bims-blobar 2025-10-05 papers

bims-blobar

Biomed News

on Blood brain barrier repair

Issue of 2025–10–05
thirteen papers selected by
Nicolas Rebergue

Rab7a is required to degrade select blood-brain barrier junctional proteins after ischemic stroke.
Inflammatory reprogramming of human brain endothelial cells compromises blood-brain barrier integrity in Alzheimer's disease.
Kisspeptin-10 Preserves the Blood-Brain Barrier's Integrity Post-Stroke by Augmenting Claudin-10 Expression.
HIV-1 viral protein effect on cerebral microvasculature: An in vitro blood-brain barrier model.
High-intensity interval training improves cognitive dysfunction in chronically stressed mice through alleviating homocysteine-induced transcriptional repression of Cldn5.
Association of Blood-Brain Barrier Function With Disease Activity and Cognitive Function in Systemic Lupus Erythematosus Patients.
Viral Infection and the Blood-Brain Barrier: Molecular Research Insights and Therapies.
Invertebrate glial barriers as a model for understanding blood-brain barrier evolution.
Neurogranin-MYH9 interaction regulates cytoskeletal remodeling in cerebral vasculature.
Stem cell-derived brain-like endothelial cells to interrogate Streptococcus pneumoniae interaction with brain endothelium.
Serum matrix metallopeptidase-9 levels in patients with infantile epileptic spasms syndrome before and after the initiation of vigabatrin therapy.
Immunogenic self-DNA drives neuropsychiatric systemic lupus erythematosus in conventional genetic background mice.
Beyond the Barrier: Targeting blood-brain interactions for neuroprotection and repair.

Acta Neuropathol Commun. 2025 Sep 29. 13(1): 203

Rab7a is required to degrade select blood-brain barrier junctional proteins after ischemic stroke.

Azzurra Cottarelli, Danny Jamoul, Mary Claire Tuohy, Sanjid Shahriar, Michael Glendinning, Grace Prochilo, Aimee L Edinger, Ahmet Arac, Dritan Agalliu.

  The integrity of adherens and tight junctions is critical for blood-brain barrier (BBB) function in the healthy brain. Disassembly of cell junctions due to degradation of adherens and tight junction-associated proteins leads to acute BBB dysfunction after ischemic stroke, but the mechanisms of this process are not fully understood. Using genetic studies in mice coupled with histopathological analysis of the brains after ischemic stroke, we demonstrate that endothelial cell deletion of Rab7a, a small GTPase crucial for protein degradation through the endolysosomal system, reduces acute BBB leakage and improves neuronal health in mice after ischemic stroke by reducing the degradation of select adherens and tight junction proteins, and preserving the structural morphology of tight junctions at both confocal and electron microscopy level. Two pro-inflammatory cytokines, TNFα and IL1β, that are known to trigger disruption of paracellular barrier properties in primary brain endothelial cells in vitro and are upregulated after ischemic stroke, contribute to Rab7a activation in primary mouse brain endothelial cells (BECs). In contrast, oxygen-glucose deprivation does not activate Rab7a in mouse BECs. Rab7a is, therefore, critical for degradation of select BEC junctional proteins during the acute increase in BBB permeability after ischemic stroke.

Keywords:  Adherens junctions; Blood-brain barrier; Claudin-5; Cytokines; Inflammation; Ischemic stroke; Rab7a; Tight junctions; VE-Cadherin; ZO-1

DOI:  https://doi.org/10.1186/s40478-025-02125-6
bioRxiv. 2025 Sep 27. pii: 2025.09.26.678918. [Epub ahead of print]

Inflammatory reprogramming of human brain endothelial cells compromises blood-brain barrier integrity in Alzheimer's disease.

Rebecca L Pinals, Md Rezaul Islam, Oisín King, Aaron Choi, Eulim Kang, Masayuki Nakano, Anjanet Tuyéras, Maeesha Tasnim Naomi, Arthur Ngo, Alan Jiang, Nhat Truong, Emre Agbas, Claudia F Lozano Cruz, Colin Staab, Tak Ko, David A Bennett, Alice E Stanton, Robert Langer, Li-Huei Tsai.

