bims-microg 2025-03-09 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–03–09
twenty-two papers selected by
Marcus Karlstetter, Universität zu Köln

Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing.
Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related systemic inflammation in COVID-19.
Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer's disease.
Microglial regulation of the retinal vasculature in health and during the pathology associated with diabetes.
Post-mortem validation of in vivo TSPO PET as a microglial biomarker.
Carbon ion stimulation therapy reverses iron deposits and microglia driven neuroinflammation and induces cognitive improvement in an Alzheimer's disease mouse model.
Microglial APOE4 promotes neuron degeneration in Alzheimer's disease through inhibition of lipid droplet autophagy.
The protective PLCγ2-P522R variant mitigates Alzheimer's disease-associated pathologies by enhancing beneficial microglial functions.
TREM2 promotes hippocampal neurogenesis through regulating microglial M2 polarization in APP/PS1 mice.
Metabolic Reprogramming in Primary Microglial Cell and Extracellular Vesicle Triggered by Aβ Exposure.
Chemogenetic activation of microglial Gi signaling decreases microglial surveillance and impairs neuronal synchronization.
cGAMP promotes inner blood-retinal barrier breakdown through P2RX7-mediated transportation into microglia.
The impact and mechanisms of YL-IPA08, a potent ligand for the translocator protein (18 kDa) on protection against LPS-induced depression and cognitive dysfunction in rodents.
Modulating lipid droplet dynamics in neurodegeneration: an emerging area of molecular pharmacology.
Adolescent binge alcohol exposure accelerates Alzheimer's disease-associated basal forebrain neuropathology through proinflammatory HMGB1 signaling.
Protein disulfide isomerase integrates toll-like receptor 4 and P2X7 receptor signaling pathways during lipopolysaccharide-induced neuroinflammation.
Computational detection, characterization, and clustering of microglial cells in a mouse model of fat-induced postprandial hypothalamic inflammation.
Antiretroviral drug therapy does not reduce neuroinflammation in an HIV-1 infection brain organoid model.
The acetyltransferase GCN5 contributes to neuroinflammation in mice by acetylating and activating the NF-κB subunit p65 in microglia.
Protective role of mitophagy on microglia-mediated neuroinflammatory injury through mtDNA-STING signaling in manganese-induced parkinsonism.
Microglial repopulation alleviates surgery-induced neuroinflammation and cognitive impairment in a ZEB1-dependent manner.
Ameboid Microglia as a Scavenger Role in Phagocytosis of Photoreceptor Outer Segment in an Experimental Retinal Detachment Model.

Nat Genet. 2025 Mar 03.

Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing.

Jack Humphrey, Erica Brophy, Roman Kosoy, Biao Zeng, Elena Coccia, Daniele Mattei, Ashvin Ravi, Tatsuhiko Naito, Anastasia G Efthymiou, Elisa Navarro, Claudia De Sanctis, Victoria Flores-Almazan, Benjamin Z Muller, Gijsje J L J Snijders, Amanda Allan, Alexandra Münch, Reta Birhanu Kitata, Steven P Kleopoulos, Stathis Argyriou, Periklis Malakates, Konstantina Psychogyiou, Zhiping Shao, Nancy Francoeur, Chia-Feng Tsai, Marina A Gritsenko, Matthew E Monroe, Vanessa L Paurus, Karl K Weitz, Tujin Shi, Robert Sebra, Tao Liu, Lot D de Witte, Alison M Goate, David A Bennett, Vahram Haroutunian, Gabriel E Hoffman, John F Fullard, Panos Roussos, Towfique Raj.

Microglia, the innate immune cells of the central nervous system, have been genetically implicated in multiple neurodegenerative diseases. Mapping the genetics of gene expression in human microglia has identified several loci associated with disease-associated genetic variants in microglia-specific regulatory elements. However, identifying genetic effects on splicing is challenging because of the use of short sequencing reads. Here, we present the isoform-centric microglia genomic atlas (isoMiGA), which leverages long-read RNA sequencing to identify 35,879 novel microglia isoforms. We show that these isoforms are involved in stimulation response and brain region specificity. We then quantified the expression of both known and novel isoforms in a multi-ancestry meta-analysis of 555 human microglia short-read RNA sequencing samples from 391 donors, and found associations with genetic risk loci in Alzheimer's and Parkinson's disease. We nominate several loci that may act through complex changes in isoform and splice-site usage.

DOI: https://doi.org/10.1038/s41588-025-02099-0
Nat Neurosci. 2025 Mar 06.

Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related systemic inflammation in COVID-19.

Rebeka Fekete, Alba Simats, Eduárd Bíró, Balázs Pósfai, Csaba Cserép, Anett D Schwarcz, Eszter Szabadits, Zsuzsanna Környei, Krisztina Tóth, Erzsébet Fichó, János Szalma, Sára Vida, Anna Kellermayer, Csaba Dávid, László Acsády, Levente Kontra, Carlos Silvestre-Roig, Judit Moldvay, János Fillinger, Attila Csikász-Nagy, Tibor Hortobágyi, Arthur Liesz, Szilvia Benkő, Ádám Dénes.

COVID-19 is associated with diverse neurological abnormalities, but the underlying mechanisms are unclear. We hypothesized that microglia, the resident immune cells of the brain, are centrally involved in this process. To study this, we developed an autopsy platform allowing the integration of molecular anatomy, protein and mRNA datasets in postmortem mirror blocks of brain and peripheral organ samples from cases of COVID-19. We observed focal loss of microglial P2Y12R, CX3CR1-CX3CL1 axis deficits and metabolic failure at sites of virus-associated vascular inflammation in severely affected medullary autonomic nuclei and other brain areas. Microglial dysfunction is linked to mitochondrial injury at sites of excessive synapse and myelin phagocytosis and loss of glutamatergic terminals, in line with proteomic changes of synapse assembly, metabolism and neuronal injury. Furthermore, regionally heterogeneous microglial changes are associated with viral load and central and systemic inflammation related to interleukin (IL)-1 or IL-6 via virus-sensing pattern recognition receptors and inflammasomes. Thus, SARS-CoV-2-induced inflammation might lead to a primarily gliovascular failure in the brain, which could be a common contributor to diverse COVID-19-related neuropathologies.

