bims-blobar 2025-11-16 papers

bims-blobar

Biomed News

on Blood brain barrier repair

Issue of 2025–11–16
23 papers selected by
Nicolas Rebergue

Disulfiram Prevents Blood-Brain Barrier Disruption in Epileptic Mice by Inhibiting Astrocyte Pyroptosis to Improve Seizure Activity.
Mechanisms and potential therapeutic molecular targets in blood-brain barrier disruption following subarachnoid hemorrhage: a review of early brain injury.
Establishment of an In Vitro Neurovascular Unit Model With Blood and Brain Components and Investigation of Its Blood-Brain Barrier.
Temporal dynamics of cisplatin-induced endothelial senescence and its association with cognitive impairment: insights into the medial prefrontal cortex.
Streptozotocin Causes Blood-Brain Barrier and Astrocytic Dysfunction In Vitro.
Enterococcus-derived cytolysin exacerbates ischemic stroke by disrupting the blood-brain barrier via NLRP3 activation.
Cerebral Perfusion and Blood-Brain Barrier Changes After Cranioplasty: A Diffusion-Prepared Arterial Spin Labeling Study.
Dual Use of Combustible and Electronic Cigarettes Progressively Disrupts Tight Junctions and Elevates Oxidative Stress, Leading to Compromised Blood-Brain Barrier Integrity.
Rehmannioside A: a therapeutic agent for cerebral ischaemia-reperfusion injury via p38 MAPK pathway modulation.
Altered Vascular and Angiogenic Transcripts in the Neurogenic Niche in Neuroinflammatory-Type Schizophrenia.
Interactive effects of blood-brain barrier breakdown and Alzheimer's disease biomarker status on cognitive decline in older adults without dementia.
Comparisons of the Effects of Low- or High-Fat Diets Rich in Soybean Oil, Lard, and Tea Seed Oil on Markers of Blood-Brain Barrier and Neuroinflammation in Ovariectomized Mice.
Urolithins and their phase II conjugates cross the blood-brain barrier and exert a stimulus-dependent anti-inflammatory effect on microglial cells by inhibiting NF-κB nuclear translocation.
Fingolimod reduces blood-brain barrier damage, inflammation, and neuronal death in experimental subarachnoid hemorrhage.
Transplantation of hiPSC-derived pericytes rescues Alzheimer's disease phenotypes in APOE4/4 mice through IGF2-rich apoptotic vesicles.
Initial assessment of blood-brain barrier permeability alterations and associated clinical characteristics in patients with primary Sjögren's syndrome: Insights from DCE-MRI.
Attenuation of blood-brain barrier dysfunction by functionalized gold nanoparticles against amyloid-β peptide in an Alzheimer's disease-on-a-chip model.
Nutritional Modulation of the Endogenous Antioxidant System in the Brain-Gut Axis Following Traumatic Brain Injury.
Amplified microglial dysfunction and brain lesions in mouse models for comorbidity of chronic stress and cerebral hypoperfusion.
Minocycline Ameliorates Cognitive Impairments Without Modulating Microglial Reactivity in Sporadic Hypercholesterolemia: A Sex-Specific Analysis in Mice.
Exogenous IL-33 mitigates inflammatory responses by suppressing the NF-Κb signaling pathway, promoting blood-spinal cord barrier repair and neural functional recovery.
An ischemic stroke-on-a-chip model integrated with machine learning for screening of drug candidates.
Nerve Root Enhancement and Elevated Cerebrospinal Fluid Protein in Four Patients With SOD1-Linked Amyotrophic Lateral Sclerosis.

Mol Neurobiol. 2025 Nov 12. 63(1): 34

Disulfiram Prevents Blood-Brain Barrier Disruption in Epileptic Mice by Inhibiting Astrocyte Pyroptosis to Improve Seizure Activity.

Mulan Zhang, Linqian Zhao, Shihao Chen, Wenting Huang, Xing Jin, Huiqin Xu.

  Epilepsy is a prevalent neurological disorder whose pathogenesis is closely associated with blood-brain barrier (BBB) disruption. Emerging evidence suggests that astrocytic pyroptosis may play a pivotal role in BBB impairment. Based on this, we propose two central hypotheses: (1) seizure activity triggers astrocytic pyroptosis and exacerbates BBB damage; (2) pharmacological inhibition of pyroptosis can restore BBB integrity and alleviate epileptic symptoms. This study established a kainic acid-induced mouse model of epilepsy and an in vitro BBB model. Cell pyroptosis was induced using LPS and ATP. The expression of BBB and pyroptosis-related proteins was assessed through Western blotting, immunofluorescence, and RT-PCR. Additionally, a pyroptosis inhibitor, disulfiram (DSF), was used to inhibit pyroptosis, and the therapeutic effects on epilepsy were evaluated through behavioral experiments, electroencephalography, and electron microscopy. BBB damage and pyroptosis were observed in the hippocampal tissue of mice following seizures, with immunofluorescence results indicating the occurrence of pyroptosis in astrocytes. In vitro experiments demonstrated that astrocyte pyroptosis leads to the downregulation of tight junction proteins in endothelial cells. Inhibition of pyroptosis by DSF improved the integrity of the BBB and resulted in reduced severity of seizure activity and improved cognitive function in mice. This study reveals the role of astrocyte pyroptosis in seizure activity and the consequent BBB damage. DSF mitigates seizure severity and cognitive impairment by inhibiting astrocyte pyroptosis and improving BBB integrity, offering new insights and targets for epilepsy treatment.

Keywords:  Astrocytes; Blood-Brain Barrier; DSF; Epilepsy; Pyroptosis

DOI:  https://doi.org/10.1007/s12035-025-05308-3
Front Neurol. 2025 ;16 1678839

Mechanisms and potential therapeutic molecular targets in blood-brain barrier disruption following subarachnoid hemorrhage: a review of early brain injury.

Hao Ouyang, Hua Gu, Yong Cai, Chenli Wang.

  Subarachnoid hemorrhage (SAH) is a devastating stroke characterized by acute onset, severe symptoms, and a poor prognosis. A series of pathological changes occur within 72 h after SAH, leading to early brain injury (EBI). Blood-brain barrier (BBB) disruption is a key factor contributing to the EBI progression. When the BBB is compromised, detrimental substances and immune cells have the potential to infiltrate brain tissues, and a range of mechanisms contribute to the disruption of the BBB following SAH. This review provides a comprehensive overview of the current knowledge regarding the underlying mechanisms and potential therapeutic targets in BBB disruption during EBI following SAH. It focuses on the dysfunction of endothelial cells, tight junctions, astrocytes, and pericytes; the specific molecular targets for EBI after SAH; and new emerging treatments for BBB disruption in EBI after SAH.

Keywords:  astrocytes; brain edema; brain herniation; endothelial cells; hemorrhagic stroke; intracranial aneurysm; neuron apoptosis; pericytes

DOI:  https://doi.org/10.3389/fneur.2025.1678839
J Biomed Mater Res A. 2025 Nov;113(11): e38013

Establishment of an In Vitro Neurovascular Unit Model With Blood and Brain Components and Investigation of Its Blood-Brain Barrier.

