bims-blobar 2025-08-10 papers

bims-blobar

Biomed News

on Blood brain barrier repair

Issue of 2025–08–10
25 papers selected by
Nicolas Rebergue

Mechanobiology of the blood-brain barrier during development, disease and ageing.
Neurovascular Restoration by Treadmill Exercise Attenuates Age-Related Cognitive Decline in Mice.
Combined Effects of Exercise and Vitamin D on Neuroinflammation, Blood-Brain Barrier Integrity, Oxidative Stress, and Cognitive Function in Nonpathological Mice.
Discovery of active compounds in Danshen-Chuanxiong formula for blood-brain barrier protection: a multi-parametric study using an OGD/R-induced spheroid model.
A mitochondrial-derived peptide MOTS-c contributes to the protective effect against brain injury associated with LPS-induced sepsis by strengthening the blood-brain barrier's ultrastructure.
Relationship between serum oxidative stress and blood brain barrier parameters in patients with major depression.
DCE-MRI reveals spatial pattern in heterogeneous blood-brain barrier leakage within white matter in cerebral small vessel disease.
Butyrate preserves entorhinal-hippocampal spatial coding and blood brain barrier integrity in mice with depleted gut microbiome.
Beyond blood-brain barrier disruption and molecular weight: compartmental kinetics of S100B and NSE for neurological prognostication after cardiac arrest.
The vascular contribution to cognitive decline in ageing and dementia.
Plasmodium falciparum egress disrupts endothelial junctions and activates JAK-STAT signaling in a microvascular 3D blood-brain barrier model.
RIPK1 kinase drove brain microvascular endothelial cells death and blood-brain barrier disruption in neonatal Escherichia coli meningitis.
Selective Deletion of NBCe1 in Reactive Astrocytes Attenuates Ischemic Stroke Brain Damage.
Correlations of retinal morphology with clinical symptoms, blood-brain barrier, and brain structure in patients with Alzheimer's disease.
Fibrinogen contributes to myelin deficit and cognitive impairment in aged mice after anesthesia and surgery.
Spatial transcriptomic profiling uncovers the molecular effects of the neurotoxicant polychlorinated biphenyls (PCBs) in the brains of adult mice.
Exploration of the Therapeutic Time Window for Thrombectomy in Rat Models of Middle Cerebral Artery Ischemia-Reperfusion.
Iridoids derived from Valeriana jatamansi Jones alleviates neuroinflammation and blood spinal cord barrier permeability after spinal cord injury by activating the Nrf2/HO-1 signaling pathway.
TREM-1 as a potential gatekeeper of neuroinflammatory responses: therapeutic validation and mechanistic insights in experimental traumatic brain injury.
Is the renin-angiotensin system a friend or foe in neurological diseases? Unveiling its role and therapeutic potential.
Neutrophil extracellular traps and neuropsychiatric lupus: Signaling pathways involved in NET formation and mechanisms affecting the central nervous system.
Brain-invading monocytes promote seizure-associated cognitive deficits and neurodegeneration.
Multiomics Profiling of Extracellular Vesicles Supports Their Involvement in Endothelial Senescence-Associated Vascular Dysfunction.
Netrin-1: Dual Roles in Neuroinflammation and Neurodegenerative Disease Dynamics.
Neutrophil extracellular traps aggravate neuronal apoptosis and neuroinflammation via neddylation after traumatic brain injury.

Nat Commun. 2025 Aug 06. 16(1): 7233

Mechanobiology of the blood-brain barrier during development, disease and ageing.

Simon Konig, Vignesh Jayarajan, Selina Wray, Roger Kamm, Emad Moeendarbary.

The blood-brain barrier (BBB) preserves brain health through selective permeability, and its disruption is a hallmark of many neurological disorders. Mechanical stimuli such as shear stress and cyclic strain are increasingly recognised to influence BBB integrity and function, while alterations in tissue stiffness and extracellular matrix composition contribute to its breakdown during ageing and disease. Despite its importance, BBB mechanobiology remains underexplored. Here we highlight the central role of mechanics in BBB development, pathology, and ageing, identify key knowledge gaps, and argue that combining innovative BBB model systems with mechanical probing techniques could transform therapeutic strategies targeting brain vascular dysfunction.

DOI: https://doi.org/10.1038/s41467-025-61888-7
Int Neurourol J. 2025 Jul;29(Suppl 1): S13-S21

Neurovascular Restoration by Treadmill Exercise Attenuates Age-Related Cognitive Decline in Mice.

Jae Min Lee, Da-Eun Sung, You Jung Choi, Seung Geun Yeo, Youn-Jung Kim.

