bims-blobar 2025-07-20 papers

bims-blobar

Biomed News

on Blood brain barrier repair

Issue of 2025–07–20
nineteen papers selected by
Nicolas Rebergue

Homocysteine Induces Brain and Retinal Microvascular Endothelial Cell Barrier Damage and Hyperpermeability via NLRP3 Inflammasome Pathway Differentially.
[S1PR5 activation or overexpression enhances barrier function of mouse brain microvascular endothelial cells against OGD/R injury by modulating oxidative stress].
Pericytes Repair Engineered Defects in the Basement Membrane to Restore Barrier Integrity in an in vitro Model of the Blood-Brain Barrier.
Tight Junction Proteins and Blood-brain Barrier Integrity in Pediatric Obsessive-compulsive Disorder: A Study on Claudin-5, Claudin-12, Occludin, Tricellulin, and Angulin-1.
The myeloid cell-driven transdifferentiation of endothelial cells into pericytes promotes the restoration of BBB function and brain self-repair after stroke.
MRI contrast accumulation in features of cerebral small vessel disease: blood-brain barrier dysfunction or elevated vascular density?
Substrate stiffness and shear stress collectively regulate the inflammatory phenotype in cultured human brain microvascular endothelial cells.
EBI2-oxysterol signalling regulates VE-cadherin expression and multiple sclerosis CD4+ T cell attachment to a human tri-cell spheroid blood-brain barrier model.
Viral immunological complications in neurological surgery: A comprehensive review of homeostatic disturbances and cognitive impairments.
TNF-α-NF-κB activation through pathological α-Synuclein disrupts the BBB and exacerbates axonopathy.
A data-mining analysis of host solute carrier family proteins in SARS-CoV-2 infection with reference to brain endothelial cells and the blood-brain barrier in COVID-19.
Astrocyte-microglia crosstalk in subarachnoid hemorrhage: mechanisms and treatments.
Integrative analysis identifies IL-6/JUN/MMP-9 pathway destroyed blood-brain-barrier in autism mice via machine learning and bioinformatic analysis.
Oxytocin seals the blood-brain barrier, improving 22q11.2 deletion syndrome trajectories.
TREM2-mediated regulation of microglial activity: a promising target for the treatment of ischemic stroke.
Astrocytic RIPK3 exerts protective anti-inflammatory activity in mice with viral encephalitis by transcriptional induction of serpins.
APOE4-driven lipid metabolic dysregulation in Alzheimer's disease: Multi-pathway mechanisms and therapeutic perspectives.
Correction to: Artesunate Protected Blood-Brain Barrier via Sphingosine 1 Phosphate Receptor 1/Phosphatidylinositol 3 Kinase Pathway After Subarachnoid Hemorrhage in Rats.
Imatinib prevents blood-spinal cord barrier disruption by inhibiting PDGFR-mediated JMJD3 expression and activation after spinal cord injury.

Microcirculation. 2025 Jul;32(5): e70019

Homocysteine Induces Brain and Retinal Microvascular Endothelial Cell Barrier Damage and Hyperpermeability via NLRP3 Inflammasome Pathway Differentially.

O'lisa Yaa Waithe, Aliyah Anderson, Saravanakumar Muthusamy, Gabriela M Seplovich, Binu Tharakan.

   OBJECTIVES: The amino acid homocysteine (HCY) has been implicated in the pathobiology of several conditions, including spaceflight-associated neuro-ocular syndrome (SANS)-a collection of symptoms affecting near vision in astronauts. Blood-retinal barrier (BRB) and blood-brain barrier (BBB) dysfunctions are implicated in the pathobiology of SANS. Our objective was to assess how HCY affects BRB/BBB permeability and the role of the NLRP3 inflammasome in the modulation of such effects.
METHODS: Human brain and retinal microvascular endothelial cells (HBMECs and HRMECs) were treated with 100 μM HCY alone or in conjunction with NLRP3 inflammasome inhibitor MCC950 at 1 μM. The assays performed included fluorometric assays to measure cell viability, an enzyme assay for caspase-1, expression of BRB/BBB tight junction protein zonula occludens-1 (ZO-1) by RT-PCR, and barrier permeability using FITC-dextran.
RESULTS: In HRMECs and HBMECs, HCY-induced endothelial monolayer hyperpermeability significantly (p < 0.05). In HBMECs, the effect was attenuated by MCC950 (p < 0.05). Increased Caspase-1 activity was observed in both cell types following the addition of HCY. Following HCY addition, gene expression results denoting barrier damage were observed, particularly that of ZO-1 (p < 0.05).
CONCLUSIONS: HCY induces hyperpermeability in retinal and brain endothelial cells. NLRP3-mediation in HCY-induced microvascular permeability is prominent in brain endothelial cells compared to retinal endothelial cells.