DOI: https://doi.org/10.1038/s41593-025-01871-z
Nat Med. 2025 Mar 06.

Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer's disease.

Lynn van Olst, Brooke Simonton, Alex J Edwards, Anne V Forsyth, Jake Boles, Pouya Jamshidi, Thomas Watson, Nate Shepard, Talia Krainc, Benney Mr Argue, Ziyang Zhang, Joshua Kuruvilla, Lily Camp, Mengwei Li, Hang Xu, Jeanette L Norman, Joshua Cahan, Robert Vassar, Jinmiao Chen, Rudolph J Castellani, James Ar Nicoll, Delphine Boche, David Gate.

Alzheimer's disease (AD) therapies utilizing amyloid-β (Aβ) immunization have shown potential in clinical trials. Yet, the mechanisms driving Aβ clearance in the immunized AD brain remain unclear. Here, we use spatial transcriptomics to explore the effects of both active and passive Aβ immunization in the AD brain. We compare actively immunized patients with AD with nonimmunized patients with AD and neurologically healthy controls, identifying distinct microglial states associated with Aβ clearance. Using high-resolution spatial transcriptomics alongside single-cell RNA sequencing, we delve deeper into the transcriptional pathways involved in Aβ removal after lecanemab treatment. We uncover spatially distinct microglial responses that vary by brain region. Our analysis reveals upregulation of the triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) in microglia across immunization approaches, which correlate positively with antibody responses and Aβ removal. Furthermore, we show that complement signaling in brain myeloid cells contributes to Aβ clearance after immunization. These findings provide new insights into the transcriptional mechanisms orchestrating Aβ removal and shed light on the role of microglia in immune-mediated Aβ clearance. Importantly, our work uncovers potential molecular targets that could enhance Aβ-targeted immunotherapies, offering new avenues for developing more effective therapeutic strategies to combat AD.

DOI: https://doi.org/10.1038/s41591-025-03574-1
Prog Retin Eye Res. 2025 Feb 26. pii: S1350-9462(25)00022-9. [Epub ahead of print]106 101349

Microglial regulation of the retinal vasculature in health and during the pathology associated with diabetes.

Andrew I Jobling, Ursula Greferath, Michael A Dixon, Pialuisa Quiriconi, Belinda Eyar, Anna K van Koeverden, Samuel A Mills, Kirstan A Vessey, Bang V Bui, Erica L Fletcher.

  The high metabolic demand of retinal neurons requires a precisely regulated vascular system that can deliver rapid changes in blood flow in response to neural need. In the retina, this is achieved via the action of a coordinated group of cells that form the neurovascular unit. While cells such as pericytes, Müller cells, and astrocytes have long been linked to neurovascular coupling, more recently the resident microglial population have also been implicated. In the healthy retina, microglia make extensive contact with blood vessels, as well as neuronal synapses, and are important in vascular patterning during development. Work in the brain and retina has recently indicated that microglia can directly regulate the local vasculature. In the retina, the fractalkine-Cx3cr1 signalling axis has been shown to induce local capillary constriction within the superficial vascular plexus via a mechanism involving components of the renin-angiotensin system. Furthermore, aberrant microglial induced vasoconstriction may be at the centre of early vascular reactivity changes observed in those with diabetes. This review summarizes the recent emerging evidence that microglia play multiple roles in retinal homeostasis especially in regulating the vasculature. We highlight what is known about the role of microglia under normal circumstances, and then build on this to discuss how microglia contribute to early vascular compromise during diabetes. Further understanding of the mechanisms of microglial-vascular regulation may allow alternate treatment strategies to be devised to reduce vascular pathology in diseases such as diabetic retinopathy.

Keywords:  Angiogenesis; Diabetic retinopathy; Microglia; Neurovascular coupling; Neurovascular unit; Vascular plexus

DOI:  https://doi.org/10.1016/j.preteyeres.2025.101349
Brain. 2025 Feb 26. pii: awaf078. [Epub ahead of print]

Post-mortem validation of in vivo TSPO PET as a microglial biomarker.

Sasvi S Wijesinghe, James B Rowe, Hannah D Mason, Kieren S J Allinson, Reuben Thomas, Davi S Vontobel, Tim D Fryer, Young T Hong, Mehtap Bacioglu, Maria Grazia Spillantini, Jelle van den Ameele, John T O'Brien, Sanne Kaalund, Maura Malpetti, Annelies Quaegebeur.

  Neuroinflammation is a feature of many neurodegenerative diseases, and is quantified in vivo by PET imaging with radioligands for the translocator protein (TSPO, e.g. [11C]-PK11195). TSPO radioligand binding correlates with clinical severity and predicts clinical progression. However, the cellular substrate of altered TSPO binding is controversial and requires neuropathological validation. We used progressive supranuclear palsy (PSP) as a demonstrator condition, to test the hypothesis that [11C]-PK11195 PET reflects microglial changes. We included people with PSP-Richardson's syndrome who had undergone [11C]-PK11195 PET in life (n=8). In post-mortem brain tissue from the same participants, we characterised cell-type specific TSPO expression and quantified microgliosis in eight cortical and eleven subcortical regions. Double-immunofluorescence labelling for TSPO and cell markers showed TSPO expression in microglia, astrocytes, and endothelial cells. Microglial (and not astrocytic) TSPO levels were higher in donors with PSP compared to controls (n=3), and correlated with changes in microglial density. There was a significant positive correlation between regional [11C]-PK11195 binding potential ante-mortem and the density of post-mortem CD68+ phagocytic microglia, as well as microglial TSPO levels. We conclude that in vivo disease-related changes in [11C]-PK11195 binding is largely driven by microglia and can be interpreted as a biomarker of microglia-mediated neuroinflammation in tauopathies.

Keywords:  PET; TSPO; microglia; neuroinflammation; post-mortem; tauopathies

DOI:  https://doi.org/10.1093/brain/awaf078
Sci Rep. 2025 Mar 07. 15(1): 7938

Carbon ion stimulation therapy reverses iron deposits and microglia driven neuroinflammation and induces cognitive improvement in an Alzheimer's disease mouse model.