Gozde E Kole, Tanil Kocagoz, Vasif Hasirci, Deniz Yucel.

  The neurovascular unit (NVU), including the blood-brain barrier (BBB), governs the interaction between neural tissue and blood vessels. The BBB is a highly selective interface that regulates molecular exchange between the bloodstream and the central nervous system. This study aimed to develop a structurally relevant, multicellular in vitro NVU model integrating both vascular and brain microenvironments to evaluate BBB function. A fibrous membrane mimicking the basement membrane was fabricated via electrospinning, while a methacrylated hyaluronic acid (MeHA)-collagen hydrogel was used on the brain side. Endothelial cells (ECs) were cultured on the vascular side, and astrocytes, pericytes, and neuronal model cells were embedded within the hydrogel. The model was optimized for cell viability and endothelial monolayer formation. Cell behavior was assessed via immunocytochemistry, and barrier function was evaluated using TEER measurements and permeability assays with fluorescein, 0.4 and 20 kDa dextran, ceftriaxone, and amikacin. CD31 expression was elevated in the multicellular model, indicating improved endothelial integrity. The model achieved a TEER of 166.86 ± 5.75 Ω versus 121.70 ± 13.58 Ω cm2 in monoculture. Permeability to tracers was significantly reduced in the multicellular model, and ceftriaxone showed higher transport than amikacin, reflecting human BBB selectivity. This model provides a physiologically relevant platform for neurovascular research and drug screening.

Keywords:  blood–brain barrier; electrospun fibrous membrane; hydrogel‐based brain microenvironment; in vitro model; neurovascular unit (NVU) model; tissue engineering

DOI:  https://doi.org/10.1002/jbm.a.38013
Front Oncol. 2025 ;15 1668372

Temporal dynamics of cisplatin-induced endothelial senescence and its association with cognitive impairment: insights into the medial prefrontal cortex.

Yue Hei, Sheng-Nan Kong, Juan-Hua Sun, Wei-Ping Liu, Qian-Fa Long, Hong-Mei Zhang.

   Background: Chemotherapy-related cognitive impairment (CRCI) poses significant challenges for cancer survivors, with its underlying mechanisms remaining inadequately understood, particularly in the medial prefrontal cortex (mPFC). This study aimed to investigate the temporal dynamics of cisplatin-induced endothelial senescence, blood-brain barrier (BBB) integrity, neuroinflammation, and their relationship with persistent working memory impairment.
Methods: Adult C57BL/6 mice were treated with cisplatin (2.3 mg/kg) and evaluated at multiple time points post-treatment. Senescence-associated β-galactosidase (SA-β-gal) staining, secretory phenotype (SASP) factors, and expression of p16/p21 proteins were assessed to determine endothelial senescence. BBB integrity was determined using dextran tracer and analysis of tight junction proteins (Claudin-5, ZO-1). Neuroinflammation was investigated via GFAP and Iba1 staining. Cognitive function expression was assessed through the Novel Object Recognition (NOR), Puzzle Box, and modified T-maze tests, focusing on working memory ability.
Results: Cisplatin triggered endothelial senescence in the mPFC, peaking at 1 week, as evidenced by elevated percentage of SA-β-gal positive area, increased SASP factors and p16/p21 expression. BBB dysfunction and glial activation emerged later (peaking at 4 weeks), with significant dextran leakage, reduced Claudin-5/ZO-1 levels and increased GFAP and Iba1 staining respectively. Unlike the early vascular events, showing initial rise followed by slow decline, cisplatin-induced working memory impairment persists through 4-12 weeks, manifested as reduced NOR discrimination index, prolonged times in Puzzle Box, and impaired T-maze performance.
Conclusion: This study delineates a temporal cascade wherein cisplatin induces early mPFC endothelial senescence with delayed BBB dysfunction and neuroinflammation, driving chronic working memory impairment, thus indicating endothelial senescence as early-stage potential target for mitigating CRCI, especially in mPFC-related working memory deficits.

Keywords:  blood-brain barrier; cisplatin-induced cognitive impairment; endothelial senescence; neuroinflammation; prefrontal cortex; working memory

DOI:  https://doi.org/10.3389/fonc.2025.1668372
Cells. 2025 Nov 06. pii: 1745. [Epub ahead of print]14(21):

Streptozotocin Causes Blood-Brain Barrier and Astrocytic Dysfunction In Vitro.

Sarah A Habib, Mohamed M Kamal, Mohamed H Aly, Heba R Ghaiad, Sherine M Rizk, William A Banks, Michelle A Erickson.

  Streptozotocin (STZ) is an alkylating agent that has neurotoxic effects when injected into the cerebral ventricles (ICV) and also models many other features of Alzheimer's disease. However, the mechanisms of STZ neurotoxicity are not well understood. In this study, we hypothesized that some of the neurotoxic effects of STZ could be due to direct activities on brain endothelial cells and astrocytes, which are key in forming and supporting the functions of the blood-brain barrier (BBB), respectively. To test this hypothesis, we characterized the changes induced by STZ either in cultures of human-induced pluripotent stem cell (iPSC)-derived brain endothelial-like cells (iBECs), which form an in vitro BBB model, or in primary human astrocytes. We found that STZ at a dosage of 5 mM caused a delayed reduction in the transendothelial electrical resistance (TEER) of iBECs at 7-11 days post-treatment, indicating induction of BBB leakage. Additionally, we observed significant increases in albumin leakage across the monolayer, altered iBEC morphology, and reductions in tight junction proteins, suggesting that STZ causes BBB disruption. We further found that the BBB glucose transporter GLUT-1 was reduced in iBECs, as was the total number of iBECs. In astrocytes, the 5 mM dose of STZ reduced the GFAP signal and total number of cells, suggesting that STZ has anti-proliferative and/or toxic effects on astrocytes. Together, these data support that STZ's neurotoxic effects could be due, in part, to its direct toxic activities on brain endothelial cells and astrocytes.

Keywords:  GLUT-1; Streptozotocin; astrocytes; blood–brain barrier; brain endothelial cells; tight junctions

DOI:  https://doi.org/10.3390/cells14211745
J Neuroinflammation. 2025 Nov 11. 22(1): 266

Enterococcus-derived cytolysin exacerbates ischemic stroke by disrupting the blood-brain barrier via NLRP3 activation.

Jia-Ni Huang, Wei-Hao Zhuang, Yi-Si Lin, Jia-Xue Xu, Yan-Lei Zhang, Jia Li, Meng Huang, Cheng-Long Xie, Ruo-Ting Xu.