   PURPOSE: Aging is associated with various physiological changes. These include microvascular dysfunction, which impairs cerebral blood flow and neuronal health, leading to cognitive impairment. Although exercise has demonstrated beneficial effects on aging, its specific impact on age-related microvascular dysfunction and blood-brain barrier (BBB) disruption requires further investigation. This study aimed to evaluate whether an 8-week treadmill exercise regimen in aged mice could improve cognitive impairment by alleviating microvascular and BBB damage and reducing neuroinflammation.
METHODS: Twenty-month-old C57BL/6J male mice engaged in a treadmill exercise program for 60 minutes daily over 8 weeks. Cognitive function was assessed using the passive avoidance test. Microvascular integrity was evaluated by measuring microvessel length and fragmentation in the cortex using platelet endothelial cell adhesion molecule-1 as a marker. Activation of microglia and astrocytes was determined by analyzing the expression of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein through immunohistochemistry and immunofluorescence. BBB integrity was assessed by examining the expression levels of tight junction proteins, including zonula occludens-1, occludin, claudin-9, and platelet-derived growth factor receptor beta (PDGFRβ), in the cortex via immunostaining and western blotting.
RESULTS: Treadmill exercise significantly improved cognitive function, as indicated by increased latency time in the passive avoidance test. Exercise intervention also increased microvessel length and decreased microvessel fragmentation in the cortex. Additionally, treadmill exercise reduced the activation of microglia and astrocytes, thereby decreasing neuroinflammatory responses. Furthermore, treadmill exercise preserved BBB integrity by maintaining the expression of tight junction proteins and PDGFRβ, counteracting age-related declines.
CONCLUSION: The findings suggest that regular treadmill exercise mitigates cognitive impairment and vascular dysfunction associated with aging by improving microvascular health and BBB integrity. These results highlight the potential of exercise intervention as a non-pharmacological strategy for treating age-related neurodegenerative diseases by preserving vascular and BBB structures and reducing neuroinflammation.

Keywords:  Aging; Bood-brain barrier; Cognitive impairment; Neuroinflammation; Treadmill exercise

DOI:  https://doi.org/10.5213/inj.2550118.059
Int Neurourol J. 2025 Jul;29(Suppl 1): S22-S34

Combined Effects of Exercise and Vitamin D on Neuroinflammation, Blood-Brain Barrier Integrity, Oxidative Stress, and Cognitive Function in Nonpathological Mice.

Taewan Kim, Donghyun Kim, Yoonhwan Kim, Jeonghyeon Kim, Seamon Kang, Jinkyung Cho.

   PURPOSE: This study investigated whether the combined application of treadmill exercise and vitamin D injections exerts neuroprotective effects in nonpathological mice by enhancing cognitive function, regulating immune responses, preserving blood-brain barrier (BBB) integrity, and improving mitochondrial efficiency.
METHODS: Forty male C57BL/6 mice were randomly assigned to control, exercise (EX), vitamin D (VD), or combined treatment (EXVD) groups. After 20 weeks of intervention, behavioral, molecular, and cellular analyses were performed to assess cognitive function, immune responses, BBB integrity, oxidative stress, and mitochondrial efficiency.
RESULTS: The EXVD group demonstrated superior spatial learning and memory compared to the other groups. Vitamin D treatment significantly increased plasma interleukin-10 and tight junction protein levels, while exercise alone elevated hippocampal tumor necrosis factor-α. Combined treatment reduced astrocyte activation, maintained BBB integrity, and improved mitochondrial respiratory efficiency without increasing oxidative stress. Expression of antioxidant enzymes was decreased in the VD and EXVD groups, indicating improved redox balance.
CONCLUSION: Treadmill exercise and vitamin D injections confer neuroprotective effects in nonpathological mice by enhancing cognition, reducing neuroinflammation, and improving both BBB integrity and mitochondrial function. These findings highlight the potential of nonpharmacological strategies to support brain health even in the absence of disease.

Keywords:  Blood-brain barrier; Exercise; Mitochondria; Neuroinflammation; Oxidative stress; Vitamin D

DOI:  https://doi.org/10.5213/inj.2550140.070
J Nat Med. 2025 Aug 09.

Discovery of active compounds in Danshen-Chuanxiong formula for blood-brain barrier protection: a multi-parametric study using an OGD/R-induced spheroid model.

Yue Zhou, Yiran Li, Zhenzhong Yang, Lu Zhao, Yule Wang.