Keywords:  blood‐retinal barrier; blood–brain barrier; endothelial cells; homocysteine; microvascular dysfunction; retina; vision

DOI:  https://doi.org/10.1111/micc.70019
Nan Fang Yi Ke Da Xue Xue Bao. 2025 Jul 20. pii: 1673-4254(2025)07-1451-09. [Epub ahead of print]45(7): 1451-1459

[S1PR5 activation or overexpression enhances barrier function of mouse brain microvascular endothelial cells against OGD/R injury by modulating oxidative stress].

Jingxian Wang, Zijing Ren, Peiyang Zhou.

   OBJECTIVES: To investigate the role of sphingosine-1-phosphate receptor 5 (S1PR5) in modulating barrier function of mouse brain microvascular endothelial cells with oxygen-glucose deprivation and reoxygenation (OGD/R).
METHODS: Mouse brain microvascular endothelial cells (bEnd.3) were exposed to OGD/R to induce barrier dysfunction following treatment with S1PR5-specific agonist A971432 or lentivirus-mediated transfection with a S1PR5-specific siRNA, a S1PR5-overexpressing plasmid, or their respective negative control sequences. The changes in viability and endothelial barrier permeability of the treated cells were evaluated with CCK-8 assay and FITC-dextran permeability assay; the levels of intracellular reactive oxygen species (ROS) and localization and expression levels of the proteins related with barrier function and oxidative stress were detected using immunofluorescence staining, DCFH-DA probe and Western blotting.
RESULTS: S1PR5 activation obviously enhanced viability of bEnd.3 cells exposed to OGD/R (P<0.0001). Both activation and overexpression of S1PR5 reduced FITC-dextran leakage, while S1PR5 knockdown significantly increased FITC-dextran leakage in the exposed bEnd.3 cells. Activation and overexpression of S1PR5 both increased the cellular expressions of the barrier proteins ZO-1 and occludin, while S1PR5 knockdown produced the opposite effect. In cells exposed to OGD/R, ROS production was significantly reduced by S1PR5 activation and overexpression but increased following S1PR5 knockdown. Overexpression of S1PR5 obviously increased the expressions of the antioxidant proteins Nrf2, HO-1 and SOD2 in the exposed cells.
CONCLUSIONS: S1PR5 activation and overexpression significantly improve cell viability and reduce permeability of a mouse brain microvascular endothelial cell model of OGD/R, the mechanism of which may involve the reduction in ROS production and upregulation of the antioxidant proteins.

Keywords:  blood-brain barrier dysfunction; oxidative stress; oxygen-glucose deprivation and reoxygenation; sphingosine 1-phosphate receptor 5

DOI:  https://doi.org/10.12122/j.issn.1673-4254.2025.07.11
bioRxiv. 2025 Jun 26. pii: 2025.06.23.661146. [Epub ahead of print]

Pericytes Repair Engineered Defects in the Basement Membrane to Restore Barrier Integrity in an in vitro Model of the Blood-Brain Barrier.

Michelle A Trempel, Yimei Du, Louis P Widom, Emily E Reitz, Alexis M Feidler, Pelin Kasap, Britta Engelhardt, Thomas R Gaborski, Harris A Gelbard, Niccolo Terrando, James L McGrath.

Pericytes play a key role in the brain where they support the blood-brain barrier (BBB). Their loss has been reported in response to systemic inflammation and neurodegenerative disease. We recently demonstrated that iPSC-derived brain pericyte-like cells (BPLCs) and brain microvascular endothelial cell (BMEC)-like cells collaboratively form a nascent, 3D basement membrane when cultured across a nanoporous membrane 1 . Building on this, we aimed to engineer defects in the basement membrane to investigate whether pericytes could facilitate its repair. In BMEC monocultures, we observed that micropore patterns in nanomembranes created discontinuities in laminin, which destabilized barrier function. Remarkably, the addition of pericytes to the basal side of the membrane restored both laminin integrity and barrier function. Our results align with the role of pericytes as support cells for microvasculature and encourage the use of our tissue barrier platform (the µSiM) to model neurological disorders involving pericyte dysfunction and/or disruption of basement membrane.

DOI: https://doi.org/10.1101/2025.06.23.661146
Clin Psychopharmacol Neurosci. 2025 Aug 31. 23(3): 444-452

Tight Junction Proteins and Blood-brain Barrier Integrity in Pediatric Obsessive-compulsive Disorder: A Study on Claudin-5, Claudin-12, Occludin, Tricellulin, and Angulin-1.

Filiz Akın-Kınay, Necati Uzun, İbrahim Kılınç, Ahmet Osman Kılıç.

