in an AD mouse model, we analysed synaptic and microglial interactions. We show that a 4-week pioglitazone treatment preserves dendritic spine density and enhances spine stability over time. Mechanistically, pioglitazone reduces synaptic C1q deposition, thereby limiting complement-mediated microglial synaptic engulfment and attenuating synapse loss. These findings identify pioglitazone as a modulator of complement-dependent microglial synaptic pruning and support its therapeutic potential in preserving synaptic integrity during early AD pathogenesis.

Keywords:  Alzheimer's disease; microglia; peroxisome proliferator-activated receptor γ; pioglitazone; synaptic plasticity

DOI:  https://doi.org/10.1093/brain/awaf462
Invest Ophthalmol Vis Sci. 2025 Dec 01. 66(15): 51

Autophagy-Induced Microglial Death Contributes to Neuroinflammation in Acute Optic Nerve Injury.

Shuping Ke, Jiajian Liang, Wai Kit Chu, Yan Tong, Suyao Wu, Weiqing Ye, Shaolang Chen, Qingping Liu, Dingguo Huang, Weiqi Chen, Zijing Huang.

Purpose: Optic neuropathy is a leading cause of blindness. Autophagy activation has been reported following optic nerve injury, but its precise role remains unclear. We investigated the involvement of autophagy in the early stages of optic nerve injury and explored potential therapeutic strategies.
Methods: A mouse optic nerve crush (ONC) model was established. Autophagy levels were assessed at different time points using electron microscopy and markers LC3 and Beclin-1. The relationship between autophagy and cell death was examined by Beclin-1 co-localization combined with TUNEL. Receptor-interacting protein (RIP3) knockout mice were used to determine its regulatory role in microglial autophagy-related cell death. Finally, the neuroprotective effect of inhibiting this pathway was evaluated with pharmacological inhibitors.
Results: A peak in autophagy activation was observed 1 day after optic nerve injury. Beclin-1 was expressed across various cell populations, including retinal ganglion cells (RGCs), microglia, and astrocytes. Excessive autophagy activation induced cell death specifically in microglia, not in RGCs or astrocytes. Knockout of RIP3 significantly reduced microglial autophagy-related cell death and attenuated retinal neuroinflammation. Moreover, intravitreal administration of the RIP3 inhibitor GSK-872 or the autophagy inhibitor 3-MA reduced RGC death and improved visual function.
Conclusions: Autophagy-related cell death represents a novel mechanism of microglial activity. Targeting RIP3-mediated autophagy may provide a promising strategy for early intervention in optic neuropathies.

DOI: https://doi.org/10.1167/iovs.66.15.51
J Headache Pain. 2025 Dec 15.

The P2Y13 receptor-mediated microglial morphological transformation through the p38MAPK signaling pathway contributes to central sensitization in a murine model of chronic migraine.

Yingjie Yang, Suya Sun, Pengtao Qin, Yalun Sun, Huijuan Li, Diandian Wang, Xin He, Zhaoming Ge, Zhenzhen Fan, Jiewen Zhang, Songtang Sun.