Blood-brain barrier (BBB) dysfunction is an early feature of Alzheimer's disease (AD), yet the endothelial gene-regulatory programs involved remain incompletely understood. We integrate postmortem human single-nucleus transcriptomics with iPSC-based BBB models to define a conserved, inflammation-driven pathway that compromises barrier integrity. We identify an NF-κB-associated endothelial gene module endoM2 that is elevated in AD, inversely correlated with cognition, and enriched for inflammation and endothelial-to-mesenchymal transition signatures. Cytokine stimulation of iPSC-derived brain endothelial cells induces morphological remodeling, lipid accumulation, junctional disruption, and transcriptomic shifts that mirror endoM2. A targeted drug screen identifies the NF-κB inhibitor BAY11-7082 as protective against cytokine-induced changes. In our perfusable iPSC-derived BBB-Chip that recapitulates human BBB signatures, single-cell profiling reveals inflammatory endothelial state-specific programs reflecting those in AD brains and demonstrates that BAY11-7082 suppresses cytokine-triggered dysfunction and reverses inflammation-associated gene activation. Together, these findings position cerebrovascular inflammation as a therapeutic target to preserve BBB integrity in AD.

DOI: https://doi.org/10.1101/2025.09.26.678918
Clin Exp Pharmacol Physiol. 2025 Nov;52(11): e70079

Kisspeptin-10 Preserves the Blood-Brain Barrier's Integrity Post-Stroke by Augmenting Claudin-10 Expression.

Liming Li, Yunlong Guo, Kaijie Zhao.

  The integrity of the Blood-Brain Barrier (BBB) is crucial in the pathophysiological progression of acute ischemic stroke (AIS). However, the potential of Kisspeptin-10 (Kp-10), with its antioxidant and anti-inflammatory properties, has not been explored experimentally in the context of stroke management. This study aimed to investigate the neurovascular protective effects of Kp-10 following cerebral ischemia using both in vivo and in vitro models. A middle cerebral artery occlusion (MCAO) model was established in C57BL/6 mice, followed by Kp-10 administration. Neurological deficits (Longa score), infarct volume (TTC staining), BBB permeability (14C-Sucrose), and Claudin-10 expression (qRT-PCR and immunohistochemistry) were assessed to evaluate the therapeutic effects of Kp-10. Human brain microvascular endothelial cells (HBMVECs) were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic ischemic conditions. Endothelial permeability, oxidative stress (OS), and nuclear factor erythroid 2-related factor 2 (Nrf2) levels were evaluated. Nrf2 silencing was performed to validate its role in Kp-10-mediated protection. Initially, we observed a significant reduction in Kp-10 expression within the cortical tissue of mice subjected to MCAO. Subsequent administration of Kp-10 not only alleviated neurological deficits but also significantly mitigated blood-brain barrier (BBB) dysfunction following stroke induction, as evidenced by reduced 14C-sucrose leakage. Furthermore, Kp-10 treatment led to an upregulation of Claudin-10 expression in the post-stroke cortical region. In our in vitro experiments, we employed HBMVECs exposed to OGD/R to simulate ischemic conditions. We found that Kp-10 effectively reduced OGD/R-induced endothelial permeability by enhancing Claudin-10 expression. Additionally, Kp-10 exhibited antioxidant capabilities by decreasing mitochondrial reactive oxygen species (ROS) levels, increasing superoxide dismutase (SOD) activity, and upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Notably, when Nrf2 was knocked down in HBMVECs, the protective effects of Kp-10 on endothelial permeability and Claudin-10 expression were abolished, indicating that the beneficial actions of Kp-10 are mediated through the Nrf2 pathway. In conclusion, our findings suggest that Kp-10 holds promise as a therapeutic strategy to preserve BBB integrity and promote neuroprotection following stroke, acting primarily via the Nrf2 signalling pathway. These findings suggest that Kp-10 may represent a promising therapeutic strategy for preserving BBB integrity following ischemic stroke.