   Objective: Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by the presence of obsessions and/or compulsions that cause significant distress and functional impairment. Despite extensive research, its etiopathogenesis remains incompletely understood. Recent evidence suggests that dysfunction in tight junctions may contribute to the pathophysiology of various psychiatric disorders. Tight junction proteins play a crucial role in maintaining blood-brain barrier integrity and regulating neuronal signaling. This study aims to investigate the involvement of tight junction proteins in the etiopathogenesis of OCD, providing new insights into their potential role in the disorder's neurobiological mechanisms.
Methods: A total of 41 medication-free children and adolescents with OCD and 41 healthy controls were included in this study. The participants filled out self-report scales to determine various psychological variables. Blood samples were collected from all participants to measure the levels of claudin-5, claudin-12, occludin, angulin-1, and tricellulin.
Results: The levels of claudin-5, claudin-12, occludin, and tricellulin were significantly higher in the OCD group compared to the control group. However, there was no significant difference in angulin-1 levels between the groups.
Conclusion: Our findings indicate that claudin-5, claudin-12, occludin, and tricellulin levels differ between individuals with OCD and healthy controls. These results suggest that tight junction proteins may contribute to the etiopathogenesis of OCD. Further research is needed to better understand the relationship between OCD and tight junction proteins.

Keywords:  Angulin-1; Claudin-12; Claudin-5; Obsessive-compulsive disorder; Occludin; Tricellulin

DOI:  https://doi.org/10.9758/cpn.25.1293
Elife. 2025 Jul 16. pii: RP105593. [Epub ahead of print]14

The myeloid cell-driven transdifferentiation of endothelial cells into pericytes promotes the restoration of BBB function and brain self-repair after stroke.

Tingbo Li, Ling Yang, Jiaqi Tu, Yufan Hao, Zhu Zhu, Yingjie Xiong, Qingzhu Gao, Lili Zhou, Guanglei Xie, Dongdong Zhang, Xuzhao Li, Yuxiao Jin, Yiyi Zhang, Bingrui Zhao, Nan Li, Xi Wang, Jie-Min Jia.

  Ischemic stroke, one of the leading causes of death in the world, is accompanied by the dysfunction of the blood-brain barrier (BBB), which aggravates neuron damage. However, the mechanisms underlying the restoration of BBB in the chronic stage after stroke remain unclear. Here, pericyte pool alterations and their consequences for BBB integrity and brain recovery were analyzed in the C57BL/6 mice stroke model. Lineage tracing, RNA-seq, and immunofluorescence staining revealed endothelial cell (EC) transdifferentiation into pericytes (E-pericytes) in C57BL/6 mice after stroke. E-pericytes depletion by diphtheria toxin A (DTA) aggravated BBB leakage and exacerbated neurological deficits in the MCAO model. The myeloid cell-driven transdifferentiation of ECs into pericytes accelerated BBB restoration and brain self-repair after stroke via endothelial-mesenchymal transformation (EndoMT). Decreasing the number of E-pericytes by specific knockout of the Tgfbr2 gene in ECs also aggravated BBB leakage and exacerbated neurological deficits. EC-specific overexpression of the Tgfbr2 gene promoting E-pericytes transdifferentiation reduced BBB leakage and exerted neuroprotective effects. Deciphering the mechanism by which E-pericytes coordinate post-stroke recovery may reveal a novel therapeutic opportunity.

Keywords:  BBB spontaneous recovery; EC; NVU; brain injury; brain recovery; cell biology; cell fate; mouse; neuroscience; pericyte; stroke; transdifferentiation

DOI:  https://doi.org/10.7554/eLife.105593
Fluids Barriers CNS. 2025 Jul 16. 22(1): 74

MRI contrast accumulation in features of cerebral small vessel disease: blood-brain barrier dysfunction or elevated vascular density?

Tomas Vikner, Anders Garpebring, Cecilia Björnfot, Jan Malm, Anders Eklund, Anders Wåhlin.

   BACKGROUND: White matter lesions (WML) and dilated perivascular spaces (PVS) are features of small vessel disease (SVD), commonly observed in aging and dementia, with unknown pathophysiology. Human studies have documented contrast accumulation within and in proximity of SVD-lesions. However, whether such observations mainly reflect excessive blood-brain barrier (BBB) leakage, or altered microvascular density in the investigated regions, remains unclear.
METHODS: To evaluate the roles of BBB leakage and vascular density in aging and SVD, dynamic contrast enhanced (DCE) MRI was used to estimate the permeability-surface area product (PS) and fractional plasma volume ([Formula: see text]) in normal-appearing brain tissue and in proximity of and within WML and PVS in a population-based cohort (N = 56; 34/22 m/f; age 64 to 84 years). Analysis of variance (ANOVA) was used to assess regional differences in PS and [Formula: see text] and analysis of covariance (ANCOVA) was used to assess regional differences in PS with [Formula: see text] and vascular risk as covariates.
RESULTS: Pronounced increases in PS and [Formula: see text] were observed from normal-appearing white matter (NAWM) to WML peripheries to WMLs. Similar PS and [Formula: see text]increases were observed from basal ganglia (BG) to BG-PVS. Further, PS in NAWM and white matter (WM) PVS were found to increase with cortex-to-ventricular depth. However, ANCOVA models with [Formula: see text] as a covariate showed that variance in PS was mainly explained by vp (η2=0.17 to η2=0.35; all p < 10- 3), whereas the effect of region was only borderline-significant when comparing NAWM, WML peripheries and WML (p = 0.03) and non-significant for the other comparisons (p > 0.29).
CONCLUSIONS: Our findings support the notion that contrast leakage across the BBB accumulates within and in proximity of SVD-related lesions. However, high contrast accumulation may mainly reflect high vascularization, and to a lesser degree than previously recognized BBB dysfunction.