   BACKGROUND: Central sensitization is a crucial pathophysiological mechanism of chronic migraine (CM), and neuroinflammation mediated by activated microglia contributes significantly to the development of central sensitization. The P2Y13 receptor (P2Y13R), belonging to the G protein-coupled receptor family, is expressed in microglia and actively participates in the intricate pathophysiological process underlying chronic neuropathic pain. However, the precise relationship between the P2Y13R and CM remains largely unclear.
METHODS: The CM mouse model was established by repeatedly injecting nitroglycerin (NTG) intraperitoneally at intermittent intervals, and the pain threshold was assessed using von Frey fiber and hot plate tests. Specific interventions were conducted on the P2Y13R and p38 MAPK signaling pathways in the Trigeminal Nucleus Caudalis (TNC) of mice through stereotactic injection. Western blotting and immunofluorescence were employed to assess the expression and localization of P2Y13R, c-Fos, calcitonin gene-related peptide (CGRP), components of the p38 MAPK signaling pathway, and inflammatory factors.
RESULTS: The expression of P2Y13R was significantly upregulated upon NTG administration and exhibited a predominant distribution within the microglia in the TNC in mice with CM. Pharmacological inhibition of P2Y13R effectively reduced hyperalgesia in CM mice, lowered CGRP and c-fos levels, thereby improving central sensitization. Furthermore, inhibiting P2Y13R suppressed microglial activation and pro-inflammatory cytokine production. Additionally, activation of the p38MAPK pathway was observed in the TNC of CM mice, with P2Y13R inhibition significantly reducing p38MAPK pathway activity. Pharmacological inhibition of p38MAPK significantly ameliorates central sensitization in CM mice, while suppressing microglial activation and pro-inflammatory cytokine levels.
CONCLUSIONS: This research emphasizes the significance of P2Y13R in mediating central sensitization in CM mice through the p38MAPK pathway, thereby suggesting that targeting P2Y13R holds promise as a potential therapeutic strategy for effectively managing CM.

Keywords:  Central sensitization; Microglia; P2Y13R; Stereotactic injection; p38MAPK

DOI:  https://doi.org/10.1186/s10194-025-02251-5
ACS Nano. 2025 Dec 16.

Piezo1-Targeted Magnetoacoustic Nanobubbles Rescue Alzheimer's Pathology by Electromechanical Neuromodulation and Amyloid-β Clearance.

Fangxuan Chu, Xiaoqing Zhou, Ren Ma, Ruixu Liu, Xu Liu, Kai Zhu, Yuheng Wang, Xin Wang, Ying Li, Shunqi Zhang, Tao Yin, Zhipeng Liu.

  Amyloid-β (Aβ) is considered a core pathological feature of Alzheimer's disease (AD), and its clearance efficiency is highly dependent on the function of the Piezo1 channel in microglia. However, the activity of Piezo1 is impaired under the pathological conditions of AD, and existing pharmacological strategies struggle to achieve precise targeted intervention in deep brain regions. To address these concerns, our research proposes a synergistic therapeutic paradigm leveraging transcranial magneto-acoustic stimulation (TMAS) to actuate microglial-Piezo1-targeted magnetic nanobubbles (PT-MNBs) for AD treatment. TMAS noninvasively focuses physical energy into deep brain lesion areas through a magnetoacoustic coupling field and drives PT-MNBs to generate responsive mechanical and electrical stimulation signals. PT-MNBs achieve microglia-specific anchoring through surface-modified phosphatidylserine, while conjugated anti-Piezo1 antibodies precisely deliver mechano-electrical stimulation signals to antibody-functionalized Piezo1 ion channels in microglial populations. This synchronously activates the mechanical- and voltage- sensitive domains of Piezo1 to recruit microglia to areas of inflammation and increase Aβ clearance, ameliorating synaptic plasticity impairment and ultimately reversing the pathological progression of AD. This dual-action mechanism achieves spatially precise manipulation of cellular mechanical and electrical activity in deep brain regions of AD mice and enhances Piezo1 function through precise energy delivery, enhancing their ability to clear Aβ plaques, opening an avenue for a noninvasive, deep-targeted physical stimulation-mediated nanoparticle synergistic therapy for AD.

Keywords:  Alzheimer’s disease; Piezo1; magnetic nanobubbles; microglia; transcranial magnetoacoustic stimulation

DOI:  https://doi.org/10.1021/acsnano.5c13702
Brain Res. 2025 Dec 17. pii: S0006-8993(25)00679-1. [Epub ahead of print] 150116

Ezetimibe mitigates microglial activation in Parkinson's disease via TLR4/JNK pathway inhibition: evidence from network pharmacology and experimental validation.

You-Hai Hua, Xin-Yue Huang, Jing-Jing Ma, Jin Wu, Zeng-Hui Zhou.