   BACKGROUND: Ischemic stroke remains a major global health burden. Enterococcus, which is enriched in the gut of stroke patients, produces cytolysin-a pore-forming toxin that disrupts cell membranes. Gut barrier damage may allow such toxins to enter circulation and impair the blood-brain barrier (BBB). In this study, cytolysin-induced BBB disruption via NLRP3 inflammasome activation was investigated with the aim of identifying new therapeutic targets for stroke.
METHODS: Ischemic stroke patients were enrolled within 48 h of onset at the First Affiliated Hospital of Wenzhou Medical University. Rectal swabs were collected for 16 S rRNA sequencing and analyzed via QIIME. To investigate the effects of cytolysin-positive Enterococcus on BBB integrity and NLRP3 activation, a photothrombotic stroke model in C57BL/6J mice and in vitro studies with bEnd.3 cells were performed. Cerebral blood flow, BBB permeability, and intestinal barrier function were assessed using established physiological and molecular assays. NLRP3 pathway activation was evaluated by RNA sequencing, qPCR, Western blotting, and ELISA, and its functional role was further confirmed by administration of the selective NLRP3 inhibitor MCC950. Statistical significance was defined as p < 0.05.
RESULTS: In a cohort of 100 stroke patients, rectal swabs were collected for 16 S rRNA sequencing and qPCR analysis, and the results identified elevated Enterococcus and cylA gene levels as potential prognostic biomarkers for 360-day mortality. In a photothrombotic stroke mouse model, cytolysin-positive Enterococcus exacerbated stroke severity by increasing BBB permeability. Mechanistically, cytolysin activated nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis, further compromising BBB integrity. Additionally, cytolysin disrupted the intestinal barrier, increased permeability, and may facilitate its entry into the circulation, potentially contributing to BBB damage. Notably, NLRP3 inhibition with MCC950 mitigated neurological deficits and restored BBB integrity.
CONCLUSION: Cytolysin aggravates ischemic stroke by compromising the BBB via NLRP3 activation and disrupting the intestinal barrier. Targeting cytolysin and NLRP3 holds promise as a therapeutic strategy for neuroprotection during ischemic stroke.

Keywords:  Blood–brain barrier (BBB); Cytolysin; Ischemic stroke; NLRP3 inflammasome; Neuroprotection

DOI:  https://doi.org/10.1186/s12974-025-03590-5
J Neuroimaging. 2025 Nov-Dec;35(6):35(6): e70106

Cerebral Perfusion and Blood-Brain Barrier Changes After Cranioplasty: A Diffusion-Prepared Arterial Spin Labeling Study.

Brandon Ojogho, Aidin Abedi, Darrin J Lee, Xingfeng Shao, Jonathan Russin, Kay Jann, Charles Y Liu, Danny J J Wang.

   BACKGROUND AND PURPOSE: Cranioplasty reconstruction after hemicraniectomy restores skull integrity and has been associated with neurological improvement, but the physiological mechanisms underlying recovery remain incompletely understood. This study investigated cerebral blood flow (CBF), arterial transit time (ATT), and blood-brain barrier (BBB) water exchange rate (Kw) as imaging metrics of hemodynamic recovery following cranioplasty.
METHODS: Fourteen patients (mean age: 33.4 ± 8.53 years; 2 females, 12 males) who previously underwent hemicraniectomy for traumatic brain injury, ruptured aneurysm, or hemorrhagic stroke were included. All participants underwent diffusion-prepared pseudo-continuous arterial spin labeling (DP-pCASL) Magnetic Resonance Imaging (MRI) at 3 Tesla before and after cranioplasty. Hemodynamic parameters were quantified globally and regionally, with particular focus on the middle cerebral artery perforator (MCA Perf) territory.
RESULTS: Post-surgical imaging revealed significant increases in CBF within the ipsilateral MCA Perf territory compared to pre-surgical values. BBB Kw asymmetry between MCA Perf territories also improved, indicating enhanced perfusion and BBB function in the impacted hemisphere. ATT changes were region-specific, with significant increases in asymmetry observed in the leptomeningeal anterior cerebral artery and posterior cerebral artery territories, but not in the MCA Perf region.
CONCLUSIONS: These findings underscore the mechanobiological role of cranioplasty reconstruction in neurological recovery. Advanced hemodynamic imaging with DP-pCASL MRI provides quantitative insight into cerebral perfusion, BBB function, and regional perfusion timing. This approach may guide future research on post-cranioplasty recovery and inform personalized rehabilitation strategies.

Keywords:  arterial transit time; blood–brain barrier; cerebral blood flow; cranioplasty; diffusion‐prepared pseudo‐continuous arterial spin labeling; neuroimaging; water exchange rate

DOI:  https://doi.org/10.1111/jon.70106
Toxicol Sci. 2025 Nov 12. pii: kfaf160. [Epub ahead of print]

Dual Use of Combustible and Electronic Cigarettes Progressively Disrupts Tight Junctions and Elevates Oxidative Stress, Leading to Compromised Blood-Brain Barrier Integrity.

Sejal Rajesh Jadhav, Khondker Ayesha Akter, David Mara, Thomas J Abbruscato.

  Despite the adverse effects of combustible (C-cig) and electronic cigarettes (E-cig) being well studied, their combined impact as dual product use on the BBB remains underexplored. This study uses both in-vitro and in-vivo models to examine the effect of dual use of C-cig and E-cig products on BBB integrity. For short (24 hours) and prolonged (5 days) duration, brain endothelial cell (bEnd.3) and primary astrocytes were exposed to C-cig, E-cig, and three dual combinations. Assessments included cell viability, NaF permeability assay across monolayer, ACM, and co-culture models, western blot analysis of TJ proteins (ZO-1, occludin, and claudin-5), and antioxidative markers (NQO1, HO-1, and SOD2). In-vivo, male mice (C57BL/6) were acutely exposed (7 days), and outcomes included changes in body weight, plasma nicotine concentration using LCMS/MS, western blot analysis of TJ proteins, and cytokine profiles. A significant increase in the NaF permeability was observed with Dual 1 exposure (1:1 C-cig: E-cig ratio), with significant downregulation of ZO-1 after short and claudin-5 expression after prolonged exposure duration. Dual exposure groups also elevated NQO1 and HO-1 levels, indicating a shift in oxidative stress, while SOD2 levels remained unchanged. In-vivo, dual use resulted in weight loss, reduced ZO-1 expression, elevated plasma nicotine concentration, and an increase in proinflammatory cytokines (IL-13, KC). Dual use of C-cig and E-cig is often misinterpreted as a safer alternative due to perceived reduction in C-cig use. Our data indicate that this might not be the case, as dual use, particularly with a 1:1 ratio, significantly alters BBB integrity.

Keywords:  Blood-brain barrier; Dual nicotine product use; Oxidative stress; Paracellular barrier integrity; Tight junction proteins

DOI:  https://doi.org/10.1093/toxsci/kfaf160
Cytotechnology. 2025 Dec;77(6): 190

Rehmannioside A: a therapeutic agent for cerebral ischaemia-reperfusion injury via p38 MAPK pathway modulation.

XiaoXia Wang, LiXia Wang, ShengXian Wu, RuiXian Wang.