Keywords:  Blood-brain barrier; MRI; Perivascular spaces; Small vessel disease; White matter lesions

DOI:  https://doi.org/10.1186/s12987-025-00675-4
Fluids Barriers CNS. 2025 Jul 15. 22(1): 73

Substrate stiffness and shear stress collectively regulate the inflammatory phenotype in cultured human brain microvascular endothelial cells.

Alexis K Yates, Heather Murray, Andrew Kjar, Daniel Chavarria, Haley Masters, Hyosung Kim, Alexander P Ligocki, Angela L Jefferson, Ethan S Lippmann.

  Brain endothelial cells experience mechanical forces in the form of blood flow-mediated shear stress and underlying matrix stiffness, but intersectional contributions of these factors towards blood-brain barrier (BBB) impairment and neurovascular dysfunction have not been extensively studied. Here, we developed in vitro models to examine the sensitivity of primary human brain microvascular endothelial cells (BMECs) to substrate stiffness, with or without exposure to fluid shear stress. Using a combination of molecular profiling techniques, we show that BMECs exhibit an inflammatory signature at both the mRNA and protein level when cultured on gelatin substrates of intermediate stiffness (~ 30 kPa) versus soft substrates (~ 6 kPa). Exposure to modest fluid shear stress (1.7 dyne/cm2) partially attenuated this signature, including reductions in levels of soluble chemoattractants and surface ICAM-1. Overall, our results indicate that increased substrate stiffness promotes an inflammatory phenotype in BMECs that is dampened in the presence of fluid shear stress.

Keywords:  Brain microvascular endothelial cell; Fluid shear stress; In vitro models; Inflammation; Vascular stiffening

DOI:  https://doi.org/10.1186/s12987-025-00683-4
Brain Behav Immun Health. 2025 Aug;47 101045

EBI2-oxysterol signalling regulates VE-cadherin expression and multiple sclerosis CD4+ T cell attachment to a human tri-cell spheroid blood-brain barrier model.

Fionä Caratis, Inez Mruk, Klaudia Konieczna-Wolska, Bartłomiej Rojek, Marek Hałas, Paulina Czaplewska, Bartosz Karaszewski, Tomomi Furihata, Aleksandra Rutkowska.

  Changes in the function of the blood-brain barrier (BBB) are one of the hallmarks of multiple sclerosis (MS) and are observed at very early stages of the disease. Several disease-modifying therapies for MS regulate tight junction and adherence junction proteins in the BBB thus limiting the entry of peripheral immune cells into the central nervous system (CNS). The Epstein-Barr virus-induced gene 2 (EBI2) was shown to drive immune cell migration towards high concentration of its endogenous ligand, oxysterol 7α,25OHC, which concentrations increase during inflammation in the CNS. Here, the data showed upregulated transcripts of EBI2 and CH25H, the first enzyme in 7α, 25OHC synthesis pathway, in MS brain lesions. In vitro, cerebrospinal fluid (CSF) from patients with MS downregulated HSD3B7, the 7α, 25OHC degrading enzyme, and VE-cadherin levels in the tri-cell human BBB spheroid model. Importantly, EBI2 signalling mediated the attachment of MS patient-derived CD4+ T cells to the BBB spheroids. The data raises the possibility that elevated oxysterol levels in an inflamed brain might trigger a downregulation of VE-cadherin in endothelial cells, potentially easing the CNS infiltration of EBI2-expressing immune cells. This process can be modulated through the use of EBI2 ligands, suggesting a potential pathway for therapeutic intervention.

Keywords:  Blood-brain barrier; CD4+ T cells; Cerebrospinal fluid; EBI2; Multiple sclerosis; Neuroinflammation; Oxysterols; VE-Cadherin

DOI:  https://doi.org/10.1016/j.bbih.2025.101045
Surg Neurol Int. 2025 ;16 241

Viral immunological complications in neurological surgery: A comprehensive review of homeostatic disturbances and cognitive impairments.

Maral Moafi, Rasa Zafari, Kamyab Rabiee, Mohammad Javad Ebrahimi, Homa Seyedmirzaei, Alireza Soltani Khaboushan.