Keywords:  BBB; Claudin‐10; Kisspeptin‐10; Nrf2; stroke

DOI:  https://doi.org/10.1111/1440-1681.70079
Physiol Rep. 2025 Oct;13(19): e70593

HIV-1 viral protein effect on cerebral microvasculature: An in vitro blood-brain barrier model.

Sinelisiwe Matubatuba, Chontrelle Willemse, Khayelihle Brian Makhathini, Carine Smith, David Fisher, Shireen Mentor.

  The central nervous system (CNS) serves as a sanctuary for the Human Immunodeficiency Virus (HIV), which is facilitated by HIV's ability to breach the blood-brain barrier (BBB). BBB dysfunction occurs in the earliest stages of an HIV-1 infection. The immune-privileged CNS reduces harmful inflammatory responses, detrimental to the neuronal environment. BBB disruption, however, contributes to comorbidities in HIV, like cerebrovascular disease and neurocognitive problems. A 2-dimensional in vitro BBB model was employed to assess the effect of HL2/3 cell paracrine factors on select physiological parameters: cell proliferation, viability, toxicity, suppression, and morphology. BBB integrity was assessed using transendothelial electrical resistance measurements. The study utilized immortalized mouse brain endothelial cell monocultures and co-cultures with the HL2/3 cell line, emulating an in vivo HIV-1 effect on the BBB. A concentration-dependent decline in cellular proliferation rates and viability was observed upon exposure to HL2/3 paracrine factors. Moreover, an elevation in cellular suppression, cell death, and cell toxicity was observed. Permeability studies confirmed decreased impermeability after exposure to HIV-1 viral proteins in select in vitro BBB model systems. The impact of HIV viral proteins on brain capillary endothelium is critical to elucidate pathogen-induced cerebrovascular disease progression and vascular cognitive impairment in patients.

Keywords:  blood–brain barrier; human immunodeficiency virus; transendothelial electrical resistance

DOI:  https://doi.org/10.14814/phy2.70593
Neurobiol Stress. 2025 Nov;39 100758

High-intensity interval training improves cognitive dysfunction in chronically stressed mice through alleviating homocysteine-induced transcriptional repression of Cldn5.

Zhao-Xin Sun, Mao-Yang Zhou, Jin-Shan Li, Yun Zhao, Fang Xie, Xue Wang, Hong Feng, Zhao-Wei Sun, Ling-Jia Qian.

  Chronic stress-induced blood-brain barrier (BBB) dysfunction contributes to neurological disorders, with homocysteine (HCY) as a key risk factor. Considering pharmacotherapy limitations, non-invasive interventions like high-intensity interval training (HIIT) are promising. To determine whether HIIT improves stress-induced BBB dysfunction and cognitive impairment, we first established a chronic unpredictable mild stress (CUMS) model and assigned mice into four groups: Control (Ctrl), CUMS, HIIT, and HIIT + CUMS. Here, we found that HIIT significantly ameliorated cognitive impairment in male CUMS mice, as evidenced by reduced escape latency in morris water maze and increased memory performance in novel object recognition test. HIIT also preserved BBB integrity by ameliorating the tight junction disruption and BBB hyper-permeability in stressed mice. Subsequently, to clarify the role of HCY in the HIIT-mediated effects, we established an HHCY model and divided mice into four groups: Ctrl, HIIT, HHCY, and HIIT + HHCY. The results showed that HIIT normalized the plasma and hippocampal HCY levels by restoring the expression of related metabolic enzymes including CBS, MTHFR and MS, and alleviated HHCY-induced cognitive decline and BBB damage. Further, HIIT reversed HCY-induced Claudin-5 downregulation by inhibiting H3K27me3 enrichment at the Cldn5 (the encoding gene of Claudin-5) promoter region. In addition, HIIT restored the expression of ETS1, one of the transcriptional activators of Cldn5, to facilitate the transcription of Cldn5 gene and the stabilization of BBB. Collectively, these findings reveal that HIIT improves chronic stress-induced cognitive impairment via eliminating the disruptive effects of HHCY on the BBB integrity, offering a non-pharmacological intervention potential for stress-related cognitive deficits.