  Derived from Rehmanniae Radix, Rehmannioside A (ReA) appears to provide a defensive effect against diseases. This study was designed to investigate ReA's role and mechanism in cerebral ischemia-reperfusion injury (CI/RI). A transient middle cerebral artery occlusion (tMCAO) mouse model was developed. tMCAO mice were intraperitoneally injected with different doses of ReA for 3 days, and then underwent neurological function examination. Then, brain histopathology was observed by HE staining, neuronal apoptosis was observed by TUNEL staining, glial fibrillary acidic protein (GFAP) expression was detected by immunofluorescence staining to assess astrocyte activation, and blood-brain barrier (BBB) integrity was assessed by determining hemoglobin content and brain water content. p38 MAPK pathway-related proteins were detected by Western blot. Treatment with ReA in tMCAO mice showed a dose-dependent reduction in BBB damage, improvements in neurological function, decreased neuronal apoptosis, and inhibition of astrocyte activation. ReA inhibited p38 MAPK pathway activation, and the p38 MAPK pathway inhibitor SB203580 potentiated the ameliorative effects of ReA on CI/RI. ReA improves CI/RI by inhibiting astrocyte activation and reducing BBB damage through modulation of the p38 MAPK pathway.
Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-025-00859-8.

Keywords:  Astrocytes; Blood brain barrier; Cerebral ischaemia-reperfusion injury; P38 MAPK; Rehmannioside A

DOI:  https://doi.org/10.1007/s10616-025-00859-8
Schizophr Bull. 2025 Nov 05. pii: sbaf177. [Epub ahead of print]

Altered Vascular and Angiogenic Transcripts in the Neurogenic Niche in Neuroinflammatory-Type Schizophrenia.

Hayley F North, Jessica Lim, Janice M Fullerton, Maree J Webster, Cynthia Shannon Weickert.

   BACKGROUND AND HYPOTHESIS: Growing evidence indicates that vascular processes, including blood-brain barrier (BBB) function and angiogenesis, may be altered in schizophrenia and related to neuroinflammation. The subependymal zone (SEZ) neurogenic niche shows reduced neurogenesis markers in schizophrenia that are more pronounced with neuroinflammation. Since inflammatory neuropathology is related to increased diapedesis-related transcripts, we hypothesize that endothelial cells would be impacted in this neurogenic niche in schizophrenia.
STUDY DESIGN: We measured the expression of four BBB-related mRNAs [claudin-5 (CLDN5), occludin (OCLN), platelet endothelial cell adhesion molecule-1 (PECAM1), and tight junction protein 1 (TJP1)] and five angiogenesis-related mRNAs [angiopoietin 1 (ANGPT1), angiopoietin 2 (ANGPT2), vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 1 (VEGFR1), and TEK receptor tyrosine kinase (TEK)] via quantitative polymerase chain reaction, followed by semi-quantitative immunofluorescence for claudin-5 and collagen-IV protein. We estimated proportions of vascular cells by running cellular deconvolution on previous bulk RNA sequencing data.
STUDY RESULTS: In high-inflammation schizophrenia, we found increased PECAM1 mRNA, CLDN5 mRNA and claudin-5 protein expression potentially relating to leukocyte trafficking and repair of endothelial tight junctions. The estimated proportion of vascular cells and VEGFA mRNA levels were increased, potentially indicating increased angiogenesis in high-inflammation schizophrenia. Higher VEGFA and CLDN5 mRNA levels were associated with higher expression of markers of immune cell transmigration but lower expression of immature neuron markers, suggesting that vascular dysfunction may impact neurogenesis.
CONCLUSIONS: These findings reveal that changes in the BBB and angiogenesis are more severe in high-inflammation schizophrenia and appear to be linked to reduced neurogenesis in the SEZ. This study underscores the importance of inflammation in shaping vascular and neurogenic pathology in schizophrenia, offering potential pathways for future therapeutic exploration.

Keywords:  Schizophrenia; angiogenesis; blood brain barrier; claudin-5; inflammation; neurogenesis

DOI:  https://doi.org/10.1093/schbul/sbaf177
Alzheimers Dement. 2025 Nov;21(11): e70910

Interactive effects of blood-brain barrier breakdown and Alzheimer's disease biomarker status on cognitive decline in older adults without dementia.

Lauren Edwards, Amanda I Gonzalez, Kelsey R Thomas, Denis S Smirnov, Einat K Brenner, Daniel A Nation, Fini Chang, Kaj Blennow, David P Salmon, Douglas Galasko, Katherine J Bangen.

   INTRODUCTION: Some research suggests that blood-brain barrier (BBB) integrity is altered in Alzheimer's disease (AD). Few studies have examined markers of BBB integrity and their interactions with AD risk factors on multi-domain cognition.
METHODS: 83 older adults without dementia underwent lumbar puncture, apolipoprotein E (APOE) genotyping, and neuropsychological testing with up to 5 years of follow-up. Soluble platelet-derived growth factor receptor beta (sPDGFRβ) was measured in cerebrospinal fluid.
RESULTS: Higher baseline sPDGFRβ was associated with better cross-sectional attention, visuospatial, and executive functioning, but with steeper longitudinal decline in executive function. When considering AD risk status, higher sPDGFRβ was associated with faster longitudinal decline in all cognitive domains in biomarker-positive relative to biomarker-negative individuals and in language in APOE ɛ4-positive relative to ɛ4-negative individuals.
DISCUSSION: Elevated sPDGFRβ may increase risk of cognitive decline, particularly in individuals with a higher risk for AD. Future studies should explore mechanisms that contribute to these relationships.
HIGHLIGHTS: Cerebrospinal fluid (CSF) soluble platelet-derived growth factor receptor beta (sPDGFRβ) is a promising marker of blood-brain barrier (BBB) integrity. Higher sPDGFRβ was cross-sectionally associated with better cognition at baseline. Higher sPDGFRβ was longitudinally associated with steeper decline in cognition, particularly among amyloid beta (Aβ) 42/Aβ40+ individuals. CSF concentration of sPDGFRβ may predict cognitive decline in those with increased dementia risk.

Keywords:  Alzheimer's disease; CSF; amyloid; apolipoprotein E; cerebrospinal fluid; cognition; pericyte; sPDGFRβ; soluble platelet‐derived growth factor receptor β

DOI:  https://doi.org/10.1002/alz.70910
Int J Food Sci. 2025 ;2025 4154633

Comparisons of the Effects of Low- or High-Fat Diets Rich in Soybean Oil, Lard, and Tea Seed Oil on Markers of Blood-Brain Barrier and Neuroinflammation in Ovariectomized Mice.

Shyh-Hsiang Lin, Cicilia Giofani Soetanto, Wan-Chun Chiu, Tzu-Wen L Cross, Ning-Jo Kao, Yih-Ru Wu, Ching-I Lin, Poulami Jha.