   Background: Neurosurgical procedures are essential for treating various brain and spinal conditions, but they also carry the risk of infections, including viral infections. These infections can disrupt brain homeostasis, leading to cognitive impairments. During surgery, protective barriers like the blood-brain barrier (BBB) can be compromised, and cerebrospinal fluid may be exposed to pathogens. This makes the brain more susceptible to viral infections, which can trigger inflammation. Over time, this inflammation can have lasting effects on cognitive function, impacting the brain's ability to maintain neural integrity.
Methods: A review of the literature was performed using PubMed, Google Scholar, Scopus, and Web of Science from inception to January 2025. We focus on the impact of viral infections after neurosurgical procedures and how these infections lead to neuroinflammation.
Results: Viral infections after neurosurgery activate neuroinflammatory responses, with microglia and astrocytes playing a key role. The release of cytokines such as tumor necrosis factor-alpha and interleukin-1 causes significant neuronal damage, impairing synaptic function and connectivity. This inflammatory process, combined with BBB disruption, leads to cognitive dysfunction both in the immediate postoperative period and in the long-term. Understanding these processes is essential for addressing cognitive decline in patients who have undergone neurosurgery.
Conclusion: Viral infections following neurosurgery are a significant risk factor for cognitive decline. Neuroinflammation, especially when coupled with BBB disruption, contributes to both short-term and long-term cognitive impairments. This review highlights the need for targeted interventions to control inflammation and protect the BBB in the perioperative period. Future research focused on neuroprotective therapies, including anti-inflammatory agents and strategies to preserve BBB integrity, is critical for improving cognitive outcomes in neurosurgical patients.

Keywords:  Brain homeostasis; Cognitive decline; Neuroinflammation; Neurological surgery; Viral infection

DOI:  https://doi.org/10.25259/SNI_337_2025
Cell Rep. 2025 Jul 12. pii: S2211-1247(25)00772-7. [Epub ahead of print]44(7): 116001

TNF-α-NF-κB activation through pathological α-Synuclein disrupts the BBB and exacerbates axonopathy.

Min-Tae Jeon, Sinnead Anne Cogill, Kyu-Sung Kim, Yongjin Kim, Hyerin Kim, Chung-Yeol Lee, Suji Kim, Suhyeon Son, Jeongyeon Kim, Jaehyeok Lee, Inyeong Park, Mookyung Cheon, Do-Geun Kim.

  Dysfunction of the blood-brain barrier (BBB) is recognized as a key factor in the progression of neurodegenerative diseases (NDs), but the detailed mechanisms behind its pathogenesis and impact on neurodegeneration remain elusive. This study aimed to reveal the pathological effects of α-Synuclein (α-Syn), an aggregation protein in synucleinopathy, on BBB integrity and function and identify therapeutic targets for α-Syn-related vasculopathy. Using a brain endothelial cell model, we investigated the pathological effect of preformed fibril α-Syn (PFF) on BBB integrity, employing generative adversarial network (GAN) deep learning to analyze pathological changes. We found that PFF activates immune responses, increasing endothelial monolayer permeability via the TNF-α-NF-κB pathway. Further in vivo studies with PFF induced α-synucleinopathy, and a transgenic animal model (G2-3) revealed that α-Syn aggregation disrupts the BBB, leading to axonal degeneration that was mitigated by treatment with a non-BBB-penetrating TNF-α inhibitor, etanercept. These findings suggest that targeting brain endothelial TNF-α signaling could be a potential therapeutic approach for synucleinopathy-related NDs.

Keywords:  BBB; CP: Neuroscience; TNF-α signaling pathway; axonal degeneration; blood-brain barrier; brain endothelial cells; vasculopathy; α-synucleinopathy

DOI:  https://doi.org/10.1016/j.celrep.2025.116001
Front Neurol. 2025 ;16 1563040

A data-mining analysis of host solute carrier family proteins in SARS-CoV-2 infection with reference to brain endothelial cells and the blood-brain barrier in COVID-19.

Talia Fradkin, Rainald Schmidt-Kastner.

   Background: The brain vasculature is a key player in neurological manifestations of COVID-19. Infection of brain endothelial cells with SARS-CoV-2 along with circulating cytokines may cause dysfunction of the blood-brain barrier (BBB). Solute carrier transporters (SLCs) in brain endothelial cells regulate substrate transport across the BBB. Here, it was hypothesized that transport functions of SLCs will be impaired by interactions with viral proteins, and subsequently, data-mining studies were performed.
Methods: Virus-host protein-protein interaction data for SARS-CoV-2 infection were retrieved from the BioGRID database, filtered for SLCs, and then annotated for relevant expression in brain endothelial cells using a mouse brain transcriptomics database. Host SLCs expressed in brain endothelial cells were further explored using publicly available databases and information in the literature. Functional Annotation Clustering was performed using DAVID, and Enrichr served for pathway analysis. Substrates were retrieved from NCBI Gene. Links to monogenic disorders were retrieved from Online Mendelian Inheritance in Man™ and screened for disorders of the nervous system. Interactome data for viral proteins of SARS-CoV-2 were retrieved from BioGRID. Reports for host SLCs in viral receptor functions, viral entry mechanisms, and other major roles in the viral cycle were explored in databases (VThunter) and literature. ATP-binding cassette transporters (ABCs) were studied in parallel.
Results: N = 80 host SLCs showed relevant expression in brain endothelial cells whereby amino acid transporter stood out. N = 24/80 host SLCs were linked to monogenic disorders of the nervous system. N = 9/29 SARS-CoV-2 viral proteins had strong links to SLCs and key functions in viral infection (e.g., interferon response). SLCs serving as viral receptors and with closely associated functions were significantly enriched among all known listed viral receptors (chi-square test, p = 0.001). Literature searches for host SLCs revealed involvement of a subset of SLCs in infection mechanisms for SARS-CoV-2 and more broadly for other viruses. N = 17 host ABCs were found in brain endothelial cells where they may serve as efflux transporters.
Discussion: This hypothesis-generating work proposes a set of N = 80 host SLCs expressed in endothelial cells as contributors to BBB impairment after SARS-CoV-2 infection. Theoretically, persistent dysfunction of SLCs at the BBB, in particular insufficient transport of amino acids, could be one of many reasons for cognitive changes in long-COVID. Functions of SLCs in viral entry and associated roles deserve close attention.