  Blood-brain barrier (BBB) dysfunction is a well-established pathological phenotype of ischemic stroke, and targeting BBB integrity has emerged as a promising therapeutic strategy. Danshen-Chuanxiong formula (DS-CX), an effective herbal combination against ischemic stroke, has demonstrated regulatory effects on the BBB at various stages of ischemic stroke. However, its specific BBB-protective components and underlying molecular mechanisms remain unclear. Recent advances in multicellular self-assembled BBB spheroids have shown distinct advantages in disease modeling and drug discovery, offering a novel approach to address these questions. To simulate ischemic stroke-induced BBB dysfunction, we developed an oxygen-glucose deprivation/reoxygenation (OGD/R)-induced BBB disruption model using multicellular spheroids. To identify the effective substances of DS-CX responsible for BBB protection, we conducted a multi-parametric evaluation to assess BBB permeability, tight junctions, cell viability, reactive oxygen species (ROS) levels, inflammatory markers, and apoptotic phenotypes using high-content imaging. Further immunofluorescence and transcription analyses were performed to elucidate the BBB-protective mechanisms of DS-CX and its active components. Similar to the overall effects of DS-CX on BBB protection, preliminary screening fortunately found that both protocatechuic acid, ferulic acid, and senkyunolide I significantly reduced OGD/R-induced leakage, and upregulated the protein and mRNA levels of ZO-1 and Claudin-5 in BBB spheroids. Further multi-phenotypic assessments manifested that DS-CX and its active compounds effectively improved cell survival, reduced ROS production, inhibited inflammation, and decreased apoptosis, compared to the damaged BBB spheroids without drug intervention. Molecular experiments showed that DS-CX and its active constituents not only rescued the abnormal protein levels of pivotal targets related to oxidative stress (HO-1), inflammation (MMP-9, TLR-4), and apoptosis (Caspase-3, Bax, Bcl-2) in OGD/R-treated BBB spheroids, but also normalized the dysregulated mRNA levels of vWF, HO-1, MMP-9, TLR-4, TNF-α, IL-6, IL-1β, and IL-18 caused by OGD/R stimulation. Collectively, the present work successfully identified protocatechuic acid, ferulic acid, and senkyunolide I as key BBB-protective components of DS-CX against ischemic stroke. These compounds likely exert their therapeutic effects through multi-target regulation of oxidative stress, inflammation, and apoptosis. Our findings provide a novel spheroid-based multi-parametric screening approach for discovering BBB-targeted therapies in ischemic stroke.

Keywords:  3D spheroid-based disruption model of BBB; Active compounds; BBB protection; Danshen–Chuanxiong formula; Multi-phenotypic and multi-parametric evaluation

DOI:  https://doi.org/10.1007/s11418-025-01939-x
Int J Neurosci. 2025 Aug 05. 1-14

A mitochondrial-derived peptide MOTS-c contributes to the protective effect against brain injury associated with LPS-induced sepsis by strengthening the blood-brain barrier's ultrastructure.

Yuanyuan Bai, Haiyan Wu, Xu Wang, Yang Guo, Bingqing Gong, Beibei Dong, Yonghao Yu.

   BACKGROUND: Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis, increasing short-term and long-term mortality. It involves neuroinflammation, neuronal damage, and blood-brain barrier (BBB) disruption. MOTS-c, a mitochondrion-derived peptide, exerts neuroprotective effects by modulating inflammatory responses and cellular functions. This study explored the protective effects of MOTS-c against brain injury in mice with LPS-induced sepsis.
METHODS: A mouse model of sepsis was established via intraperitoneal injection of LPS. The mice were divided into four groups: Control, Control + MOTS-c, LPS, and LPS + MOTS-c groups. The mice in the latter two groups received MOTS-c (20 mg/kg) four hours before model establishment. Survival rates and the murine sepsis score (MSS) were recorded. H&E staining, ELISA, Evans blue staining, brain water content detremination, immunofluorescence staining, western blotting, and qPCR were performed to assess brain tissue damage, inflammation, BBB permeability, and BBB-related protein expression.
RESULTS: MOTS-c treatment increased the survival rate, decreased the MSS score, alleviated brain tissue damage, downregulated the expression of inflammatory factors, reversed the increase in BBB permeability, upregulated the expression of BBB-related proteins and CD31/PDGFRβ, decreased the expression of GFAP/Iba-1/MMP-9, and increased the expression of neurotrophic factors in septic mice.
CONCLUSION: MOTS-c effectively reduced mortality rates and the MSS, attenuated neuroinflammatory responses, mitigated increase in BBB permeability, promoted neurotrophic factor production, and protecting against brain injury in mice with LPS-induced sepsis.

Keywords:  MOTS-c; Sepsis-associated encephalopathy; blood-brain barrier; inflammation; neurotrophic factors; ultrastructure

DOI:  https://doi.org/10.1080/00207454.2025.2542883
J Psychiatr Res. 2025 Aug 02. pii: S0022-3956(25)00460-1. [Epub ahead of print]190 25-31

Relationship between serum oxidative stress and blood brain barrier parameters in patients with major depression.

Hatice Solak, Merve Akkuş, Pınar Aydogan Avşar.