  High-fat diets (HFDs) may affect the blood-brain barrier (BBB) function and cause neuroinflammation. Different dietary oils may influence BBB and neuroinflammatory responses due to their unique fatty acid compositions. To elucidate the potential effects of different dietary oils, this study compared the effects of tea seed oil with those of soybean oil and lard on markers of BBB and neuroinflammation. Six-week-old ovariectomized mice were fed a normal or HFD for 12 weeks. The mice's brain lipid profiles, brain-derived neurotrophic factor (BDNF), BBB function-related markers (i.e., S100 calcium-binding protein β [S100β], matrix metalloproteinase-9 [MMP-9], zonula occludens-1, and glial fibrillary acidic protein [GFAP]), and inflammation marker levels were evaluated. When mice were fed diets containing large amounts of fat (i.e., HFDs), different types of fat seemed to elicit different effects on these measures. However, different dietary fats had no different effects on the measurements during normal diet intervention. The mice fed the tea seed oil-based HFD exhibited upregulated levels of BDNF and downregulated levels of GFAP, S100β, MMP-9, and proinflammatory cytokines compared to those fed the soybean oil- and lard-based HFDs. While HFDs might impact BBB function and neuroinflammation, the type of dietary fat consumed might play a significant role, suggesting that tea seed oil might have beneficial effects on BBB markers and neuroinflammation compared to soybean oil and lard in ovariectomized mice under HFD conditions. However, further studies are warranted to determine the effects of these HFDs on cellular composition within the brains of these ovariectomized mice.

Keywords:  BDNF; blood–brain barrier; lard; neuroinflammation; soybean; tea seed oil

DOI:  https://doi.org/10.1155/ijfo/4154633
Food Funct. 2025 Nov 11.

Urolithins and their phase II conjugates cross the blood-brain barrier and exert a stimulus-dependent anti-inflammatory effect on microglial cells by inhibiting NF-κB nuclear translocation.

Beatriz Garay-Mayol, Juan Antonio Giménez-Bastida, Diego José López-Cánovas, Sabrina Poveda-Lora, Silvia Navarro-Orcajada, María Alexandra Brito, Claudia Nunes Dos Santos, Juan Carlos Espín, María Ángeles Ávila-Gálvez, Antonio González-Sarrías.

Neuroinflammation plays a central role in ageing and the progression of neurodegenerative diseases. Epidemiological studies suggest that consuming ellagitannins (ETs)- and ellagic acid (EA)-rich foods like pomegranate or walnuts may confer neuroprotective benefits. However, ETs and EA have low bioavailability and are extensively metabolized by the human gut microbiota into urolithins (Uros), which circulate mainly as glucuronide and sulphate conjugates. This study evaluated the ability of the main colonic Uros (Uro-A, Uro-B, and IsoUro-A), and their respective phase II conjugates, to cross human brain microvascular endothelial cells (HBMECs) as an in vitro model of the blood-brain barrier (BBB), and assessed their anti-(neuro)inflammatory effects on the BBB endothelium and human microglial cells (HMC3) under different inflammatory stimuli. UPLC-qTOF-MS analyses revealed that all Uros and their conjugates crossed the BBB, with Uro-B and its sulphate showing the highest transport efficiency. Moreover, Uros preserved BBB integrity against TNFα-induced damage. In HMC3 cells, all Uros significantly reduced IL-6 secretion, whereas only the free forms decreased IL-8 levels under LPS stimulation. However, no effects were observed in TNFα-stimulated cells, indicating a stimulus-dependent response. Additionally, all Uros prevented NF-κB nuclear translocation in LPS-treated cells, and Uro-A specifically interfered with the canonical MyD88-dependent arm of TLR4 signalling, without broadly inhibiting receptor expression or affecting the TRIF-dependent branch. These findings suggest that consuming ETs and EA-rich foods as precursors of Uros could exert anti-neuroinflammatory activity, potentially preventing or delaying the development of neurodegenerative diseases.

DOI: https://doi.org/10.1039/d5fo03678j
Exp Neurol. 2025 Nov 12. pii: S0014-4886(25)00419-4. [Epub ahead of print] 115554

Fingolimod reduces blood-brain barrier damage, inflammation, and neuronal death in experimental subarachnoid hemorrhage.

Joseph R Geraghty, Suresh B Rangasamy, Haoliang Xu, Jeffrey A Loeb, Fernando D Testai.

  Subarachnoid hemorrhage (SAH) is a severe form of hemorrhagic stroke associated with high morbidity and mortality. There are limited pharmacological treatment options available to prevent or treat secondary neurologic injury after SAH. We have previously shown that the immunomodulatory agent fingolimod (FTY720) reduces early adhesion of leukocytes to pial venules, preserves pial arteriolar dilating function, and improves neurologic outcome in a rodent model of SAH. However, the direct effect on cells residing within the brain is less well understood. We employed the endovascular perforation model of SAH in 6-8-week-old male rats to measure blood-brain barrier damage, downstream pro-inflammatory signaling pathways in microglia and astrocytes, and neuronal cell death. Animals were divided into sham, SAH-vehicle, and SAH-FTY720 groups. The SAH-FTY720 group received a single dose of fingolimod (0.5 mg/kg) intraperitoneally, three hours after surgery to replicate timing in which acute interventions can be administered following SAH. Blood-brain barrier dysfunction was seen in SAH-vehicle animals based on Evans blue extravasation and cerebral water content. Microglia and astrocytes increase expression of nitric oxide synthase after SAH, and microglia in particular upregulate NF-ĸB signaling. These changes are associated with neuronal cell death. Treatment with FTY720 improves blood-brain barrier integrity, inhibits pro-inflammatory signaling within microglia and astrocytes, and decreased neuronal apoptosis in the rat cortex and hippocampus. This data further elucidates proinflammatory and neurotoxic pathways activated within the brain following SAH, and suggests that immunomodulation with FTY720 has a beneficial effect on several pathogenic mechanisms of SAH-associated brain injury.

Keywords:  Astrocyte; Blood-brain barrier; Fingolimod; Microglia; Neuroinflammation; Subarachnoid hemorrhage

DOI:  https://doi.org/10.1016/j.expneurol.2025.115554
Transl Neurodegener. 2025 Nov 13. 14(1): 57

Transplantation of hiPSC-derived pericytes rescues Alzheimer's disease phenotypes in APOE4/4 mice through IGF2-rich apoptotic vesicles.

Chuanfeng Xiong, Yao Tang, Junhua Chen, Mingming Fan, Lan Wei, Zhaoran Dong, Xingqiang Lai, Xuejiao Men, Qiumin Chen, Dairui Li, Wenjin Ye, Yuanchen Ma, Xiaoyong Chen, Weijun Huang, Zhengqi Lu, Hong Chen, Yunfeng Shen, Yanming Chen, Andy Peng Xiang, Weiqiang Li.