   OBJECTIVE: Neuroinflammation driven by microglial hyperactivation plays a critical role in Parkinson's disease (PD). Ezetimibe, a cholesterol absorption inhibitor widely used for hyperlipidemia, has recently been implicated in neuroprotection. However, its impact on microglial activation in PD remains poorly understood. This study aimed to investigate the therapeutic potential and mechanisms of ezetimibe in modulating microglial activation in PD model.
METHODS: Network pharmacology was employed to predict ezetimibe targets in PD, followed by validation in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Protein-protein interaction (PPI) analysis and Gene Ontology (GO) enrichment were used to identify relevant pathways. Molecular docking assessed ezetimibe-TLR4 binding. The effects of ezetimibe on pro-inflammatory mediator production, TLR4/JNK signaling, and microglia-induced dopaminergic neurotoxicity were evaluated using western blotting, qPCR, ELISA, and BV2-SH-SY5Y co-culture assays.
RESULTS: Network pharmacology identified 53 common targets between ezetimibe and PD, with TLR4, TNF, and IL-1β as hub genes enriched in inflammatory processes. In BV2 cells, ezetimibe markedly reduced LPS-induced expression and secretion of iNOS, COX-2, Nitric oxide (NO), and IL-6 at both protein and transcriptional levels. Molecular docking revealed a strong binding affinity of ezetimibe to TLR4, although ezetimibe did not alter the basal expression of TLR4. Mechanistically, ezetimibe pretreatment suppressed LPS-induced JNK phosphorylation and AP-1 transcriptional activity, key downstream events of TLR4 activation. Consistently, pharmacological inhibition of TLR4 with TLR4-IN-C34 did not produce additional anti-inflammatory effects, confirming that ezetimibe acts through the TLR4 signaling pathway. Moreover, conditioned medium from ezetimibe-pretreated BV2 cells significantly reduced SH-SY5Y neuronal death, as indicated by decreased PI staining, LDH release, CCK8 assay, tyrosine hydroxylase (TH) protein levels and caspase-3 activation.
CONCLUSION: Ezetimibe suppresses microglial activation by targeting the TLR4/JNK pathway, thereby alleviating dopaminergic neuronal death. These findings highlight ezetimibe as a promising candidate for repurposing in PD therapy.

Keywords:  Ezetimibe; Microglia; Neuroinflammation; Parkinson’s disease; The TLR4/JNK pathway

DOI:  https://doi.org/10.1016/j.brainres.2025.150116
Int J Pharm. 2025 Dec 13. pii: S0378-5173(25)01326-2. [Epub ahead of print]689 126489

Stainless Steel-Synthesized gold Nanoparticles: Insights into Blood-Brain barrier permeability and microglial interaction.

Zaira I González-Sánchez, Ángela Inmaculada López-Lorente, Julia Castillo-González, Elena González-Rey, Soledad Cárdenas, David Pozo.

  Effective drug delivery to the Central Nervous System (CNS) remains a formidable challenge in neurotherapeutics, primarily due to the restrictive Blood-Brain Barrier (BBB). Gold nanoparticles (AuNPs) are emerging as promising tools to bypass this barrier and manage neuroinflammation, key factor in numerous neurological disorders. In this work, we evaluate the potential of highly stable, small-sized AuNPs-synthesized via an environmentally benign method using stainless steel-as a dual-function nanocarrier system for CNS applications. We specifically investigate their capacity for BBB permeability using in vitro models and their subsequent interaction with resident immune cells (microglia), which is critical for safety and efficacy. We demonstrate that stainless steel-synthesized AuNPs (ss-AuNPs) effectively cross the barrier without compromising its integrity. In microglial cells, ss-AuNPs exhibited dose-dependent cytotoxic effects, with higher concentrations reducing cell viability while inducing minimal inflammatory responses. Similarly, in primary microglial cultures, ss-AuNPs at higher doses stimulated interleukin-6 (IL-6) release, although no significant pro-inflammatory activation was observed at lower doses. These results highlight the potential of green-synthesized AuNPs for CNS-targeted applications, validating their promise as stable and safe nanocarriers for future drug formulation targeting neurological diseases.