   OBJECTIVE: Research emphasises the critical role of blood-brain barrier (BBB) integrity in psychiatric disorders. This study aimed to investigate the relationship between serum Zonula occludens protein - 1 (ZO-1) and serum occludin levels, which are blood brain barrier markers, and serum oxLDL levels, which are known to be associated with oxidative stress and inflammation, in patients with major depression.
METHODS: The study included 44 drug-naïve patients diagnosed with Major Depressive Disorder (MDD) and 48 healthy controls matched for Body Mass Index (BMI), gender, age. Laboratory data, together with concentrations of Ox-LDL, Occludin, ZO-1, were evaluated. The Hamilton Depression Rating Scale (HADRS) was employed to evaluate the severity of depression in the major depression cohort.
RESULT: Compared to healthy controls, patients with major depression exhibited significantly lower serum levels of ZO-1 (p = 0.001) and occludin (p = 0.001), while oxLDL levels were significantly higher (p = 0.001). The differences maintained as significant after corrections for age, sex, smoking, and BMI via ANCOVA (all p = 0.001). A positive correlation was identified between ZO-1 and occludin levels (r = .400, p = 0.001), whereas a negative correlation was found between ZO-1 and oxLDL levels (r = -.369, p = 0.001).
CONCLUSION: This study's findings indicate that serum oxLDL levels, related with oxidative stress and inflammation in the pathogenesis of MDD, may influence the alteration of serum ZO-1 and occludin levels, recognised as indicators of the BBB.

Keywords:  1 (ZO-1); Major depressive disorder; Ox-LDL; Zonula occludens protein; occludin

DOI:  https://doi.org/10.1016/j.jpsychires.2025.07.023
J Cereb Blood Flow Metab. 2025 Aug 04. 271678X251364151

DCE-MRI reveals spatial pattern in heterogeneous blood-brain barrier leakage within white matter in cerebral small vessel disease.

Damon Verstappen, Joost J A de Jong, Paulien H M Voorter, Maud van Dinther, Robert J van Oostenbrugge, Julie Staals, Jacobus F A Jansen, Walter H Backes.

  Cerebral small vessel disease (cSVD) is associated with vascular cognitive impairment, dementia, and stroke. Blood-brain barrier (BBB) dysfunction is central to its pathophysiology and is involved in the formation of tissue lesions. The spatial heterogeneity of BBB leakage remains largely unclear. This cross-sectional study assessed BBB leakage rate (Ki), fractional volume of leaking tissue (vl), and blood plasma volume (vp) in various tissue regions, including gray matter (GM), normal appearing white matter (NAWM), and white matter hyperintensities (WMH) of 59 patients with cSVD and 32 controls using a high spatial resolution dynamic-contrast enhanced MRI protocol. Using regionally averaged measures, patients with cSVD had higher vl (p = 0.020) and lower vp (p < 0.001) within WMH compared to controls, Ki did not differ in any region. To evaluate the spatial heterogeneity of leakage in the NAWM, we analyzed 2-mm-wide shells extending outward from WMH edges. This revealed stronger BBB leakage in perilesional NAWM (p = 0.032) of cSVD patients compared to controls, with a striking dip close to the WMH. Ki, vl, and vp increased with distance from WMH edges (all p < 0.001). This pattern of lower BBB leakage in the perilesional NAWM could be caused by local reductions in microvascular blood flow or vessel surface area.

Keywords:  Blood-brain barrier; Cerebral small vessel disease; Dynamic contrast-enhanced MRI; Vascular cognitive impairment; White matter hyperintensities

DOI:  https://doi.org/10.1177/0271678X251364151
bioRxiv. 2025 Jul 31. pii: 2025.07.24.666609. [Epub ahead of print]

Butyrate preserves entorhinal-hippocampal spatial coding and blood brain barrier integrity in mice with depleted gut microbiome.

Joshua M Glynn, Joshua J Strohl, Ciara Bagnall-Moreau, Joseph Carrión, Patricio T Huerta.

Given the widespread and increasing consumption of oral antibiotics globally, understanding their impact on cognition through the gut-brain axis is crucial. We investigated whether broad-spectrum antibiotics disrupt spatial cognition by altering behavior, neural dynamics, brain metabolism, and blood- brain barrier integrity. Here we show that male mice receiving antibiotic-treated water display significant impairments in spatial memory tasks and abnormal encoding of space by entorhinal grid cells and hippocampal place cells. These cognitive deficits are accompanied by altered brain metabolism and blood-brain barrier permeability in the hippocampal formation. Remarkably, supplementation with butyrate, a key microbiome-derived metabolite, preserves spatial cognition, neural dynamics, and blood-brain barrier function despite antibiotic treatment. These findings reveal that gut microbiome depletion disrupts the hippocampal-entorhinal network underlying spatial cognition, while suggesting butyrate supplementation as a potential therapeutic approach to mitigate antibiotic-induced cognitive impairments.