Won-Seok Lee, Toshiaki Kokubo, Younshick Choi, Tsuyoshi Hamano, Alexander Zaboronok, Takaaki Ishikawa, Oh-Dae Kwon, EunHo Kim, Jong-Ki Kim.

  Insoluble iron deposits often exist as iron oxide nanoparticles in protein aggregates, impaired ferritin, or activated microglia and have been implicated as major causes of neuroinflammation in Alzheimer's disease. However, no crucial evidence has been reported to support the therapeutic effects of current iron chelators on the deposition of various molecular forms of insoluble iron. We investigated the therapeutic effect of carbon ion stimulation (CIS) via a transmission beam on insoluble iron deposits, iron inclusion bodies, and the associated biological response in 5xFAD AD mouse brains. Compared with no treatment, CIS dose-dependently induced a 33-60% reduction in the amount of ferrous-containing iron species and associated inclusion bodies in the brains of AD mice. CIS induced considerable neuroinflammation downregulation and, conversely, anti-inflammatory upregulation, which was associated with improved memory and enhanced hippocampal neurogenesis. In conclusion, our results suggest that the effective degradation of insoluble iron deposits in combination with pathogenic inclusion bodies promotes AD-modifying properties and offers a potential CIS treatment option for AD.

Keywords:  Carbon beam transmission; Iron deposition; Iron oxide nanoparticles; Microglial polarization; Neuroinflammation

DOI:  https://doi.org/10.1038/s41598-025-91689-3
Acta Pharm Sin B. 2025 Jan;15(1): 657-660

Microglial APOE4 promotes neuron degeneration in Alzheimer's disease through inhibition of lipid droplet autophagy.

Meng Mao, Xiwen Ma, Xiaochuan Wang, Jianping Ye.



Keywords:  ACSL1; APOE4; Alzheimer's disease (AD); Lipid droplets; Microglia

DOI:  https://doi.org/10.1016/j.apsb.2024.10.009
J Neuroinflammation. 2025 Mar 05. 22(1): 64

The protective PLCγ2-P522R variant mitigates Alzheimer's disease-associated pathologies by enhancing beneficial microglial functions.

Mari Takalo, Heli Jeskanen, Taisia Rolova, Inka Kervinen, Marianna Hellén, Sami Heikkinen, Hennariikka Koivisto, Kimmo Jokivarsi, Stephan A Müller, Esa-Mikko Koivumäki, Petra Mäkinen, Sini-Pauliina Juopperi, Roosa-Maria Willman, Rosa Sinisalo, Dorit Hoffmann, Henna Jäntti, Michael Peitz, Klaus Fließbach, Teemu Kuulasmaa, Teemu Natunen, Susanna Kemppainen, Pekka Poutiainen, Ville Leinonen, Tarja Malm, Henna Martiskainen, Alfredo Ramirez, Annakaisa Haapasalo, Stefan F Lichtenthaler, Heikki Tanila, Christian Haass, Juha Rinne, Jari Koistinaho, Mikko Hiltunen.

   BACKGROUND: Phospholipase C gamma 2, proline 522 to arginine (PLCγ2-P522R) is a protective variant that reduces the risk of Alzheimer's disease (AD). Recently, it was shown to mitigate β-amyloid pathology in a 5XFAD mouse model of AD. Here, we investigated the protective functions of the PLCγ2-P522R variant in a less aggressive APP/PS1 mouse model of AD and assessed the underlying cellular mechanisms using mouse and human microglial models.
METHODS: The effects of the protective PLCγ2-P522R variant on microglial activation, AD-associated β-amyloid and neuronal pathologies, and behavioral changes were investigated in PLCγ2-P522R knock-in variant mice crossbred with APP/PS1 mice. Transcriptomic, proteomic, and functional studies were carried out using microglia isolated from mice carrying the PLCγ2-P522R variant. Finally, microglia-like cell models generated from human blood and skin biopsy samples of PLCγ2-P522R variant carriers were employed.
RESULTS: The PLCγ2-P522R variant decreased β-amyloid plaque count and coverage in female APP/PS1 mice. Moreover, the PLCγ2-P522R variant promoted anxiety in these mice. The area of the microglia around β-amyloid plaques was also increased in mice carrying the PLCγ2-P522R variant, while β-amyloid plaque-associated neuronal dystrophy and the levels of certain cytokines, including IL-6 and IL-1β, were reduced. These alterations were revealed through [18F]FEPPA PET imaging and behavioral studies, as well as various cytokine immunoassays, transcriptomic and proteomic analyses, and immunohistochemical analyses using mouse brain tissues. In cultured mouse primary microglia, the PLCγ2-P522R variant reduced the size of lipid droplets. Furthermore, transcriptomic and proteomic analyses revealed that the PLCγ2-P522R variant regulated key targets and pathways involved in lipid metabolism, mitochondrial fatty acid oxidation, and inflammatory/interferon signaling in acutely isolated adult mouse microglia and human monocyte-derived microglia-like cells. Finally, the PLCγ2-P522R variant also increased mitochondrial respiration in human iPSC-derived microglia.
CONCLUSIONS: These findings suggest that the PLCγ2-P522R variant exerts protective effects against β-amyloid and neuronal pathologies by increasing microglial responsiveness to β-amyloid plaques in APP/PS1 mice. The changes observed in lipid/fatty acid and mitochondrial metabolism revealed by the omics and metabolic assessments of mouse and human microglial models suggest that the protective effects of the PLCγ2-P522R variant are potentially associated with increased metabolic capacity of microglia.

Keywords:  Alzheimer’s disease; Lipid droplets; Microglia; PLCγ2-P522R variant; Phospholipase C gamma 2; β-amyloid pathology

DOI:  https://doi.org/10.1186/s12974-025-03387-6
Exp Neurol. 2025 Mar 04. pii: S0014-4886(25)00069-X. [Epub ahead of print] 115205

TREM2 promotes hippocampal neurogenesis through regulating microglial M2 polarization in APP/PS1 mice.

Xiao-Qian Peng, Hong-Song Guo, Xiao Zhang, Xiang-Yuan Wu, John Bosco Ruganzu, Song-Di Wu, Ming-Tao Zhao, Lei Li, Yang Yang, Sheng-Feng Ji, Wei-Na Yang, Peng-Yu Ren.