Keywords:  BBB damage; Cldn5 transcriptional repression; HCY; HIIT; Stress-induced cognitive dysfunction

DOI:  https://doi.org/10.1016/j.ynstr.2025.100758
J Magn Reson Imaging. 2025 Oct 04.

Association of Blood-Brain Barrier Function With Disease Activity and Cognitive Function in Systemic Lupus Erythematosus Patients.

Xueying Zhao, Zexi Yi, Yimin Cao, Cong Zhang, Zhijuan Li, Duo Gao, Sicong Wang, Zuojun Geng, Haiqing Yang, Shifeng Xiang, Yali Wang, Yue Zhang, Lixia Zhou.

   BACKGROUND: Disruption of the blood-brain barrier (BBB) is an important mechanism in the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE), potentially influencing disease progression and cognitive function.
PURPOSE: To investigate voxel-wise BBB permeability differences among NPSLE, non-NPSLE, and healthy controls (HC) using dynamic contrast-enhanced MRI (DCE-MRI), and explore associations with disease activity and cognitive function.
STUDY TYPE: Multicenter, cross-sectional study.
SUBJECTS: 22 NPSLE patients, 24 non-NPSLE patients, and 27 age- and sex-matched HC.
FIELD STRENGTH/SEQUENCE: 3.0 Tesla, GE: 3D T1-FSPGR, DCE-LAVA-Flex sequences; Philips: 3D T1-FFE, eTHRIVE sequences.
ASSESSMENT: Post-processing of DCE-MRI images was conducted to calculate the volume transfer constant (Ktrans) and plasma volume fraction (Vp) maps, which were transformed to Montreal Neurological Institute space. Brain regions were defined using the Anatomical Automatic Labeling (AAL) atlas. Group differences among NPSLE, non-NPSLE, and HC were assessed. Mean Ktrans/Vp values from suprathreshold clusters were evaluated for associations with the Disease Activity Index (SLEDAI) and Montreal Cognitive Assessment (MoCA) scores. Mean Ktrans/Vp from corresponding AAL regions was extracted for further validation of the observed correlations.
STATISTICAL TESTS: Voxel-wise ANOVA with Tukey's HSD test; Spearman correlation and linear regression. Threshold: Voxel-wise p < 0.001, cluster size > 20; group comparisons p < 0.05.
RESULTS: A significantly elevated Ktrans was observed in the right caudate of NPSLE patients compared to non-NPSLE patients, and hippocampal Ktrans was significantly higher in NPSLE than both non-NPSLE and HC. Both NPSLE and non-NPSLE patients exhibited widespread significant increases in Vp compared to HC. In the entire SLE cohort, right caudate Ktrans was positively associated with SLEDAI (ρ = 0.43, R2 = 0.18) and negatively associated with MoCA scores (ρ = -0.35, R2 = 0.12) after adjusting for confounding factors.
DATA CONCLUSION: This study provided voxel-level evidence linking regional BBB leakage to both disease activity and cognitive impairment in SLE.
EVIDENCE LEVEL: 2.
TECHNICAL EFFICACY: Stage 2.

Keywords:  cognitive dysfunction; dynamic contrast enhanced MRI; systemic lupus erythematosus

DOI:  https://doi.org/10.1002/jmri.70143
J Infect Dis. 2025 Sep 29. pii: jiaf455. [Epub ahead of print]

Viral Infection and the Blood-Brain Barrier: Molecular Research Insights and Therapies.