Keywords:  Blood–brain barrier; Central nervous system; Gold nanoparticles; Microglia; interleukin-6 (IL-6)

DOI:  https://doi.org/10.1016/j.ijpharm.2025.126489
J Neuroinflammation. 2025 Dec 15.

Regulatory T cells promote microglia-mediated synapse engulfment and functional recovery via the OPN-CD74 axis after spinal cord injury in mice.

Rui Liu, Hao Yan, Xuantong Liu, Yi Xie, Ying Li, Ziyue Wang, Hao Huang, Zhiyuan Yu, Wensheng Qu, Minghuan Wang, Xiang Luo.



Keywords:  Microglia; Spinal cord injury; Synapse engulfment; Tregs

DOI:  https://doi.org/10.1186/s12974-025-03661-7
Brain Res. 2025 Dec 15. pii: S0006-8993(25)00676-6. [Epub ahead of print]1872 150113

Tirzepatide reverses hypothalamic inflammation, cellular stress, and neuropeptide imbalance in metabolic-menopausal dysfunction.

Thatiany Souza Marinho, Julie Oliveira A Bittencourt, Marcia Barbosa Aguila, Carlos A Mandarim-de-Lacerda.

  Obesity, diabetes, and menopause impair hypothalamic regulation of energy balance by inducing inflammation, cellular stress, and disruption of neuropeptide signaling. In a female mouse model combining these conditions, we investigated whether tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, restores hypothalamic homeostasis by integrating gene and protein expression analyses. Ovariectomized and sham-operated mice were fed either a control or high-fat, high-sucrose diet and then treated with tirzepatide for four weeks. Metabolic and hormonal stress induced robust activation of inflammatory pathways, elevated cytokine and chemokine expression, marked endoplasmic reticulum stress, and enhanced microglial reactivity, accompanied by a shift toward appetite-stimulating neuropeptides and reduced expression of appetite-suppressing neuropeptides. Tirzepatide produced broad hypothalamic benefits, markedly suppressing inflammatory and stress-related markers, reprogramming microglia toward an anti-inflammatory phenotype, and restoring neuropeptide balance by reducing agouti-related peptide and neuropeptide Y while increasing proopiomelanocortin and melanocortin 4 receptor expression. Treatment also lowered suppressor of cytokine signaling 3 and normalized doublecortin expression, indicating enhanced neuronal plasticity and recovery of hypothalamic circuitry. Multivariate analysis demonstrated that tirzepatide shifted the overall hypothalamic molecular profile of obese-diabetic and ovariectomized mice to that of control groups, highlighting coordinated improvement across inflammatory, glial, and neuropeptidergic pathways. In conclusion, these findings show that tirzepatide exerts potent and broad central nervous system actions capable of counteracting hypothalamic inflammation, cellular stress, microglial activation, and neuropeptide dysregulation under severe metabolic-hormonal challenge, supporting its therapeutic potential to restore hypothalamic integrity and metabolic control in obesity and diabetes during menopause.

Keywords:  Endoplasmic reticulum stress; Energy homeostasis; GLP-1; Microglial activation; Neuroinflammation

DOI:  https://doi.org/10.1016/j.brainres.2025.150113
Adv Healthc Mater. 2025 Dec 17. e03579

Immuno-Regulation of Brain Region-Specific Organoids Containing Isogenic Microglia-Like Cells.

Chang Liu, Justice Ene, Wenyan Lu, Falak Syed, Li Sun, Ana-Caroline Raulin, Yi Ren, Xueju Wang, Takahisa Kanekiyo, Yan Li.