  Triggering receptor expressed on myeloid cells-2 (TREM2) mainly expressed on microglia in the brain, and its mutations can increase the risk of Alzheimer's disease (AD). Upregulation or activation of TREM2 has been found to ameliorate several pathological features of AD, such as the reduction of amyloid beta (Aβ) plaques and tau hyperphosphorylation. However, the effects of TREM2 on neurogenesis are little understood. Here, we aimed to investigate the effects of TREM2 on hippocampal neurogenesis associated with microglial M2 polarization in APP/PS1 mice. Lentivirus vectors were used to interfere with the expression of TREM2 on microglia in the hippocampus of APP/PS1 mice and BV2 cells. The supernatant was collected from BV2 cells as a conditioned medium (CM) to culture neural stem cells (NSCs) in vitro. Upregulation of TREM2 partially salvaged the proliferation of NSCs and the decrease of the number of immature/mature neurons in the hippocampus of APP/PS1 mice, which was accompanied by an improvement in cognitive ability. Furthermore, upregulation of TREM2 increased the M2 microglia marker CD206, brain-derived neurotrophic factor (BDNF), and anti-inflammatory factors, while decreased the M1 microglia markers CD16/32 and CD86 and pro-inflammatory factors in vivo and in vitro. Importantly, the upregulation of TREM2 also led to a significant increase in the phosphorylation of PI3K and Akt. In vitro, treatment with LY294002, a PI3K inhibitor, abolished the beneficial effects of TREM2 on shifting microglia from M1 to M2 and the proliferation and differentiation of NSCs. Taken together, these findings indicated that upregulation of TREM2 activated the PI3K/Akt signaling pathway to promote microglial M2 polarization and led to the secretion of more BDNF, accompanied by an improved hippocampal neurogenesis and spatial cognitive function in APP/PS1 mice. Thus, TREM2 might be a promising target for the treatment of neurodegenerative disease.

Keywords:  Alzheimer's disease; BDNF; Microglia; Neurogenesis; TREM2

DOI:  https://doi.org/10.1016/j.expneurol.2025.115205
J Neurochem. 2025 Mar;169(3): e70030

Metabolic Reprogramming in Primary Microglial Cell and Extracellular Vesicle Triggered by Aβ Exposure.

Seong-Hun Bong, Hayoung Choi, Hyun-Ho Song, Dong Kyu Kim, Inhee Mook-Jung, Do Yup Lee.

  Microglia, key immune cells in the brain, play a pivotal role in brain homeostasis and immune responses. Emerging evidence suggests their critical involvement in Alzheimer's disease (AD) pathogenesis and propagation. The propagation of AD pathology is related to the extracellular matrix of microglia, including extracellular vesicles (EV). Recently, microglia-derived EVs are implicated in inflammatory processes and neuronal death. This study aimed to extensively profile and propose the metabolic role of microglial EVs in AD. Accordingly, we determined the significant alterations of the EV metabolome associated with the metabolites in primary microglial cells. Aβ exposure induced significant metabolic alteration of 39, 18, and 28 metabolites in microglial cells, cultured media, and EVs, respectively. Aβ exposure triggered common alteration of key metabolic pathways between microglial cells and EVs, including purine, amino acid, and fatty acid metabolisms. While most of the common metabolites showed the same directional changes among the microglial system, N-acetyl aspartic acid displayed the opposite directional change in EVs. N-acetyl aspartic acid decreased 2.3-fold and twofold in microglial cells and media, respectively, but increased 3.5-fold in EVs under Aβ exposure. Moreover, mediation analysis proposed key EV metabolites that were directly affected by the metabolic dysregulation of Aβ-exposed microglial cells. The up-regulation of cysteic acid in EVs was mediated by up-regulated IMP in microglial cells. The down-regulation of 1-16:0-lysoPE in EVs was mediated by stearoyl-L-carnitine in microglial cells. Our study sheds new light on the role of microglia and EVs in neurodegenerative diseases, offering promising avenues for future therapeutic interventions.

Keywords:  Alzheimer's disease; Anaplerosis; extracellular vesicle; metabolomics; microglial cell

DOI:  https://doi.org/10.1111/jnc.70030
Sci Adv. 2025 Feb 28. 11(9): eado7829

Chemogenetic activation of microglial Gi signaling decreases microglial surveillance and impairs neuronal synchronization.

Shunyi Zhao, Lingxiao Wang, Dimitrios Kleidonas, Fangfang Qi, Yue Liang, Jiaying Zheng, Anthony D Umpierre, Long-Jun Wu.

Microglia actively survey the brain and dynamically interact with neurons to maintain brain homeostasis. Microglial Gi protein-coupled receptors (Gi-GPCRs) play a critical role in microglia-neuron communications. However, the impact of temporally activating microglial Gi signaling on microglial dynamics and neuronal activity in the homeostatic brain remains largely unknown. In this study, we used Gi-based designer receptors exclusively activated by designer drugs (Gi-DREADD) to selectively and temporally modulate microglial Gi signaling pathway. By integrating this chemogenetic approach with in vivo two-photon imaging, we observed that exogenous activation of microglial Gi signaling transiently inhibited microglial process dynamics, reduced neuronal activity, and impaired neuronal synchronization. These altered neuronal functions were associated with a decrease in interactions between microglia and neuron somata. Together, this study demonstrates that acute, exogenous activation of microglial Gi signaling regulates neuronal circuit function, offering a potential pharmacological target for the neuromodulation through microglia.

DOI: https://doi.org/10.1126/sciadv.ado7829
J Neuroinflammation. 2025 Mar 01. 22(1): 58

cGAMP promotes inner blood-retinal barrier breakdown through P2RX7-mediated transportation into microglia.

Xiangyu Ge, Xingfei Zhu, Wei Liu, Mingsen Li, Zhaotian Zhang, Ming Zou, Mi Deng, Haifeng Cui, Ziqing Chen, Li Wang, Xuebin Hu, Rong Ju, Xiangcheng Tang, Xiaoyan Ding, Lili Gong.