DOI: https://doi.org/10.1101/2025.07.24.666609
Crit Care. 2025 Aug 04. 29(1): 342

Beyond blood-brain barrier disruption and molecular weight: compartmental kinetics of S100B and NSE for neurological prognostication after cardiac arrest.

So-Young Jeon, Changshin Kang, Yenho You, Jung Soo Park, Jin Hgon Min, Wonjoon Jeong, Hyun Shik Ryu, Jiyoung Choi, Byung Kook Lee.

   BACKGROUND: The prognostic value of serum biomarkers after out-of-hospital cardiac arrest (OHCA) depends on timing, but the physiological basis remains unclear. We investigated whether blood-brain barrier (BBB) integrity and biomarker-specific properties explain the time-dependent differences in prognostic performance.
METHODS: This retrospective study included comatose adult OHCA survivors who underwent paired serum and cerebrospinal fluid (CSF) measurements of neuron-specific enolase (NSE; 47 kDa) and S100 calcium-binding protein B (S100B; 21 kDa) at 0 (H0), 24 (H24), 48 (H48), and 72 (H72) h after return of spontaneous circulation. BBB disruption was assessed using the CSF/serum albumin quotient (QA). Prognostic performance was assessed using AUC analysis for 6-month poor neurological outcome (Cerebral Performance Category 3-5).
RESULTS: Among 111 patients (59% poor outcome), 646 serum and 620 CSF samples were analyzed. BBB disruption was more severe in the poor outcome group at all timepoints (all P < 0.001), peaking at H24 (QA 0.0282 [IQR 0.0150-0.120]) and remaining elevated at H72 (0.0228 [IQR 0.0147-0.0598]). In the poor outcome group, serum S100B levels peaked at H0 (0.80 ng/mL [IQR 0.39-2.81]) and declined despite a persistent elevation in CSF levels at or above the upper detection limit (≥ 30 ng/mL). Conversely, NSE levels progressively increased in both compartments, with serum and CSF levels increasing in parallel over time. Serum NSE concentrations showed a time-dependent improvement in prognostic accuracy, peaking at H72 (AUC 0.88), whereas S100B concentrations maintained stable performance across all timepoints (AUCs 0.79-0.85, all P > 0.4). Notably, the prognostic performance of S100B remained relatively consistent regardless of BBB disruption severity, whereas NSE showed progressively improved predictive accuracy with increased BBB disruption. Across all timepoints, CSF biomarkers-particularly S100B and NSE-showed consistently higher AUCs than serum, suggesting superior prognostic utility.
CONCLUSIONS: Serum NSE levels closely reflect the degree of BBB disruption and CSF levels, while S100B exhibits a transient early-phase profile, with decreased serum detectability over time, even in the presence of sustained CSF elevation or severe BBB disruption. These findings highlight the importance of interpreting biomarker kinetics across compartments and timepoints rather than relying on molecular weight or BBB status alone.

Keywords:  Biomarker; Blood-brain barrier integrity; Cerebrospinal fluid; Compartment kinetics; Molecular weight; Neuron-specific enolase; Out-of-hospital cardiac arrest; Prognostication timing; S100 calcium-binding protein

DOI:  https://doi.org/10.1186/s13054-025-05572-8
Nat Rev Neurosci. 2025 Aug 04.

The vascular contribution to cognitive decline in ageing and dementia.

Silvia Anderle, Michael Dixon, Tania Quintela-Lopez, George Sideris-Lampretsas, David Attwell.

There is increasing evidence to suggest that vascular dysfunction can contribute to cognitive decline in ageing and dementia. This dysfunction can take the form of a reduction of cerebral blood flow (CBF), a loss of blood-brain barrier (BBB) function or a combination of the two. Indeed, CBF and BBB changes may be causally linked, although this possible causality and its directionality are understudied. Appreciation of the role of vascular dysfunction in initiating cognitive decline in ageing and dementia, as well as the mechanisms involved, is important because it opens up new avenues for the development of much-needed therapies for these conditions, which are becoming major causes of death. Here we assess the evidence for the importance of vascular contributions to dementia, draw parallels with changes that occur in normal ageing and discuss the initiating cells and signalling mechanisms involved. We suggest that attempting to maintain or restore CBF should be a central aim of therapeutic strategies.

DOI: https://doi.org/10.1038/s41583-025-00950-1
Nat Commun. 2025 Aug 06. 16(1): 7262

Plasmodium falciparum egress disrupts endothelial junctions and activates JAK-STAT signaling in a microvascular 3D blood-brain barrier model.