   BACKGROUND: Effective therapies for Alzheimer's disease (AD) remain to be developed. APOE4 is the strongest genetic risk factor for late-onset AD. Pericyte degeneration and blood-brain barrier (BBB) disruption are thought to be early biomarkers of AD and contribute to cognitive decline in APOE4 carriers, representing potential therapeutic targets. Our previous studies have shown that pericyte transplantation is one of the most effective strategies for BBB restoration, exhibiting great therapeutic potential for APOE4-related BBB damage and AD phenotypes.
METHODS: APOE4/4 mice were treated with pericytes derived from APOE3/3 human induced pluripotent stem cells (hiPSCs). Behavioral tests, AD pathologies, and BBB integrity were assessed. Subsequently, temporal and spatial distribution of the transplanted pericytes was analyzed using tdTomato+ lentivirus labeling. Next, therapeutic effects of apoptotic vesicles (ApoVs) generated from APOE3/3 pericytes were evaluated in APOE4/4 pericytes in vitro. Additionally, transcriptomic and proteomic profiling were performed to identify key effector molecules in pericyte-derived ApoVs. Finally, the therapeutic effects of ApoVs derived from pericytes were evaluated in APOE4/4 mice.
RESULTS: Early, multiple transplantations of pericytes derived from APOE3/3 hiPSCs robustly rescued cognitive decline and AD pathologies, restored BBB integrity, and prevented in situ pericyte degeneration in aged APOE4/4 mice. Intriguingly, ApoVs released from the infused cells, rather than the transplanted pericytes, were predominantly distributed in the brain, which were ingested by in situ APOE4/4 pericytes and then promoted functional recovery. We further characterized insulin growth factor-2 (IGF-2) as a key factor in APOE3/3 pericyte-derived ApoVs. Infusion of the in vitro generated ApoVs from APOE3/3 pericytes demonstrated distinct therapeutic effects in APOE4/4 mice, which were reversed by IGF2 knockout.
CONCLUSIONS: APOE3/3 pericytes or APOE3/3 pericyte-derived IGF2-rich ApoVs may offer promising therapeutic strategies for APOE4-associated AD.

Keywords:   APOE4; Alzheimer’s disease; ApoVs; IGF2; Pericytes

DOI:  https://doi.org/10.1186/s40035-025-00512-6
Clin Rheumatol. 2025 Nov 14.

Initial assessment of blood-brain barrier permeability alterations and associated clinical characteristics in patients with primary Sjögren's syndrome: Insights from DCE-MRI.

Zhicheng Liu, Yifan Yang, Shuang Liu, Guofang Zhang, Ruotong Zhao, Xinyu Xu, Ru Bai, Shu Li, Yuqi Cheng, Jian Xu.

   OBJECTIVE: To quantitatively evaluate blood-brain barrier (BBB) permeability alterations in primary Sjögren's syndrome (pSS) using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and their associations with clinical immune-inflammatory indicators.
METHODS: In this retrospective study, 19 pSS patients and 23 controls underwent 3.0 T DCE-MRI. BBB permeability was quantified using voxel-wise Ktrans maps on the Patlak model. Whole-brain voxel-wise t-tests were conducted with age and sex as covariates, followed by threshold-free cluster enhancement (TFCE) (1000 permutations, P_TFCE < 0.05) and exploratory uncorrected analysis (P_uncorr < 0.005, cluster ≥ 50 voxels). Whole-brain and ROI Ktrans values were analyzed by ANCOVA with the same covariates. Correlations between regional Ktrans and clinical markers were evaluated by Pearson/Spearman tests and multivariate regression.
RESULTS: Voxel-wise analysis using TFCE correction (P_TFCE < 0.05) identified significantly elevated Ktrans values in the right cerebellum, whereas exploratory uncorrected analysis (P_uncorr < 0.005, cluster size ≥ 50 voxels) revealed increases in right cerebellum, right temporal pole of the middle temporal gyrus, and right inferior temporal gyrus. No significant differences were observed in whole-brain mean Ktrans (P > 0.05) or ROI Ktrans (all P_uncorr > 0.05). Uncorrected correlations indicated positive associations between regional mean Ktrans and serum globulin, IgM, ESR, and platelets; only limbic Ktrans remained significantly correlated with globulin after FDR correction. Multivariate regression confirmed globulin and ESR as independent predictors of regional Ktrans elevation.
CONCLUSION: This study provides the first in vivo DCE-MRI evidence of focal BBB permeability alterations in pSS, potentially associated with immune activation and systemic inflammation. These preliminary findings suggest that DCE-MRI may enable early detection of subclinical central nervous system involvement in pSS and provide insights into its underlying neuroimmunological mechanisms. Key Points • First in vivo DCE-MRI evidence of focal BBB permeability alterations in pSS. • Elevated Ktrans values, especially in the right cerebellum, were correlated with serum globulin and ESR levels, suggesting that BBB alterations may be associated with immune activation and systemic inflammation. • DCE-MRI may serve as a sensitive, noninvasive tool for detecting subclinical CNS involvement in pSS.

Keywords:  Autoimmune diseases; Blood–brain barrier; Central nervous system; Dynamic contrast-enhanced MRI; Primary Sjögren's syndrome

DOI:  https://doi.org/10.1007/s10067-025-07806-0
Mater Today Bio. 2025 Dec;35 102453

Attenuation of blood-brain barrier dysfunction by functionalized gold nanoparticles against amyloid-β peptide in an Alzheimer's disease-on-a-chip model.

Andreas Arellano, Sujey Palma-Florez, Pablo Cabrera, Elizabeth Cortés-Adasme, Karen Bolaños, Freddy Celis, Aurora J Araya-Vergara, Melina Pérez, Andrés Crespo, Maycol Huerta Matus, Eyleen Araya, Rebeca Aldunate, Marcelo J Kogan, Josep Samitier, Anna Lagunas, Mònica Mir, Natalia Hassan.

  Gold nanoparticles (GNP) are highly valuable in nanotechnology due to their biocompatibility and unique physicochemical properties, which make them attractive as nanocarriers for targeted drug delivery. In the context of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), GNP hold promise for reducing the toxicity of Amyloid-β peptide (Aβ) aggregates. However, a major challenge in developing new therapies for NDDs lies in the limited reliance on animal models and the difficulty of crossing the blood-brain barrier (BBB). This study investigates the effects of GNP on Aβ toxicity using a human-based BBB-organ-on-a-chip model (BBB-oC), mimicking the 3D cellular architecture of the BBB under both normal and pathological conditions. We rationally designed a novel nanosystem functionalized with the peptide D3, which functions both as a selective Aβ toxicity inhibitor and a BBB-targeting agent. The results show that GNP can cross the BBB, reduce the Aβ-induced cytotoxicity, and promote the maintenance of the BBB integrity. Moreover, controlling the shape of GNP further enhanced their protective effect. Overall, this work highlights the feasibility of rationally designed GNP as a promising therapeutic strategy for AD, evaluated through a more reliable and predictive human-relevant model.

Keywords:  Alzheimer's disease; Amyloid-β peptide; Blood-brain barrier; Gold nanoparticles; Microfluidic; Organ-on-a-chip

DOI:  https://doi.org/10.1016/j.mtbio.2025.102453
Nutrients. 2025 Oct 29. pii: 3404. [Epub ahead of print]17(21):

Nutritional Modulation of the Endogenous Antioxidant System in the Brain-Gut Axis Following Traumatic Brain Injury.