  Most brain organoids derived from human induced pluripotent stem cells (iPSCs) lack microglia and thus immune function. Microglia-like cells (MGCs) can be differentiated from iPSCs, while the characteristics of isogenic MGC-containing brain organoids in modeling neurodegeneration and cell-cell communications have not been well investigated. In this study, iPSC-derived MGCs are co-cultured with isogenic forebrain cortical organoids (iFCo), which are stimulated with extracellular vesicles (EVs) of brain organoids differentiated from Alzheimer's disease (AD) patient-derived iPSCs (APOE ε4/ε4 and presenilin 1). The AD EV-stimulated co-culture organoids are treated with EVs from healthy MGCs or co-culture. Differential responses of the co-cultured organoids and the MGCs to AD EVs are demonstrated. The co-cultured organoids mitigated pro-inflammatory gene expressions. EVs from healthy MGCs or co-culture reduced the expression of IL-12β, iNOS, TREM2, and CASS4, which are associated with neural inflammation and degeneration, as well as showed regulation on genes involved in microglial activation and carbon metabolism. AD EV cargo analysis by proteomics and microRNA-sequencing revealed APOE and APP proteins and microRNAs regulated pathways such as mitophagy. This study paves the way for understanding the role of microglia and brain organoids in modeling neural degeneration and the development of EV-based cell-free therapeutics for AD treatment.

Keywords:  brain organoids; co‐culture; extracellular vesicles; human pluripotent stem cells; microglia‐like cells; multi‐omics; neural degeneration

DOI:  https://doi.org/10.1002/adhm.202503579
Nature. 2025 Dec 17.

Lesion-remote astrocytes govern microglia-mediated white matter repair.

Sarah McCallum, Keshav B Suresh, Timothy S Islam, Manish K Tripathi, Ann W Saustad, Oksana Shelest, Aditya Patil, David Lee, Brandon Kwon, Katherine Leitholf, Inga Yenokian, Sophia E Shaka, Connor H Beveridge, Palak Manchandra, Caitlin E Randolph, Gordon P Meares, Ranjan Dutta, Jasmine Plummer, Vinicius F Calsavara, Riki Kawaguchi, Simon R V Knott, Gaurav Chopra, Joshua E Burda.

Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1. Lesion-remote astrocytes (LRAs), which interact with viable neurons and glia, undergo reactive transformations whose molecular and functional properties are poorly understood2. Here, using multiple transcriptional profiling methods, we investigated LRAs from spared regions of mouse spinal cord following traumatic spinal cord injury. We show that LRAs acquire a spectrum of molecularly distinct, neuroanatomically restricted reactivity states that evolve after spinal cord injury. We identify transcriptionally unique reactive LRAs in degenerating white matter that direct the specification and function of local microglia that clear lipid-rich myelin debris to promote tissue repair. Fuelling this LRA functional adaptation is the secreted matricellular protein CCN1. Loss of astrocyte-derived CCN1 results in excessive, aberrant activation of local microglia, characterized by abnormal molecular specification, impaired debris processing reflected by the intracellular accumulation of myelin and axon debris, and dysregulated lipid metabolism with distinctive attenuation in lipid droplet accumulation. Mechanistically, we find that CCN1 binds microglial SDC4 to augment lipid storage, linking this signalling axis to a vital repair-associated lipid buffering response in debris-clearing microglia. Accordingly, microglial deficits resulting from astrocyte CCN1 depletion culminate in blunted clearance of white matter debris and impaired neurological recovery from spinal cord injury. Ccn1-expressing white matter astrocytes are induced by local myelin damage and are generated in diverse demyelinating disorders in mice and humans, pointing to their fundamental, evolutionarily conserved role in white matter repair. Our findings show that context-specific cues shape regionally distinct LRA reactivity states with functional adaptations that orchestrate multicellular processes underlying neural repair and influence disease outcome.

DOI: https://doi.org/10.1038/s41586-025-09887-y
Signal Transduct Target Ther. 2025 Dec 20. 10(1): 407

Anti-BCMA CAR-T cells attenuate microglial activation in progressive multiple sclerosis: indicating a plasma cell-microglia crosstalk.

Fatme S Ismail, Hans-Peter Hartung, Nico Melzer.