Keywords:  COVID-19; SARS-CoV-2; amino acid transport; blood-brain barrier; brain endothelial cells; protein-protein interactions; solute carrier proteins; virus-host interactions

DOI:  https://doi.org/10.3389/fneur.2025.1563040
Front Immunol. 2025 ;16 1547858

Astrocyte-microglia crosstalk in subarachnoid hemorrhage: mechanisms and treatments.

Kaibo Yu, Ding Wang, Wenhua Yu.

  Subarachnoid hemorrhage (SAH) is a frequently encountered critical emergency characterized by the rupturing of an unhealthy blood vessel, resulting in high mortality and disability rates. Alterations in the neurovascular unit (NVU) are closely related to the pathogenesis of SAH. Microglia, the primary innate immune cells in the brain, and astrocytes, the most abundant cells in the brain, both play crucial roles in the response to SAH-associated cerebral injuries. Recently, the crosstalk between these two cells in the pathology and treatment of central nervous system (CNS) diseases, including SAH, has been revealed. Following acute brain insult, activated microglia and astrocytes can further activate each other, contributing to amplified neuroinflammatory reactions and thus inducing secondary brain injury. This review addresses the pathophysiological mechanisms of microglia and astrocytes in SAH, including neuroinflammation, neuronal damage, blood-brain barrier (BBB) disruption, vasospasm, and hematoma clearance. In addition, the newly identified therapeutic strategies against SAH by regulating astrocytes-microglia crosstalk through targeting damage-associated molecular patterns (DAMPs), immune mediators, and their receptors are also discussed. A thorough comprehension of microglia-astrocyte communication could provide novel ideas for future research and treatment of SAH.

Keywords:  astrocyte; crosstalk; microglia; neuroinflammation; subarachnoid hemorrhage

DOI:  https://doi.org/10.3389/fimmu.2025.1547858
Transl Psychiatry. 2025 Jul 11. 15(1): 239

Integrative analysis identifies IL-6/JUN/MMP-9 pathway destroyed blood-brain-barrier in autism mice via machine learning and bioinformatic analysis.

Cong Hu, Heli Li, Jinru Cui, Yunjie Li, Feiyan Zhang, Hao Li, Xiaoping Luo, Yan Hao.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by social communication deficits and restricted, repetitive behaviors. Growing evidence implicates neuroinflammation-induced blood-brain barrier (BBB) dysfunction as a key pathogenic mechanism in ASD, although the underlying molecular pathways remain poorly understood. This study aimed to identify critical genes linking BBB function and neuroinflammatory activation, with the ultimate goal of evaluating potential therapeutic targets. Through integrative analysis combining differential gene expression profiling with three machine learning algorithms - Least Absolute Shrinkage and Selection Operator (LASSO) regression, Support Vector Machine Recursive Feature Elimination (SVM-RFE), and RandomForest combined with eXtreme Gradient Boosting (XGBoost) - we identified four hub genes, with JUN emerging as a core regulator. JUN demonstrated strong associations with both BBB integrity and microglial activation in ASD pathogenesis. Using a maternal immune activation (MIA) mouse model of ASD, we observed significant downregulation of cortical tight junction proteins ZO-1 and occludin, confirmed through immunofluorescence and qPCR analysis. Bioinformatics analysis revealed a close correlation between JUN and IL-6/MMP-9 signaling in ASD-associated microglial activation. These findings were validated in vivo, with immunofluorescence and qPCR demonstrating elevated IL-6 and MMP-9 expression in ASD mice. Pharmacological intervention using ventricular JNK inhibitor administration effectively downregulated JUN and MMP-9 expression. In vitro studies using IL-6-stimulated BV-2 microglial cells replicated these findings, showing JNK inhibitor-mediated suppression of JUN and MMP-9 upregulation. These results collectively identify the IL-6/JUN/MMP-9 pathway as a specific mediator of barrier dysfunction in ASD, representing a promising target for personalized therapeutic interventions.