Livia Piatti, Alina Batzilla, Fumio Nakaki, Hannah Fleckenstein, François Korbmacher, Rory K M Long, Daniel Schraivogel, John A Hawkins, Tais Romero-Uruñuela, Borja López-Gutiérrez, Silvia Sanz Sender, Yannick Schwab, Lars M Steinmetz, James Sharpe, Maria Bernabeu.

Cerebral malaria is a severe neurovascular complication of Plasmodium falciparum infection, with high mortality rates even after treatment with effective antimalarials. Limitations in current experimental models have hindered our knowledge of the disease. We developed a 3D blood-brain barrier (BBB) model with enhanced barrier properties using primary brain endothelial cells, astrocytes, and pericytes. Exposure to parasite egress products increases microvascular permeability, likely due to transcriptional downregulation of junctional and vascular development genes in endothelial cells. In addition, it increases the expression of ferroptosis markers, antigen presentation and type I interferon genes and upregulates the JAK-STAT pathway across all BBB cell types. Incubation with cytoadherent schizont-stage P. falciparum-infected erythrocytes induces a similar, but highly localized transcriptional shift, along with inter-endothelial gaps at sites of parasite egress, leading to enhanced permeability. Treatment with the JAK-STAT inhibitor Ruxolitinib prevents the increase in permeability induced by P. falciparum egress products. These findings provide key insights into the parasite-mediated mechanisms driving brain microvascular pathogenesis in cerebral malaria and suggest potential avenues for adjunctive therapies.

DOI: https://doi.org/10.1038/s41467-025-62514-2
Nat Commun. 2025 Aug 07. 16(1): 7309

RIPK1 kinase drove brain microvascular endothelial cells death and blood-brain barrier disruption in neonatal Escherichia coli meningitis.

Xuhang Wang, Yuhan Zhang, Xinru Chen, Kailai Fu, Jiaqi Cui, Jiaoling Wu, Yu Sun, Jianluan Ren, Feng Xue, Jianjun Dai, Fang Tang.

Neonatal meningitis Escherichia coli (NMEC) breaching the blood-brain barrier (BBB) is a critical event in the development of E. coli meningitis. Brain microvascular endothelial cells (BMECs), the primary structural component of the BBB, play a central role in defending against pathogen invasion. In this study, we employ the NMEC strain RS218 (O18:K1:H7) to investigate the molecular mechanisms of cell death in BMECs and its pivotal contribution to BBB disruption. The study reveals that RS218 infection promotes assembly of the Ripoptosome complex. This leads to the coordinated activation of apoptosis, pyroptosis, and necroptosis. Notably, necroptosis can also occur through RIPK1-independent pathways. By generating Ripk1 D138N/D138N, Gsdmd -/-, and Casp8 -/- Ripk3 -/- mice, we demonstrate that the regulation of BMECs death was an important factor in BBB resistance to infection. Among these models, kinase-dead Ripk1 D138N/D138N mice exhibit the most effective BBB protection, independent of innate immune responses. Inhibition of RIPK1 kinase significantly preserves BBB integrity, and lowers RS218 invasion and neuroinflammation. Moreover, the combination of RIPK1 inhibition with antibiotics yields additive therapeutic effects. Our study advances the understanding of NMEC pathogenesis and supports the potential of RIPK1 as a therapeutic target for E. coli meningitis.

DOI: https://doi.org/10.1038/s41467-025-62760-4
Glia. 2025 Aug 05.

Selective Deletion of NBCe1 in Reactive Astrocytes Attenuates Ischemic Stroke Brain Damage.

Okan Capuk, Elise Berthold, Kathiravan Kaliyappan, Mansi Avunoori, Rajesh Muduganti, Sanjana Krishna, Shamseldin Metwally, Mary McFarland, Shanshan Song, Victoria Fiesler, Sydney Fischer, Lesley M Foley, T Kevin Hitchens, Susannah Waxman, Ian A Sigal, Shefeeq M Theparambil, Gulnaz Begum.

  The electrogenic sodium bicarbonate transporter 1 (NBCe1/Slc4a4), predominantly expressed in astrocytes, is important for brain pH regulation and homeostasis. Increased NBCe1 expression in reactive astrocytes has been associated with neuronal degeneration in ischemic stroke. However, the effects of astrocytic NBCe1 inhibition in stroke remain contradictory, and the underlying mechanisms are unclear. Here, we show that wild-type (WT) mice exhibited elevated NBCe1 expression in the peri-lesional regions at 3 days post-stroke. Astrocytic Nbce1 gene deletion in inducible Gfap-CreERT2+/-; Nbce1f/f mice (Nbce1iΔAstro) resulted in a significant reduction in NBCe1 mRNA and protein expression in astrocytes. Compared to WT stroke mice, Nbce1iΔAstro mice displayed reduced infarct volume, decreased brain swelling, improved cerebral blood flow, and accelerated neurological function recovery in the 1-5-day acute post-stroke period. Moreover, Nbce1iΔAstro stroke mice exhibited decreased blood-brain barrier (BBB) permeability, accompanied by preserved perivascular AQP4 polarization, upregulation of Kir4.1 protein expression, and reduced astrocyte domain volume. Importantly, Nbce1iΔAstro stroke brains revealed an anti-inflammatory cytokine profiling signature, marked by increased TIMP-1 expression. Together, our findings suggest that astrocytic upregulation of pH regulatory protein NBCe1 after stroke contributes to increased BBB permeability, reactive astrogliosis, inflammation, and perivascular AQP4 dysregulation. Targeting astrocytic NBCe1 may represent a promising new therapeutic strategy to mitigate astroglial dysfunction in the post-stroke brain.