DOI: https://doi.org/10.1038/s41392-025-02510-6
J Neuroinflammation. 2025 Dec 13.

Microglial clearance, neuroprotection and cognitive recovery via a novel synthetic sulfolipid in Alzheimer's disease.

Carmela Gallo, Lucia Verrillo, Emiliano Manzo, Emma Cauzzi, Livia La Barbera, Giuseppina Sabatino, Maria Luisa De Paolis, Michele Francesco Maria Sciacca, Giusi Barra, Elisa Peroni, Olivier Monasson, Mario Dell'Isola, Dalila Carbone, Annalisa Nobili, Marcello Ziaco, Laura Fioretto, Marinella Pirozzi, Giuliana D'Ippolito, Daniela Castiglia, Andrea Soluri, Genoveffa Nuzzo, Danilo Milardi, Maria Giuseppina Miano, Marcello D'Amelio, Angelo Fontana.



Keywords:  Alzheimer’s disease; Amyloid-β; Dopamine neurons; Drug discovery; Microglia; Natural Product; Neuroinflammation; Small molecule; TREM2

DOI:  https://doi.org/10.1186/s12974-025-03634-w
Stem Cell Res Ther. 2025 Dec 15. 16(1): 677

Neurotrauma induced retinal basement membrane COL4A1 defects are restored by adipose tissue derived mesenchymal stem cell concentrated conditioned medium.

Pratheepa Kumari Rasiah, Kumar Abhiram Jha, Jordy Gentry, Nobel A Del Mar, Lawrence M Pfeffer, Anton Reiner, Rajashekhar Gangaraju.

   BACKGROUND: COL4A1 defects are known to cause a variety of multisystem disorders with significant vascular dysfunction leading to neuronal damage. Case reports suggest that patients with COL4A1 mutations or extracellular COL4A1 deficiency in the basement membrane may put individuals at increased risk for developing visual deficits with neurotrauma. However, no experimental evidence is available. This study investigated the impact of Col4a1 deficiency on visual dysfunction following mild traumatic brain injury (mTBI) and evaluated the therapeutic efficacy of COL4A1-enriched adipose-derived stem cell-conditioned medium (ASC-CCM) in mitigating associated neurovascular deficits.
METHODS: Using a retina-targeted knockdown approach in C57Bl/6 mice via intravitreal delivery of AAV2-Col4a1 shRNA, followed by a controlled 50-psi air-blast to induce mTBI, we assessed visual performance, retinal histopathology, and gene expression profiles for 4 weeks post-injury. Treatment with ASC-CCM was administered intravitreally post-blast. In-vitro, Col4a1 knockdown in human retinal endothelial cells (HRECs) assessed the therapeutic benefit of COL4A1-enriched ASC-CCM.
RESULTS: After blast injury, Col4a1-deficient mice displayed significantly greater reductions in visual acuity and contrast sensitivity thresholds compared to control mice, which were substantially restored following ASC-CCM treatment. Histological and molecular analyses revealed marked glial activation, vascular instability, and synaptic disorganization in Col4a1-deficient retinas post-injury, which were attenuated upon ASC-CCM administration. In-vitro assays further confirmed that COL4A1 plays a crucial role in endothelial integrity. After Col4a1 knockdown, HRECs showed impaired cell migration and increased leukocyte transmigration, effects that were reversed by treatment with COL4A1-enriched, but not COL4A1-depleted, ASC-CCM. Moreover, COL4A1-enriched ASC-CCM suppressed inflammatory responses in cytokine-stimulated microglia and stabilized TNF-α-induced endothelial permeability.
CONCLUSIONS: These findings collectively identify COL4A1 deficiency as a sensitizing factor for post-traumatic visual dysfunction and demonstrate that ASC-CCM exerts therapeutic effects by preserving retinal vascular structure and modulating inflammatory responses, positioning it as a promising candidate for treating TBI-related ocular neurovascular injury.