DOI: https://doi.org/10.1038/s41398-025-03452-x
Brain. 2025 Jul 15. pii: awaf112. [Epub ahead of print]

Oxytocin seals the blood-brain barrier, improving 22q11.2 deletion syndrome trajectories.

Giulia Castellani, Mariasole Ciampoli, Arianna Benedetti, Valentina Ferretti, Gabriella Trigilio, Weronika Barcik, Marta Busnelli, Gabriella Contarini, Camilla Paolini, Celine Devroye, Maria Rodriguez Aburto, Alessandra Cucinelli, Federica Antonelli, Federica Maltese, Clarissa Braccia, Giada Pacinelli, Francesca Managò, Alejandra Rodríguez-Gimeno, Maria Angela Mazzarella, Sara Sannino, Ennio Albanesi, Marco Nigro, Fabio Bertozzi, Andrea Armirotti, Sara De Martin, Bice Chini, Francesco Papaleo.

  Understanding the connection between genetic susceptibility and immune alterations in neurodevelopmental disorders remains limited. Here, we investigated the 22q11.2 hemideletion syndrome (22q11.2DS), a prominent genetic risk factor for psychiatric disorders, focusing on its interaction with immune alterations. Using the 22q11.2DS mouse model LgDel/+, we identified adolescence as a critical period for the emergence of behavioural and cortical anomalies, associated with peripheral regulatory T cell reduction, microglial inflammatory activation and cerebral myeloid cell infiltration. Neonatal intranasal oxytocin supplementation prevented the appearance of sensorimotor gating, social behaviour and immune system deficits in 22q11.2DS mice. This was related to an early and long-lasting effect of oxytocin in upregulating tight junction molecules claudin-5 and claudin-1, with claudin-5 leading to reduced permeability of the blood-brain barrier. Consequently, myeloid cell infiltration into the brains of 22q11.2DS mice was reduced. Our findings elucidate a genetic-immune interplay in the aberrant development associated with 22q11.2DS, supporting a novel therapeutic potential for oxytocin in sealing a critical brain barrier.

Keywords:  22q11.2 deletion syndrome; blood–brain barrier; claudin-5; immune system; oxytocin

DOI:  https://doi.org/10.1093/brain/awaf112
J Transl Med. 2025 Jul 11. 23(1): 782

TREM2-mediated regulation of microglial activity: a promising target for the treatment of ischemic stroke.

Haihan Yu, Li Zhang, Bo Song, Kaidi Ren, Xing Chen, Yuwan Dai, Yang Yang, Yuming Xu, Ziqing Wei.

  Ischemic stroke, the most prevalent type of stroke globally, poses significant challenges due to its high incidence, morbidity, and long-term disability. Microglia, the resident immune cells of the central nervous system (CNS), play a dual role in the context of ischemic stroke. While they contribute to neuroinflammation by releasing pro-inflammatory cytokines and exacerbating neuronal injury, they also facilitate tissue repair, angiogenesis, and restoration of the blood-brain barrier (BBB) integrity through the secretion of anti-inflammatory and neurotrophic factors. Triggering receptor expressed on myeloid cells 2 (TREM2), predominantly expressed on microglia, is a critical regulator of microglial proliferation, survival, phagocytosis, polarization, inflammation, and metabolism. TREM2 has emerged as a key modulator of immune responses in ischemic stroke. This review provides a comprehensive examination of the multifaceted roles of TREM2 in microglial biology during ischemic stroke, integrating current insights into its molecular mechanisms. Furthermore, it highlights TREM2's potential as a transformative therapeutic target, advancing our understanding of neuroimmune regulation and promoting recovery after stroke.

Keywords:  Ischemic stroke; Microglia; Neuroinflammation; Therapeutic target; Triggering receptor expressed on myeloid cells 2 (TREM2)

DOI:  https://doi.org/10.1186/s12967-025-06799-3
Sci Signal. 2025 Jul 15. 18(895): eadq6422

Astrocytic RIPK3 exerts protective anti-inflammatory activity in mice with viral encephalitis by transcriptional induction of serpins.

Marissa Lindman, Irving Estevez, Eduard Marmut, Evan M DaPrano, Tsui-Wen Chou, Kimberly Newman, Colm Atkins, Natasha M O'Brown, Brian P Daniels.

Flaviviruses pose a substantial threat to public health because of their ability to infect the central nervous system (CNS). Receptor-interacting protein kinase 3 (RIPK3) is a central coordinator that promotes neuroinflammation during viral infection of the CNS, a role that occurs independently of its canonical function in inducing necroptosis. Here, we used mouse genetic tools to induce astrocyte-specific deletion, overexpression, and chemogenetic activation of RIPK3 to demonstrate an anti-inflammatory function for astrocytic RIPK3. RIPK3 activation in astrocytes promoted host survival during flavivirus encephalitis by limiting immune cell recruitment to the CNS. Despite inducing a proinflammatory transcriptional program, astrocytic RIPK3 restrained neuroinflammation by increasing the abundance of the protease inhibitor SerpinA3N, which preserved blood-brain barrier integrity, reduced leukocyte infiltration, and improved survival outcomes during flavivirus encephalitis. These findings highlight a previously unappreciated role for astrocytic RIPK3 in suppressing pathologic neuroinflammation.