Keywords:  AQP4; NBCe1; astrocytic end‐feet; brain pH homeostasis; ischemic stroke

DOI:  https://doi.org/10.1002/glia.70075
J Alzheimers Dis. 2025 Aug 08. 13872877251364736

Correlations of retinal morphology with clinical symptoms, blood-brain barrier, and brain structure in patients with Alzheimer's disease.

Jing Qi, Mingyue He, Tenghong Lian, Shuran Wang, Peng Guo, Jinghui Li, Jing Li, Dongmei Luo, Yanan Zhang, Yue Huang, Gaifen Liu, Huiying Guan, Weijia Zhang, Hao Yue, Zijing Zheng, Fan Zhang, Zhan Liu, Ruidan Wang, Wenjing Zhang, Yao Meng, Wei Zhang.

  BackgroundPatients with Alzheimer's disease (AD) displayed abnormal retinal morphology; however, its potential associations with clinical symptoms, damage of the blood-brain barrier (BBB), and brain structure are unclear.ObjectiveTo investigate the correlations of retinal morphology with clinical symptoms, BBB damage, and brain structure in AD patients.MethodsIn 97 patients with mild cognitive impairment due to AD (AD-MCI) and dementia due to AD (AD-D), retinal morphology, clinical symptoms, BBB variables in cerebrospinal fluid, and brain structure variables, including medial temporal atrophy (MTA), global cortical atrophy (GCA), and white matter hyperintensities scores were evaluated.ResultsIn AD patients, peripapillary superotemporal retinal nerve fiber layer thickness (NFLT) was positively correlated with memory score; the NFLTs of average, inferior, and inferotemporal quadrants were negatively correlated with the level of matrix metalloproteinase 3 level in cerebrospinal fluid; the NFLTs of average, superior, and inferior quadrants were negatively correlated with MTA and GCA scores; superotemporal NFLT was negatively correlated with GCA score. In AD-MCI group, superotemporal NFLT maintained a positive correlation with memory score; the NFLTs in superior and nasoupper quadrants were negatively associated with GCA score. In AD-D group, superonasal NFLT was negatively correlated with matrix metalloproteinase 9 level in cerebrospinal fluid.ConclusionsIn AD patients, thinner peripapillary NFLT mirrors worse memory, significant BBB damage, the atrophy of medial temporal lobe and cortex. In AD-MCI patients, thinner NFLT mirrors worse memory and cortical atrophy. In AD-D patients, thinner NFLT mirrors significant BBB damage.

Keywords:  Alzheimer's disease; blood-brain barrier; brain structure; clinical symptoms; retinal morphology

DOI:  https://doi.org/10.1177/13872877251364736
J Cereb Blood Flow Metab. 2025 Aug 06. 271678X251338953

Fibrinogen contributes to myelin deficit and cognitive impairment in aged mice after anesthesia and surgery.

Xueji Wang, Sufang Jiang, Tianyu Cao, Peiying Huang, Lichao Di, Jiaqi Li, Lining Huang.

  Perioperative neurocognitive disorder (PND) is a common complication of anesthesia and surgery, which is more prevalent in elderly patients. Fibrinogen is known to contribute to the pathophysiology of neurodegenerative disorders. This study investigated whether fibrinogen induces myelin deficit and cognitive impairment in aged mice after anesthesia and surgery. Here, abdominal surgery was performed on 17-month-old C57BL/6 mice to establish a PND model. Following anesthesia and surgery, cognitive function and exploratory locomotion of mice were assessed using behavioral tests. We used in vivo two-photon brain microscopy to track the perivascular accumulation of blood-derived fibrinogen in the central nervous system (CNS). Immunostaining, electron microscopy (EM), and western blotting were used to measure myelin sheath density and oligodendrocyte alterations, and inflammatory markers were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In the current study, we found that fibrinogen deposited in the CNS after blood-brain barrier (BBB) disruption, induces oligodendrocyte loss, myelin deficits and causes behavioral abnormalities in PND model. Fibrinogen depletion could reverse myelin deficits and cognitive function which induced by anesthesia and surgery. In summary, our data support that fibrinogen is a key determinant in the early pathogenesis of PND.