Sarah A Boardman, Claire Hetherington, Thomas Hughes, Callum Cook, Ian Galea, Orla Hilton, Tom Solomon, Andrew D Luster, Stuart Allan, Evelyn Kurt-Jones, Joe Forth, Adjanie Patabendige, Franklyn N Egbe, Cordelia Dunai, Benedict D Michael.

  The blood-brain barrier (BBB) protects the brain from pathogenic microorganisms. Neurologic complications from viral infections, including herpes simplex virus, varicella zoster virus, HIV, Japanese encephalitis virus, and SARS-CoV-2, are linked to BBB dysfunction and loss of barrier integrity. Increased BBB permeability associated with viral infections can occur through several mechanisms, such as direct neurotropism, Trojan horse mechanisms, or systemic infection and inflammation. Viruses cause direct and indirect immune-mediated damage. Understanding these neuroimmune mechanisms is critical to establish therapeutic strategies to protect BBB function. This review describes the effect of viral infection on the BBB, clinical methods to assess BBB integrity, and clinical management approaches to address viral-induced BBB damage.

Keywords:  blood-brain barrier; mechanisms; virology

DOI:  https://doi.org/10.1093/infdis/jiaf455
Fluids Barriers CNS. 2025 Sep 30. 22(1): 93

Invertebrate glial barriers as a model for understanding blood-brain barrier evolution.

Sofía Paredes-González, Jennifer Salazar-Tirado, Antonia Recabal-Beyer, Esteban G Contreras.

  Biological barriers play a crucial role in maintaining tissue homeostasis across diverse animal taxa, from invertebrates to mammals. In the nervous system, they regulate ion balance, metabolic exchange, and immune protection, ensuring proper neuronal function. In arthropods, the blood-brain barrier (BBB) is primarily formed by the perineurium, consisting of perineurial and subperineurial glial cells that establish septate junctions to restrict diffusion. Cephalopods, such as octopuses and squids, possess two distinct BBBs: one formed by glial cells and another by pericytes, depending on the type of brain blood vessel. Similarly, in vertebrates such as sharks, skate, rays, and sturgeons, the BB is also formed by glial cells. In contrast, the BBBs of most vertebrates rely on endothelial tight junctions, although astrocytes and pericytes contribute significantly to BBB maintenance and function. Importantly, glial barriers also exist in vertebrates, including the blood-nerve barrier (BNB), and the blood-cerebrospinal fluid barrier (BCSFB). Despite structural differences, the molecular mechanisms governing barrier formation, function, and plasticity show remarkable evolutionary conservation between invertebrates and vertebrates. In this review, we examine the diversity of glial barriers, their structural and functional parallels, evolutionary origins, and the key molecular pathways that regulate their development.

Keywords:   Drosophila melanogaster ; Blood–brain barrier; Glial barrier; Glial cells

DOI:  https://doi.org/10.1186/s12987-025-00694-1
Fluids Barriers CNS. 2025 Sep 30. 22(1): 94

Neurogranin-MYH9 interaction regulates cytoskeletal remodeling in cerebral vasculature.

Adesewa Akande, Ji Eun Park, Rona Scott, J Steven Alexander, Hyung W Nam.

  Neurogranin (Ng), a known regulator of neuronal Ca²⁺-calmodulin (CaM) signaling, is linked to Alzheimer's disease. Though well-studied in neurons, Ng is also expressed in brain vasculature, where its function remains unclear. To investigate Ng's role in brain microvascular endothelial cells, we defined its interactome using immunoprecipitation-mass spectrometry (IP-MS) under high- and low-Ca²⁺ conditions. Among 119 Ng-binding proteins, we discovered a novel interaction between Ng and MYH9, a key regulator of cytoskeletal remodeling. Ng-MYH9 binding was prominent in high Ca²⁺ and validated via CaM affinity pulldown and proximity ligation assays. Ng knockdown reduced F-actin levels, while MYH9 knockdown decreased both Ng and F-actin. Loss of Ng-MYH9 also impaired AKT-GSK3β signaling and elevated the endothelial activation marker VCAM1. Ng-null mice exhibited disrupted brain microvascular architecture and reduced MYH9 expression in endothelial cells. These findings reveal a novel Ng pathway promoting MYH9-dependent cytoskeletal remodeling and a potential role in maintaining blood-brain barrier integrity, a previously unrecognized function for Ng in brain health and Alzheimer's disease.