Keywords:  Endothelial; GFAP; Microglia; Traumatic brain injury; VE-cadherin; Vision

DOI:  https://doi.org/10.1186/s13287-025-04804-6
Aging Dis. 2025 Dec 15.

Single Cell RNAseq Analysis of Thyroid Hormone Effects on Retinal Glial Cells.

Hongwei Ma, Shujuan Li, Yun Le, David Stanford, Willard M Freeman, Xi-Qin Ding.

Thyroid hormone (TH) signaling regulates cellular metabolism and stress response in the retina. Increased TH levels in circulation are associated with a higher incidence of age-related macular degeneration. Furthermore, stimulation of TH signaling induces retinal degeneration in mice, which is accompanied by the activation of retinal glial cells. Here, we investigated the transcriptional changes induced by triiodothyronine (T3) in retinal glial cells using single-cell RNA sequencing (scRNAseq) and bioinformatic analyses. One-month-old C57BL/6 mice were given T3 (20 μg/ml in drinking water) for four weeks, after which their retinal cells were collected to assess viability and undergo scRNAseq. The resulting data were analyzed using the Seurat package, visualized by the Loupe Browser, and Ingenuity Pathway Analysis. Analyses of differentially expressed genes (DEGs) in Müller cells, astrocytes, and microglia revealed significant enrichment in pathways associated with stress, immune response, and degeneration. Müller cells exhibited upregulation of mitochondrial dysfunction, acute-phase response, and sirtuin signaling pathways. Astrocytes displayed downregulation of synaptogenesis, neurovascular coupling, cAMP response elements, and calcium signaling. Microglia showed upregulation of coordinated lysosomal expression and regulation signaling, systemic lupus erythematosus in T cells, and multiple sclerosis signaling, and downregulation of actin-binding Rho activating signaling, retinoic acid receptor activation signaling, and IL-17 signaling. The distinct and overlapping transcriptional responses suggest that each retinal glial cell type plays a specific and coordinated role in adapting to stress. This study offers new insights into TH-induced retinal stress and degeneration at the transcriptional and pathway-level responses of retinal glial cells.

DOI: https://doi.org/10.14336/AD.2025.1221
Eye (Lond). 2025 Dec 15.

Quantitative assessment of hyperreflective dots in the outer nuclear layer over neovascular lesion components.

Yariv Keshet, Wei Kiong Ngo, Alfredo Salcedo-Ledesma, Jasjit Jay Walia, Richard F Spaide.

OBJECTIVES: To evaluate the outer nuclear layer for hyperreflective dots (HRD), a proposed imaging correlate of retinal microglia, in eyes with neovascular age-related macular degeneration (nAMD).
METHODS: High-resolution optical coherence tomography (OCT) of eyes with nAMD was evaluated with the aid of a custom ImageJ plugin that automatically identified HRD and plotted them on the corresponding near infrared (IR) fundus image. Areas of subretinal fluid (SRF), double layer sign (DLS), and the area of neovascularisation as imaged by OCT angiography (A) were mapped to the near-IR image. The number of HRD overlying these regions was tabulated.
RESULTS: There were 38 eyes of 38 patients. SRF was present in 23 eyes, there was a median 8.5 HRD /mm2 over this area. DLS was present in all eyes and with a median of 6.5 HRD/mm2 over this area. Neovascularisation was detectable using OCTA with a median of 6.8 HRD/mm2. The density of HRD/mm2 was not significantly different over areas of DLS with fluid compared to areas of DLS without SRF (P = 0.22). The median HRD/mm2 for uninvolved areas of the retina was 0.7, a difference that was significantly less than over areas of SRF, DLS, and OCTA detected neovascularisation (P < 0.001 for all comparisons).
CONCLUSIONS: There is an aggregation of HRD in the outer retina over lesion components of nAMD. These HRD may be present in response to SRF, but their existence over regions of the neovascular lesion without SRF suggests that additional factors are involved in their recruitment.

DOI: https://doi.org/10.1038/s41433-025-04157-7