BACKGROUND: Impairment of the inner blood-retinal barrier (iBRB) leads to various blinding diseases including diabetic retinopathy (DR). The cGAS-STING pathway has emerged as a driving force of cardiovascular destruction, but its impact on the neurovascular system is unclear. Here, we show that cGAMP, the endogenous STING agonist, causes iBRB breakdown and retinal degeneration thorough P2RX7-mediated transport into microglia.
METHODS: Extracellular cGAMP and STING pathway were determined in tissue samples from patients with proliferative DR (PDR) and db/db diabetic mice. Histological, molecular, bioinformatic and behavioral analysis accessed effects of cGAMP on iBRB. Single-cell RNA sequencing identified the primary retinal cell type responsive to cGAMP. Specific inhibitors and P2RX7-deficienct mice were used to evaluate P2RX7' role as a cGAMP transporter. The therapeutic effects of P2RX7 inhibitor were tested in db/db mice.
RESULTS: cGAMP was detected in the aqueous humor of patients with PDR and elevated in the vitreous humor with STING activation in db/db mouse retinas. cGAMP administration led to STING-dependent iBRB breakdown and neuron degeneration. Microglia were the primary cells responding to cGAMP, essential for cGAMP-induced iBRB breakdown and visual impairment. The ATP-gated P2RX7 transporter was required for cGAMP import and STING activation in retinal microglia. Contrary to previous thought that mouse P2RX7 nonselectively transports cGAMP only at extremely high ATP concentrations, human P2RX7 directly binds to cGAMP and activates STING under physiological conditions. Clinically, cGAMP-induced microglial signature was recapitulated in fibrovascular membranes from patients with PDR, with P2RX7 being predominantly expressed in microglia. Inhibiting P2RX7 reduced cGAMP-STING activation, protected iBRB and improved neuron survival in diabetic mouse retinas.
CONCLUSIONS: Our study reveals a mechanism for cGAMP-mediated iBRB breakdown and suggests that targeting microglia and P2RX7 may mitigate the deleterious effects of STING activation in retinal diseases linked to iBRB impairment.

DOI: https://doi.org/10.1186/s12974-025-03391-w
Metab Brain Dis. 2025 Mar 06. 40(3): 137

The impact and mechanisms of YL-IPA08, a potent ligand for the translocator protein (18 kDa) on protection against LPS-induced depression and cognitive dysfunction in rodents.

Lin-Yu Cui, Jing-Yao Duan, Jiao-Zhao Yan, Jing-Ya Wang, Peng Ren, Li-Ming Zhang, Wen-Zhi Guo, Wei Dai, Yun-Feng Li.

  Translocator protein (18 kDa) (TSPO) has been implicated in the development of depression and cognitive dysfunction. This study aimed to investigate the anti-depression/anti-anxiety and cognitive enhancing impacts and potential mechanisms of TSPO ligand YL-IPA08 in lipopolysaccharide (LPS)-induced inflammatory model. The effects of YL-IPA08 in LPS induced mice were identified by behavioral tests, and the target of YL-IPA08 was validated using the TSPO antagonist PK11195. The microglia in PFC were analyzed by immunofluorescence, and the inflammatory cytokines (IL-6, IL-1β and TNF-α) and anti-inflammatory factors (IL-4, IL-10, TGF-β1) in PFC was detected by ELISA or WB. Effect of TGF-β1 inhibitor Repsox on the actions of YL-IPA08 in LPS-treated mice was further verified. We found that YL-IPA08 administration ameliorated LPS-induced depression/anxiety-like behaviors and cognitive impairment, which were blocked by PK11195. YL-IPA08 reversed the increased number and inflammatory morphological changes of microglia in PFC of LPS mice by targeting TSPO. YL-IPA08 reversed the increased inflammatory cytokines (IL-6, IL-1β and TNF-α) and decreased anti-inflammatory factors (IL-4, IL-10) in the PFC of LPS mice by TSPO activation. In addition, YL-IPA08 elevated the suppressed levels of TGF-β1 and smad3 (member of TGF-β1 pathway) in PFC of LPS mice by TSPO activation. TGF-β1 inhibitor Repsox blocked the anti-depression/anxiety and cognition enhancing effects of YL-IPA08 in LPS mice. Our data implicated that central inflammation regulation and TSPO-TGF-β1/Smad pathway activation contributed to the anti-depressant/anxiety and cognitive promoting impacts of YL-IPA08.

Keywords:  Anxiety; Cognitive dysfunction; Depression; Transforming growth factor-β1 (TGF-β1); Translocator protein (18 kDa)

DOI:  https://doi.org/10.1007/s11011-025-01565-2
Mol Biol Rep. 2025 Mar 03. 52(1): 277

Modulating lipid droplet dynamics in neurodegeneration: an emerging area of molecular pharmacology.

Reet Verma, Prateek Sharma, Veerta Sharma, Thakur Gurjeet Singh.

  Neurodegenerative diseases (NDDs) are characterised by the progressive loss of neurons in the central nervous system (CNS), resulting in memory impairment, cognition abnormalities, and motor dysfunctions. The common pathological features include altered energy metabolism, neuroinflammation, loss of neurons, aberrant protein aggregation, and synaptic dysfunction. Lipids, fundamental components of cell membranes play a critical role in energy storage and cell signaling. The brain, comprising approximately 60% lipid content by dry weight, underscores the significance of lipid dynamics in maintaining CNS integrity. Variations in lipid distribution across brain regions further highlight their specialised functions. Dysregulation of lipid metabolism, encompassing synthesis, transport, and utilization, has been implicated in the pathogenesis of neurodegenerative diseases. Lipid droplets (LDs), key intermediates of lipid metabolism, accumulate in neurons, microglia, and astrocytes, particularly in aging brains. The deposition of these LDs disrupts cellular homeostasis and links the dynamics of LDs to pathology of disease. Therefore, this review explores the pivotal role of lipid metabolism and LDs in NDDs, providing insights into their contributions to neuronal dysfunction and potential therapeutic implications.

Keywords:  Cellular lipid dynamics; Lipid droplets; Neurodegeneration; Neuroinflammation; Oxidative stress

DOI:  https://doi.org/10.1007/s11033-025-10381-x
Front Aging Neurosci. 2025 ;17 1531628

Adolescent binge alcohol exposure accelerates Alzheimer's disease-associated basal forebrain neuropathology through proinflammatory HMGB1 signaling.