Keywords:  Cytoskeletal remodeling; Immunoprecipitation-mass spectrometry; Interactome; Myosin-9; Neurogranin

DOI:  https://doi.org/10.1186/s12987-025-00709-x
Virulence. 2025 Dec;16(1): 2564281

Stem cell-derived brain-like endothelial cells to interrogate Streptococcus pneumoniae interaction with brain endothelium.

Henry D Mauser, Taryn E Keyzer, Jessica M Surma, Natalie G Alexander, William D Cutts, Sarah F Hathcock, Kimberly H Lackey, Daryl W Lam, Justin A Thornton, Nadine Vollmuth, Brandon J Kim.

  Streptococcus pneumoniae (pneumococcus) is an opportunistic pathogen that remains the leading cause of bacterial meningitis worldwide. For meningitis to occur, pneumococcus must breach the blood-brain barrier (BBB), a highly specialized network of brain endothelial cells that comprise the microvasculature of the brain. Here, we report the use of human induced pluripotent stem cell-derived brain-like endothelial cells (iBECs) to model the BBB during pneumococcal infection. iBECs were infected with the S. pneumoniae strain TIGR4. Adherence assays showed that pneumococcal adherence to iBECs was a saturable process. Moreover, deletion of two pneumococcal adhesins resulted in an adherence defect, supporting a receptor-mediated interaction between pneumococcus and iBECs. Next, the integrity of several tight junction components was assessed via western blot and RT-qPCR, revealing the loss of abundance and expression in iBECs during infection with pneumococcus. Simultaneously, the expression of VEGFA and the tight junction repressor SNAI1 was upregulated. Semi-automated analysis of junction images also demonstrated a loss of ZO-1 and occludin continuity during pneumococcal infection. Consistent with these findings, the loss of TEER and the increase in barrier permeability were observed in pneumococcus-infected iBECs. The toxin pneumolysin (Ply) was important for this disruption, as the loss of Ply in pneumococcus partially arrested the reduction of TEER and the increase in permeability. Finally, RT-qPCR showed that pneumococcus was sufficient to upregulate a panel of inflammatory cytokines in iBECs. Taken together, these findings show that pneumococcus interacts with and disrupts iBECs during infection, supporting iBECs as an important model for studying pneumococcus-BBB interactions.

Keywords:  Streptococcus pneumoniae; blood-brain barrier; brain endothelial cells; iPSC-BEC; pneumococcal meningitis

DOI:  https://doi.org/10.1080/21505594.2025.2564281
Brain Dev. 2025 Sep 26. pii: S0387-7604(25)00129-9. [Epub ahead of print]47(5): 104447

Serum matrix metallopeptidase-9 levels in patients with infantile epileptic spasms syndrome before and after the initiation of vigabatrin therapy.

Ryuki Matsuura, Shin-Ichiro Hamano, Atsuro Daida, Azusa Oba, Haruhito Horita, Yuko Hirata, Reiko Koichihara, Kenjiro Kikuchi, Akira Oka.