Nicla Tranchida, Francesca Inferrera, Rosalba Siracusa, Daniela Impellizzeri, Ramona D'Amico, Rosanna Di Paola, Marika Cordaro, Roberta Fusco.

  Background/Objectives: Traumatic brain injury (TBI) disrupts both the intestinal epithelium and blood-brain barrier (BBB), contributing to oxidative stress, neuroinflammation, and behavioral impairments. Vitis vinifera leaf (VVL) extract possesses antioxidant and anti-inflammatory properties, but its protective effects on the brain-gut axis following TBI remain unclear. This study aimed to evaluate whether VVL supplementation preserves barrier integrity and improves neurobehavioral outcomes after TBI. Methods: A murine model of TBI was used, with animals receiving daily oral supplementation of the VVL extract. Neurobehavioral performance was assessed through behavioral testing, while histopathological examinations, biochemical assays, and gene expression profiling were performed to evaluate neuronal and intestinal integrity, antioxidant defense, and inflammatory responses. Results: VVL supplementation significantly alleviated anxiety- and depression-like behaviors and preserved the structural integrity of neuronal and intestinal tissues. Antioxidant defense mechanisms were strengthened, as shown by increased catalase and superoxide dismutase activities, together with upregulation of Nrf2 and HO-1 expression. Tight junction proteins, including ZO-1 and occludin, were upregulated in both brain and gut tissues, reflecting improved barrier integrity. Furthermore, VVL markedly reduced pro-inflammatory cytokine expression. Conclusions: VVL extract confers dual protection of the gut and brain barriers after TBI by enhancing endogenous antioxidant defenses, maintaining tight junction integrity, and suppressing inflammation. These findings suggest that VVL may represent a natural therapeutic strategy to mitigate oxidative stress, neuroinflammation, and behavioral dysfunctions associated with TBI.

Keywords:  functional food; gut health; neuroinflammation; nutrition

DOI:  https://doi.org/10.3390/nu17213404
Brain Behav Immun. 2025 Nov 12. pii: S0889-1591(25)00422-2. [Epub ahead of print] 106180

Amplified microglial dysfunction and brain lesions in mouse models for comorbidity of chronic stress and cerebral hypoperfusion.

Yuan Zhang, Shunying Wang, Jie Weng, Yueyan Zhu, Jiaying Li, Daijing Sun, Yanqin Gao, Bo Yu, Yan Jiang.

  Both clinical and preclinical evidence demonstrates a robust association between mood disorders and cerebrovascular diseases, but the underlying mechanism remains elusive. In this study, to model the comorbidity of depression and cerebral hypoperfusion, we combined two different types of chronic stress paradigms, chronic unpredictable mild stress (CUMS) and social defeat (SD), with bilateral carotid artery stenosis (BCAS). Mice in the comorbidity group exhibited additive impairments in cognitive behaviors, surpassing the effects observed in the sham, stress-only, or BCAS-only groups. Notably, the most prominent change was massive microglial activation in the comorbidity group extending into critical gray matter areas, accompanied by severe brain lesion including blood-brain barrier (BBB) damage, demyelination, localized neuronal disruption, and abnormal vessel formation. Importantly, microglia emerged as central players in all observed cellular events, displayed stage-specific roles mediated by distinct subpopulations, driving neuroinflammation in response to BCAS and promoting angiogenesis under comorbid condition. Our findings suggest chronic stress impairs microglial function, increasing vulnerability to cerebral hypoperfusion. This study highlights chronic stress as a key risk factor for cerebrovascular events and underscores the importance of stress management in patients with this comorbidity.

Keywords:  Carotid stenosis; Chronic stress; Depression; Ischemia; Microglia

DOI:  https://doi.org/10.1016/j.bbi.2025.106180
Mol Neurobiol. 2025 Nov 10. 63(1): 22

Minocycline Ameliorates Cognitive Impairments Without Modulating Microglial Reactivity in Sporadic Hypercholesterolemia: A Sex-Specific Analysis in Mice.

Matheus Scarpatto Rodrigues, Natalia Baltazar do Nascimento, Gabriela Joras Baumart, Taina Schons, Alex Paulo Padilha, Mariana Viana Costa, Hémelin Resende Farias, Lilian Corrêa Costa-Beber, Fernanda Telles Fróes, Ariadni Mesquita Peres, Ricardo Maia Dantas, Alessandra Gonçalves Machado, Lucas Santos, Rachel Krolow Bast, Josiane Budni, Daniel Pens Gelain, Jose Claudio Fonseca Moreira, David Engblom, Andreza Fabro de Bem, Jade de Oliveira.

  High blood cholesterol levels have been progressively recognized as an important risk factor for dementia, yet the underlying mechanisms remain poorly understood. Emerging evidence indicates that blood-brain barrier (BBB) dysfunction and microglia-mediated neuroinflammation are key mechanisms contributing to the cognitive decline associated with hypercholesterolemia. In this study, we investigated sex-dependent differences in cognitive impairments, synaptic protein levels, microglial reactivity, and neurovascular changes associated with sporadic hypercholesterolemia, as well as the potential modulatory effects of minocycline. Adult male and female CF-1 mice (3-month-old) were fed either a normal or high-fat high-cholesterol diet for 8 weeks, with daily oral minocycline administered during the final 4 weeks. Mice fed a cholesterol-rich diet exhibited a significant increase in plasma cholesterol levels, which remained unaffected by minocycline treatment. Hypercholesterolemia was associated with memory deficits in the object recognition task, accompanied by decreased claudin-5 expression, reduced numbers of lectin-positive cells, and diminished microglial presence in the hippocampal perivascular area. While minocycline treatment ameliorated cognitive deficits and increased claudin-5 levels and lectin-positive cell numbers in the hippocampus, no significant effects of either diet or treatment were observed on classical microglial reactivity parameters. In addition, diet seemed to impact the content of synaptophysin in the prefrontal cortex and hippocampus. Notably, female mice exhibited greater susceptibility to hypercholesterolemia-induced metabolic and cognitive alterations and showed a more pronounced response to minocycline treatment compared to males. Overall, our findings highlight sex-dependent differences in susceptibility to hypercholesterolemia-induced cognitive dysfunction and in the therapeutic response to minocycline. These results underscore the relevance of BBB alterations and perivascular microglial changes, independent of classical microglial activation, in the pathophysiology of hypercholesterolemia-associated cognitive impairment.

Keywords:  Blood–brain barrier; Cognition; Microglia; Minocycline; Sex differences; Sporadic hypercholesterolemia

DOI:  https://doi.org/10.1007/s12035-025-05317-2
J Neuroimmunol. 2025 Nov 07. pii: S0165-5728(25)00281-4. [Epub ahead of print]410 578800

Exogenous IL-33 mitigates inflammatory responses by suppressing the NF-Κb signaling pathway, promoting blood-spinal cord barrier repair and neural functional recovery.