Rachael P Fisher, Lindsay Matheny, Sarrah Ankeny, Liya Qin, Leon G Coleman, Ryan P Vetreno.

  Human studies suggest that heavy alcohol use may be an etiological factor contributing to the development of Alzheimer's disease (AD) neuropathology. Both alcohol use disorder (AUD) and AD share common underlying neuropathology, including proinflammatory high-mobility group box 1 (HMGB1)-mediated neuroimmune signaling and basal forebrain cholinergic neuron degeneration. Adolescent onset of binge drinking represents a significant risk factor for later development of an AUD, and accumulating evidence suggests that adolescent initiation of heavy alcohol use induces HMGB1 signaling and causes degeneration of the basal forebrain cholinergic system that persists into adulthood. However, it is unknown whether adolescent binge drinking confers increased risk for later development of AD-associated neuropathology through persistent induction of proinflammatory HMGB1 neuroimmune signaling. To investigate this question, we first (Experiment 1) assessed AD-associated neuropathology in the post-mortem human basal forebrain of individuals with AUD and an adolescent age of drinking onset relative to age-matched moderate drinking controls (CONs). In Experiment 2, we treated non-transgenic and 5xFAD male and female mice, which overexpress both mutant human APP and PS1, with adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g. 2-days on/2-days off; postnatal day [P]30 - P55), and assessed AD-associated neuropathology in the adult (P100) basal forebrain. In Experiment 3, 5xFAD female mice received AIE treatment followed by glycyrrhizic acid (150 mg/L), an HMGB1 inhibitor, in drinking water from P56 to P100, and basal forebrain tissue was collected on P100 for assessment of AD-associated neuropathology. In the post-mortem human AUD basal forebrain (Experiment 1), we report upregulation of Hmgb1 and the HMGB1 receptors Rage and Tlr4 as well as microglial activation and increased intraneuronal Aβ1-42 accumulation in association with reduced cholinergic neuron marker expression (ChAT). In the 5xFAD mouse model (Experiment 2), AIE accelerated AD-associated induction of Hmgb1 proinflammatory neuroimmune genes, microglial activation, and reductions of ChAT+ basal forebrain cholinergic neurons in the adult female, but not male, basal forebrain. In Experiment 3, post-AIE treatment with glycyrrhizic acid rescued the AIE-induced acceleration of AD-associated increases in proinflammatory HMGB1 neuroimmune signaling, microglial activation, and persistent reductions of basal forebrain cholinergic neurons in adult 5xFAD female mice. Together, these findings suggest that adolescent binge ethanol exposure may represent an underappreciated etiological factor contributing to onset of AD-associated neuropathology in adulthood through HMGB1- mediated neuroimmune signaling.

Keywords:  HMGB1; cholinergic neurons; ethanol; microglia; neuroinflammation

DOI:  https://doi.org/10.3389/fnagi.2025.1531628
Sci Rep. 2025 Mar 06. 15(1): 7906

Protein disulfide isomerase integrates toll-like receptor 4 and P2X7 receptor signaling pathways during lipopolysaccharide-induced neuroinflammation.

Ji-Eun Kim, Su Hyeon Wang, Duk-Shin Lee, Tae-Hyun Kim.

  P2X7 receptor (P2X7R) augments lipopolysaccharide (LPS)-toll-like receptor 4 (TLR4)-mediated neuroinflammation. These roles of P2X7R in neuroinflammation are relevant to nitrosative stress through nuclear factor-κB (NF-κB)-inducible nitric oxide synthase (iNOS) pathway, while the underlying mechanisms are largely unknown. In the present study, we investigated whether protein disulfide isomerase (PDI) is involved in the integration of TLR4-P2X7R functions in response to LPS in vivo. The present study showed that LPS elicited NF-κB-mediated PDI upregulation, iNOS induction and S-nitrosylated PDI (SNO-PDI) level, independent of S-nitrosylation of NF-κB p65 subunit, in P2X7R+/+ mice more than P2X7R-/- mice. SN50 (an NF-κB inhibitor) effectively diminished LPS-induced PDI upregulation in both P2X7R+/+ and P2X7R-/- mice. PDI knockdown attenuated LPS-induced p65 S276 phosphorylation and iNOS induction in both strains. Of interest, S-nitroso-N-acetyl-DL-penicillamine (SNAP, a NO donor) increased SNO-PDI level, surface P2X7R expression and p65 S276 phosphorylation in P2X7R+/+ mice under physiological condition. In P2X7R-/- mice, SNAP was less effective on NF-κB S276 phosphorylation, although SNO-PDI level was similar to that in P2X7R+/+ mice. Taken together, the present data demonstrate that PDI may be an intermediator to integrate TLR4- and P2X7R-mediated signaling pathways in a positive feedback loop, which would exert NF-κB-iNOS-mediated nitrosative stress during LPS-induced neuroinflammation.

Keywords:  Astrocyte; LPS; Microglia; Nitrosative stress; S-nitrosylation; SN50; SNAP; TLR4-P2X7R interaction

DOI:  https://doi.org/10.1038/s41598-025-92780-5
Methods. 2025 Feb 26. pii: S1046-2023(25)00047-7. [Epub ahead of print]236 28-38

Computational detection, characterization, and clustering of microglial cells in a mouse model of fat-induced postprandial hypothalamic inflammation.

Clara Sanchez, Morgane Nadal, Céline Cansell, Sarah Laroui, Xavier Descombes, Carole Rovère, Éric Debreuve.