DOI: https://doi.org/10.1126/scisignal.adq6422
Biochem Biophys Res Commun. 2025 Jul 10. pii: S0006-291X(25)01050-2. [Epub ahead of print]778 152335

APOE4-driven lipid metabolic dysregulation in Alzheimer's disease: Multi-pathway mechanisms and therapeutic perspectives.

Wen-Xuan Zhang, Yi-Liang Yang, Jia-Xin Yu, Li-Hong Jia, Han-Chang Huang.

  Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by senile plaques deposition and hyperphosphorylated Tau. As the primary genetic risk factor for late-onset AD (LOAD), Apolipoprotein E4 (APOE4) might drive the core pathological progression of this disease through lipid metabolism dysregulation. Due to its relatively lower lipid-binding efficiency compared to APOE3, APOE4 impairs cholesterol efflux, leading to lipid droplet (LD) accumulation and lysosomal dysfunction in neurons and glial cells. APOE4 also disrupts the microglia TREM2-APOE signaling axis asnd exacerbates neuroinflammation by activating the TLR4/NF-κB pathway. In oligodendrocytes, APOE4 induces dysregulation of the LXRβ/ABCA1 pathway and results in sphingolipid metabolism imbalance and demyelination. Furthermore, APOE4 compromises the integrity of blood-brain barrier and activates the CypA-MMP9 pathway, facilitating the infiltration of peripheral inflammatory cytokine and cerebrovascular pathology. This article summarized the evidence that APOE4 affects lipid metabolism through various pathways and proposed the potential therapeutic strategies to alleviate the progression of AD.

Keywords:  APOE4; Alzheimer's disease; Blood-brain barrier; Lipid metabolism; cholesterol

DOI:  https://doi.org/10.1016/j.bbrc.2025.152335
Mol Neurobiol. 2025 Jul 17.

Correction to: Artesunate Protected Blood-Brain Barrier via Sphingosine 1 Phosphate Receptor 1/Phosphatidylinositol 3 Kinase Pathway After Subarachnoid Hemorrhage in Rats.

Shilun Zuo, Hongfei Ge, Qiang Li, Xuan Zhang, Rong Hu, Shengli Hu, Xin Liu, John H Zhang, Yujie Chen, Hua Feng.

DOI: https://doi.org/10.1007/s12035-025-05207-7
Fluids Barriers CNS. 2025 Jul 16. 22(1): 76

Imatinib prevents blood-spinal cord barrier disruption by inhibiting PDGFR-mediated JMJD3 expression and activation after spinal cord injury.

Chan Sol Park, Jee Youn Lee, Tae Young Yune.

   BACKGROUND: After a spinal cord injury (SCI), disruption of the blood-spinal cord barrier (BSCB) leads to secondary injuries, including inflammatory responses and apoptotic cell death, ultimately causing permanent neurological deficits. Imatinib, a tyrosine kinase inhibitor, has been reported to enhance BSCB integrity and improve functional recovery after SCI. However, the mechanism by which imatinib regulates BSCB integrity remains unclear. Recent studies have identified the histone H3K27me3 demethylase JMJD3 as a key mediator of BSCB disruption, with high expression observed in blood vessels after SCI. In this study, we investigated whether imatinib regulates JMJD3 expression and activation through PDGFR signaling, thereby mitigating BSCB disruption following SCI.
METHODS: Imatinib (100 mg/kg) was administered intraperitoneally to rats subjected to a contusion injury at the T9 level of the spinal cord and was continued daily for 14 days.
RESULTS: Our results indicate that imatinib inhibited the phosphorylation of PDGFRα and PDGFRβ, both tyrosine kinase receptors, without affecting their expression levels. Additionally, imatinib reduced JMJD3 and MMP-9 expression and activation in blood vessels, thereby decreasing macrophage infiltration after SCI. In an oxygen-glucose deprivation (OGD)-induced bEnd.3 cell model, phosphorylated PDGFRα and PDGFRβ, along with JMJD3 expression and activation, were significantly upregulated but were effectively inhibited by imatinib treatment. Furthermore, imatinib suppressed secondary damage, including cell death, blood cell infiltration (e.g., neutrophils and macrophages), inflammation, axonal and myelin loss, and lesion volume. These effects collectively resulted in significant improvements in functional recovery after SCI.
CONCLUSION: Based on these findings, we propose that imatinib exerts a neuroprotective effect, in part by inhibiting PDGFR-mediated JMJD3 expression and activation following SCI.

Keywords:  Blood-spinal cord barrier; Imatinib; JMJD3; MMP; PDGFR; Spinal cord injury

DOI:  https://doi.org/10.1186/s12987-025-00690-5