Minghao Xie, Yuhang Diao, Jing Zhang, Mingyu Hao, Zhitan Wang, Rui Tan, Jing Ma, Xiaojun Hu, Zhenghao Hao, Tao Zhu.

   BACKGROUND: Neuroinflammation following spinal cord injury (SCI) is a critical contributor to secondary damage. This inflammatory response disrupts the integrity of the blood-spinal cord barrier (BSCB), leading to neural tissue edema and impaired neural function. Interleukin-33 (IL-33), a tissue-derived cytokine belonging to the IL-1 family, is detectable in both tissues and blood following neural injury. While the neuroprotective effects of exogenous IL-33 have been demonstrated in models of traumatic brain injury (TBI) and epilepsy, its role in spinal cord injury remains unexplored. Therefore, this study employs a mouse spinal cord contusion model to investigate the potential role of exogenous IL-33 in BSCB repair.
METHODS: We established a spinal cord contusion model in mice and administered exogenous IL-33 via intraperitoneal injection to investigate its mechanisms in neural repair. Behavioral assessments were conducted on days 1, 3, 7, and 14 post-SCI, revealing the effects of IL-33 on long-term neural function. Additionally, immunofluorescence staining, Western blotting, ELISA, Evans blue leakage assays, TUNEL staining, hematoxylin-eosin (HE) staining, and Nissl staining were performed on day 3 or 7 post-SCI to evaluate the impact of IL-33 on neuroinflammation, BSCB integrity, and neuronal apoptosis.
RESULTS: We found that exogenous IL-33 significantly promoted neural functional recovery in SCI mice, with particularly pronounced effects observed after 7 days. Subsequent analysis confirmed that IL-33 was primarily expressed in the nuclei of astrocytes following SCI and exhibited high expression levels in the spinal cord of SCI mice. Exogenous IL-33 modulated the NF-κB signaling pathway, suppressing the expression of downstream pro-inflammatory cytokines. Additionally, IL-33 inhibited microglial activation and facilitated their polarization toward an anti-inflammatory phenotype, thereby mitigating spinal cord inflammation.Furthermore, the administration of recombinant IL-33 increased the expression of tight junction proteins, including ZO-1, Occludin, and Claudin-5. These changes contributed to BSCB repair, reducing spinal cord edema and improving neurological recovery in mice. Lastly, IL-33 demonstrated a protective effect against neuronal apoptosis, further underscoring its neuroprotective potential.
CONCUSION: In summary, we demonstrated the anti-inflammatory and anti-apoptotic effects of exogenous IL-33, elucidating its underlying mechanisms. Notably, we identified its role in promoting BSCB repair for the first time. These findings support the potential use of exogenous IL-33 as a therapeutic strategy for early intervention in spinal cord injury.

Keywords:  Apoptosis; Blood-spinal cord barrier; Inflammation; Interleukin-33; Spinal cord injury

DOI:  https://doi.org/10.1016/j.jneuroim.2025.578800
Lab Chip. 2025 Nov 12.

An ischemic stroke-on-a-chip model integrated with machine learning for screening of drug candidates.

Jiayue Liu, Peng Wang, Peihan Lian, Jianhua Qin.

Ischemic stroke is a leading cause of death and long-term disability worldwide, characterized by the sudden loss of cerebral blood flow, resulting in energy failure, oxidative stress, inflammation, and blood-brain barrier (BBB) disruption. Despite their clinical significance, current preclinical models inadequately recapitulate the multifaceted pathophysiology of cerebral ischemia, hindering systematic therapeutic exploration. Here, we engineered a human iPSC-derived BBB-on-a-chip (iBBB-on-a-chip) platform that can simulate ischemic pathology through controlled oxygen-glucose deprivation. The model exhibited characteristic features of ischemia-induced BBB impairment, including disruption of endothelial tight junctions, pericyte fragmentation, and increased permeability. By integrating transcriptomic profiling with a weighted gene co-expression network analysis algorithm, we identified stroke-related pathways and applied machine learning (random forest and LASSO) to screen hub genes for biomarker discovery. Using the Connectivity Map database and molecular docking calculations, we identified coumarin as a potential therapeutic agent and experimentally confirmed its protective role in the iBBB-on-a-chip. This strategy establishes a novel paradigm combining organ-on-a-chip technology with machine learning-driven data analysis, creating an innovative platform for the study of cerebrovascular disease and drug screening.

DOI: https://doi.org/10.1039/d5lc00517e
Eur J Neurol. 2025 Nov;32(11): e70434

Nerve Root Enhancement and Elevated Cerebrospinal Fluid Protein in Four Patients With SOD1-Linked Amyotrophic Lateral Sclerosis.

Veria Vacchiano, Cosmanna Ragucci, Giovanni Rizzo, Vitantonio Di Stasi, Francesca Pastorelli, Rita Rinaldi, Federica Provini, Emanuela Postiglione, Alessia Fiorentino, Valerio Carelli, Rocco Liguori.

   INTRODUCTION: The superoxide dismutase type 1 (SOD1) gene has been implicated in both sporadic and familial forms of amyotrophic lateral sclerosis (ALS). We report four ALS cases carrying pathogenic or likely pathogenic SOD1 variants, characterized by albuminocytologic dissociation and nerve root enhancement.
METHODS: We present the results of the diagnostic work-up, including lumbosacral magnetic resonance imaging (MRI) with gadolinium, electromyography (EMG), and cerebrospinal fluid (CSF) analysis. We also assessed the relationship between the albumin quotient (Q-Alb)-an index of blood-brain barrier (BBB) dysfunction-and the disease progression rate (DPR) in 12 SOD1-linked ALS patients (including the four described above) and in a cohort of 137 non-genetic ALS (NgALS) cases.
RESULTS: The four patients presented with spinal onset (progressive lower limb weakness). The EMG ultimately showed diffuse subacute neurogenic changes, while CSF analysis revealed albuminocytologic dissociation. Lumbosacral MRI demonstrated contrast enhancement of the cauda equina roots. Immunomodulatory treatment was administered due to suspected immune-mediated neuropathy, but all patients continued to deteriorate. Genetic testing revealed pathogenic or likely pathogenic variants in the SOD1 gene, confirming the diagnosis of ALS. CSF Q-Alb and protein levels were similarly distributed between SOD1-linked and NgALS patients. Q-Alb and CSF protein levels showed a positive correlation with DPR in SOD1-linked patients (Rho = 0.625, p = 0.03; Rho = 0.755, p = 0.005), but not in NgALS patients.
CONCLUSION: Albuminocytologic dissociation and nerve root enhancement may occur in SOD1-related ALS, expanding the spectrum of atypical ALS phenotypes.

Keywords:  SOD1 gene; albuminocytologic dissociation; amyotrophic lateral sclerosis; nerve root enhancement

DOI:  https://doi.org/10.1111/ene.70434