  Obesity is associated with brain inflammation, glial reactivity, and immune cells infiltration. Studies in rodents have shown that glial reactivity occurs within 24 h of high-fat diet (HFD) consumption, long before obesity development, and takes place mainly in the hypothalamus (HT), a crucial brain structure for controlling body weight. Understanding more precisely the kinetics of glial activation of two major brain cells (astrocytes and microglia) and their impact on eating behavior could prevent obesity and offer new prospects for therapeutic treatments. To understand the mechanisms pertaining to obesity-related neuroinflammation, we developed a fully automated algorithm, NutriMorph. Although some algorithms were developed in the past decade to detect and segment cells, they are highly specific, not fully automatic, and do not provide the desired morphological analysis. Our algorithm copes with these issues and performs the analysis of cells images (here, microglia of the hypothalamic arcuate nucleus), and the morphological clustering of these cells through statistical analysis and machine learning. Using the k-Means algorithm, it clusters the microglia of the control condition (healthy mice) and the different states of neuroinflammation induced by high-fat diets (obese mice) into subpopulations. This paper is an extension and re-analysis of a first published paper showing that microglial reactivity can already be seen after few hours of high-fat diet (Cansell et al., 2021 [5]). Thanks to NutriMorph algorithm, we unravel the presence of different hypothalamic microglial subpopulations (based on morphology) subject to proportion changes in response to already few hours of high-fat diet in mice.

Keywords:  Automatic clustering; Glial cells; Image processing and analysis; K-means; Machine learning; Microglia; Morphometric tools; Neuroinflammation; Obesity; Object characterization

DOI:  https://doi.org/10.1016/j.ymeth.2025.02.008
J Neuroinflammation. 2025 Mar 05. 22(1): 66

Antiretroviral drug therapy does not reduce neuroinflammation in an HIV-1 infection brain organoid model.

Samuel Martinez-Meza, Thomas A Premeaux, Stefano M Cirigliano, Courtney M Friday, Stephanie Michael, Sonia Mediouni, Susana T Valente, Lishomwa C Ndhlovu, Howard A Fine, Robert L Furler O'Brien, Douglas F Nixon.

   BACKGROUND: HIV-1-associated neurocognitive impairment (HIV-1-NCI) is marked by ongoing and chronic neuroinflammation with loss and decline in neuronal function even when antiretroviral drug therapy (ART) successfully suppresses viral replication. Microglia, the primary reservoirs of HIV-1 in the central nervous system (CNS), play a significant role in maintaining this neuroinflammatory state. However, understanding how chronic neuroinflammation is generated and sustained by HIV-1, or impacted by ART, is difficult due to limited access to human CNS tissue.
METHODS: We generated an in vitro model of admixed hematopoietic progenitor cell (HPC) derived microglia embedded into embryonic stem cell (ESC) derived Brain Organoids (BO). Microglia were infected with HIV-1 prior to co-culture. Infected microglia were co-cultured with brain organoids BOs to infiltrate the BOs and establish a model for HIV-1 infection, "HIV-1 M-BO". HIV-1 M-BOs were treated with ART for variable directions. HIV-1 infection was monitored with p24 ELISA and by digital droplet PCR (ddPCR). Inflammation was measured by cytokine or p-NF-kB levels using multiplex ELISA, flow cytometry and confocal microscopy.
RESULTS: HIV-1 infected microglia could be co-cultured with BOs to create a model for "brain" HIV-1 infection. Although HIV-1 infected microglia were the initial source of pro-inflammatory cytokines, astrocytes, neurons and neural stem cells also had increased p-NF-kB levels, along with elevated CCL2 levels in the supernatant of HIV-1 M-BOs compared to Uninfected M-BOs. ART suppressed the virus to levels below the limit of detection but did not decrease neuroinflammation.
CONCLUSIONS: These findings indicate that HIV-1 infected microglia are pro-inflammatory. Although ART significantly suppressed HIV-1 levels, neuronal inflammation persisted in ART-treated HIV-1 M-BOs. Together, these findings indicate that HIV-1 infection of microglia infiltrated into BOs provides a robust in vitro model to understand the impact of HIV-1 and ART on neuroinflammation.

Keywords:  Antiretroviral drug therapy (ART); Brain; CCL2; HIV-1; IRIS; Inflammation; Microglia; Neural stem cells; Neurocognitive; Neuroinflammation; Neurons; Organoid; p-NF-kB

DOI:  https://doi.org/10.1186/s12974-025-03375-w
Sci Signal. 2025 Mar 04. 18(876): eadp8973

The acetyltransferase GCN5 contributes to neuroinflammation in mice by acetylating and activating the NF-κB subunit p65 in microglia.

Duk-Yeon Cho, Jun-Hyuk Han, In-Su Kim, Ji-Hong Lim, Hyun Myung Ko, Byungwook Kim, Dong-Kug Choi.

Neuroinflammation promotes the progression of various neurological and neurodegenerative diseases. Disrupted homeostasis of protein acetylation is implicated in neurodegeneration, and the lysine acetyltransferase GCN5 (also known as KAT2A) is implicated in peripheral inflammation. Here, we investigated whether GCN5 plays a role in neuroinflammation in the brain. Systemic administration of the bacterial molecule LPS in mice to induce peripheral inflammation increased the abundance of GCN5 in various organs, including in the brain and specifically in microglia. In response to LPS, GCN5 mediated the induction of the proinflammatory cytokines TNF-α and IL-6 and the inflammatory mediators COX-2 and iNOS in microglia. Further investigation in cultured microglial cells revealed that GCN5 was activated downstream of the innate immune receptor TLR4 to acetylate Lys310 in the NF-κB subunit p65, thereby enabling the nuclear translocation and transcriptional activity of NF-κB and the resulting inflammatory response. Thus, targeting GCN5 might be explored further as a strategy to reduce neuroinflammation in the treatment of associated diseases.

DOI: https://doi.org/10.1126/scisignal.adp8973
J Neuroinflammation. 2025 Feb 28. 22(1): 55

Protective role of mitophagy on microglia-mediated neuroinflammatory injury through mtDNA-STING signaling in manganese-induced parkinsonism.

Yang Lu, Liang Gao, Yuqing Yang, Dihang Shi, Zhipeng Zhang, Xiaobai Wang, Ying Huang, Jie Wu, Jia Meng, Hong Li, Dongying Yan.