   PURPOSE: Epileptic spasms are the predominant seizure type in infantile epileptic spasms syndrome (IESS). The pathophysiology of IESS, including blood-brain barrier (BBB) function involvement, remains unclear. To address this issue, we evaluated the serum matrix metallopeptidase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels in patients with IESS before and after initiating vigabatrin therapy.
METHODS: IESS was defined as epileptic spasms occurring within 2 years after birth. We prospectively assessed serum MMP-9 and TIMP-1 levels before and after initiating vigabatrin therapy in patients with IESS who attended Saitama Children's Medical Center between February 2019 and December 2024 (n = 12; 5 boys) and compared them with those in age-matched controls (n = 14; 8 boys).
RESULTS: The median ages at epileptic spasm onset and vigabatrin therapy initiation were 3.5 (1-11) and 8 (3-13) months, respectively. Serum MMP-9 levels were higher in patients with IESS than in the controls (p < 0.001). Serum MMP-9 and MMP-9/TIMP-1 ratios decreased significantly after vigabatrin therapy (MMP-9: 308 [160-664] ng/mL vs. 220 [112-367] ng/mL, p < 0.01; MMP-9/TIMP-1 ratio: 1.48 [0.61-8.14] vs. 1.11 [0.31-1.92], p < 0.05). MMP-9 levels decreased in 9 of 11 patients whose epileptic spasms had disappeared by the time of the last measurement.
CONCLUSION: Decreased MMP-9 levels after the initiation of vigabatrin therapy suggested an improvement in BBB dysfunction. Our findings shed light on the role of the BBB in IESS and the role of vigabatrin in the recovery of this function.

Keywords:  Antiseizure medicine; Biomarker; Blood–brain barrier; Child; Epilepsy

DOI:  https://doi.org/10.1016/j.braindev.2025.104447
Autoimmunity. 2025 Dec;58(1): 2561610

Immunogenic self-DNA drives neuropsychiatric systemic lupus erythematosus in conventional genetic background mice.

Fuyou Xu, Zhenke Wen, Sidong Xiong.

  Neuropsychiatric systemic lupus erythematosus (NPSLE) represents a significant and growing challenge in both clinical practice and research, with its mechanistic investigation hindered by the lack of reliable animal models. Over the past two decades, we have established that immunogenic self-DNA can induce SLE disease model, which has been widely utilized in the academic community. To modify the doses of immunogenic self-DNA, validate the induction of SLE disease, and systematically characterize the resulting neuropsychiatric manifestations, aiming to provide an optimal model for NPSLE. Conventional genetic background BALB/c mice were immunized with 75 µg of immunogenic self-DNA. Based on the criteria and diagnostic recommendations from the ACR and EULAR, we conducted neurobehavioral experiments to assess the neuropsychiatric manifestations of clinical NPSLE patients. Whole-cell patch-clamp electrophysiological recordings were performed on mouse brain slices to assess electroencephalographic (EEG) abnormalities associated with NPSLE. Cerebrospinal fluid (CSF) abnormalities were evaluated by measuring inflammatory factors in the CSF. Additionally, histopathological analyses were conducted to evaluate MRI abnormalities in self-DNA immunized mice. Self-DNA immunized mice developed progressive cognitive impairments, exhibiting spatial and working memory deficits from week 8 post-immunization, which worsened by week 12, alongside the emergence of anxiety-like and depression-like behaviors. In parallel, electrophysiological analysis revealed synaptic transmission deficits and reduced neuronal excitability beginning at week 8, further deteriorating by week 12. Of note, blood-brain barrier (BBB) disruption was observed at 4-8 weeks post immunization, which was evidenced by IgG leakage and FITC-dextran extravasation. Such BBB disruption was accompanied by elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-10), resembling neuropsychiatric lupus pathology. Finally, histologically, hippocampal neuronal loss and dendritic spine reduction in CA1, CA3, and DG subregions were observed, providing structural correlates for the observed memory deficits in self-DNA immunized mice. This model induced by immunogenic self-DNA recapitulated the neurological manifestations observed in clinical patients, rendering it a robust model for the research of NPSLE.

Keywords:  NPSLE; SLE; autoimmune disease; mouse model; self-DNA

DOI:  https://doi.org/10.1080/08916934.2025.2561610
Neural Regen Res. 2025 Sep 29.

Beyond the Barrier: Targeting blood-brain interactions for neuroprotection and repair.

Anddre O Valdivia, Caroline Brandt, Mark A Petersen.

DOI: https://doi.org/10.4103/NRR.NRR-D-25-00723