  Manganese (Mn), the third most abundant transition metal in the earth's crust, has widespread applications in the emerging field of organometallic catalysis and traditional industries. Excessive Mn exposure causes neurological syndrome resembling Parkinson's disease (PD). The pathogenesis of PD is thought to involve microglia-mediated neuroinflammatory injury, with mitochondrial dysfunction playing a role in aberrant microglial activation. In the early stages of PD, PINK1/Parkin-mediated mitophagy contributes to the microglial inflammatory response via the cGAS/STING signaling pathway. Suppression of PINK1/Parkin-mediated mitophagy due to excessive Mn exposure exacerbates neuronal injury. Moreover, excessive Mn exposure leads to neuroinflammatory damage via the microglial cGAS-STING pathway. However, the precise role of microglial mitophagy in modulating neuroinflammation in Mn-induced parkinsonism and its underlying molecular mechanism remains unclear. Here, we observed that Mn-exposed mice exhibited neurobehavioral abnormalities and detrimental microglial activation, along with increased apoptosis of nerve cells, proinflammatory cytokines, and intracellular ROS. Furthermore, in vivo and in vitro experiments showed that excessive Mn exposure resulted in microglial mitochondrial dysfunction, manifested by increased mitochondrial ROS, decreased mitochondrial mass, and membrane potential. Additionally, with the escalating Mn dose, PINK1/Parkin-mediated mitophagy changed from activation to suppression. This was evidenced by decreased levels of LC3-II, PINK1, p-Parkin/Parkin, and increased levels of p62 protein expression level, as well as the colocalization between ATPB and LC3B due to excessive Mn exposure. Upregulation of mitophagy by urolithin A could mitigate Mn-induced mitochondrial dysfunction, as indicated by decreased mitochondrial ROS, increased mitochondrial mass, and membrane potential, along with improvements in neurobehavioral deficits and attenuated detrimental microglial activation. Using single-nucleus RNA-sequencing (snRNA-seq) analysis in the Mn-exposed mouse model, we identified the microglial cGAS-STING signaling pathway as a potential mechanism underlying Mn-induced neuroinflammation. This pathway is associated with an increase in cytosolic mtDNA levels, which activate STING signaling. These findings point to the induction of microglial mitophagy as a viable strategy to alleviate Mn-induced neuroinflammation through mtDNA-STING signaling.

Keywords:  Manganese; Microglia; Mitophagy; Neuroinflammation; STING

DOI:  https://doi.org/10.1186/s12974-025-03396-5
FASEB J. 2025 Mar 15. 39(5): e70440

Microglial repopulation alleviates surgery-induced neuroinflammation and cognitive impairment in a ZEB1-dependent manner.

Xinyue Zhang, Xiaotong Cui, Naihui Sun, Xinyi Wu, Xue Pan, Renyi Wang, Zitong Chen, Yilong Li, Yue Hu, Fang Liu, Xuezhao Cao.

  Microglia play a crucial role in postoperative cognitive dysfunction (POCD). This study investigated the effects of microglial depletion and subsequent repopulation on POCD and its underlying mechanisms. An aged mouse model of POCD was induced by partial hepatectomy, and the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 was administered to facilitate microglial depletion and repopulation. Neutrophil involvement was assessed with anti-Ly6G antibodies, while ZEB1 was manipulated through shRNA knockdown and lentiviral overexpression in the BV2 microglial cell line. A TGF-β1 neutralizing antibody was employed to elucidate the relationship between ZEB1 and its downstream pathways. The results indicated that microglial depletion alone did not reverse cognitive impairments. However, microglial repopulation significantly reduced neutrophil infiltration and improved cognitive function post-surgery. This improvement correlated with ZEB1 upregulation in microglia, which decreased CXCL1 production by astrocytes via TGF-β1 signaling, thereby reducing neutrophil migration to the hippocampus. These findings suggest that microglial repopulation, dependent on ZEB1 and TGF-β1 signaling, effectively alleviates neuroinflammation, reduces neutrophil infiltration, and enhances cognitive function, highlighting microglia as a promising target for the prevention and treatment of POCD.

Keywords:  TGF‐β1 signaling; ZEB1; cognitive dysfunction; microglia; neuroinflammation; neutrophil

DOI:  https://doi.org/10.1096/fj.202402492R
Invest Ophthalmol Vis Sci. 2025 Mar 03. 66(3): 4

Ameboid Microglia as a Scavenger Role in Phagocytosis of Photoreceptor Outer Segment in an Experimental Retinal Detachment Model.

Manjing Cao, Yahan Zhang, Yan Li, Xian Zhang, Mingming Ma.

Purpose: Photoreceptor (PR) death is the ultimate cause of irreversible vision loss in retinal detachment (RD). Previous studies have shown that microglia may have a dual role in RD. Nevertheless, the potential protective effects of microglia on PR are largely unknown. We aimed to uncover the phagocytic role of microglia in RD and propose a new concept to regulate PR survival.
Methods: An RD model was conducted by injecting sodium hyaluronate into the subretinal space (SRS) of C57BL/6J wild type mice. Bioinformatics analysis was used to evaluate the highly enriched pathways and terms relating to phagocytosis in human datasets and mouse transcriptomes of RD. The observation of microglial morphology was performed by immunofluorescence through cryosection and flat mount. PLX 3397 was used for microglial ablation. Phagocytosis of the outer segment (OS) by microglia was confirmed by immunofluorescence and hematoxylin and eosin staining. Expression of phagocytic markers in microglia was detected by immunofluorescence of cryosection. The PR survival was measured by TUNEL assay and hematoxylin and eosin staining. The optical coherence tomography (OCT) images through the center of the fovea in twelve patients were obtained to observe the clinic features of IS/OS dynamics after RD.
Results: The results showed that OS went through an accumulation-clearance process after RD. Ameboid microglia accumulated in the SRS and engulfed OS. Upregulation of phagocytic markers was observed in subretinal microglia. Depletion of microglia led to failure of OS clearance and retinal ruffling, which had the same characteristics as outer retinal undulation (ORU) in some patients with RD. PR did not benefit from microglial depletion, as no morphology and thickness recovery of PR was observed in the long term.
Conclusions: These results elucidate that microglial phagocytosis of OS is a critical process after RD. Insufficient phagocytosis leads to the accumulation of OS in the SRS and PR abnormalities. Appropriate regulation of microglial phagocytosis to remove OS may be a new concept to regulate photoreceptor survival.

DOI: https://doi.org/10.1167/iovs.66.3.4