Keywords:  Perioperative neurocognitive disorder; blood-brain barrier; fibrinogen; myelination; oligodendrocyte

DOI:  https://doi.org/10.1177/0271678X251338953
bioRxiv. 2025 Jul 26. pii: 2025.07.24.665575. [Epub ahead of print]

Spatial transcriptomic profiling uncovers the molecular effects of the neurotoxicant polychlorinated biphenyls (PCBs) in the brains of adult mice.

Budhaditya Basu, Nicole M Breese, Sal Lombardi, Hui Wang, Xueshu Li, Destiny Tiburcio, Zachary Niemasz, Stacy E Beyer, Laura E Dean, Rachel F Marek, Michal Toborek, Hans-Joachim Lehmler, Snehajyoti Chatterjee.

Environmental toxicants, such as polychlorinated biphenyls (PCBs), are highly stable synthetic organic compounds that are present in air, water, and soil. PCBs have been identified in post-mortem human brains of individuals with neurodegenerative diseases, indicating a possible link between environmental factors and disease risk. Research has revealed an association between PCB exposure and cognitive decline. Therefore, it is crucial to evaluate how PCB mixtures relevant to humans affect brain function and cognition. To investigate the effects of PCBs on memory and transcriptomic profiles, we exposed adult male C57BL/6J mice orally to a synthetic PCB mixture daily. After seven weeks of exposure, the mice were assessed in a spatial object recognition task (SOR) to evaluate long-term spatial memory. Our findings showed that mice exposed to PCBs exhibited deficits in long-term spatial memory. To examine the molecular effects of PCB on the brain, we used a spatial transcriptomics technique to analyze gene expression changes in five brain regions: the hippocampus, neocortex, thalamus, caudal putamen, and fiber tracts. Our analysis of spatial gene expression revealed the molecular signatures influenced by PCB in these susceptible brain regions of mice. Network analysis suggests that these changes are associated with higher chlorinated PCBs present in the brain. Additionally, we show that PCB exposure disrupts the expression of tight junction proteins, which are crucial for maintaining the integrity of the blood-brain barrier (BBB). Thus, our results offer mechanistic insights into how PCB exposure affects brain function and cognition.

DOI: https://doi.org/10.1101/2025.07.24.665575
Brain Behav. 2025 Aug;15(8): e70713

Exploration of the Therapeutic Time Window for Thrombectomy in Rat Models of Middle Cerebral Artery Ischemia-Reperfusion.

Yuting He, Pengcheng Huang, Shumeng Li, Jing Lin, Xiao Ren, Ying Xiong, Yuanjian Yang, Daojun Hong.

   OBJECTIVE: To investigate the therapeutic time window of middle cerebral artery occlusion (MCAO) reperfusion in rats and the potential mechanism of injury beyond the time window.
METHODS: Male Sprague Dawley (SD) rats were randomly divided into eight groups: a sham operation group, six ischemia-reperfusion groups (reperfusion initiated 1, 2, 3, 4, 5, and 6 h after infarction, respectively), and a 24-h infarction group without reperfusion therapy. Neurological function scores were assessed 24 h after reperfusion, and then brain samples were collected to explore the mechanisms.
RESULTS: After 4 h of MCAO reperfusion for 24 h, the infarct area reached its peak, while the neurological function score reached its bottom, and both indicators exhibited a trend toward stabilization. Additionally, a significant increase in the mortality rate was observed in the 5-h group. Compared to the MCAO 2-h group, the 5-h group exhibited a significant increase in the number of dead neurons, more serious disruption of the blood-brain barrier (BBB), and elevated expression levels of IL-6, IL1-β, and TNF-α.
CONCLUSION: Taken together, our study indicates that MCAO 4 h is likely to be the therapeutic time window for thrombectomy in rat models of middle cerebral artery ischemia-reperfusion. Reperfusion injury beyond the time window leads to more severe disruption of the BBB, a significant increase in inflammatory products, and may ultimately result in a significant decline in neural function scores.

Keywords:  blood–brain barrier; cerebral ischemia; reperfusion injury; thrombolysis

DOI:  https://doi.org/10.1002/brb3.70713
Front Pharmacol. 2025 ;16 1597719

Iridoids derived from Valeriana jatamansi Jones alleviates neuroinflammation and blood spinal cord barrier permeability after spinal cord injury by activating the Nrf2/HO-1 signaling pathway.

Yongzhi He, Jiachun Lu, Rizhao Pang, Lijuan Ding, Yunyun Wang, Hua Xiao, Chao Cheng, Yushan Luo, Xiaoming Hu, Wenchun Wang.

   Background: Valeriana jatamansi Jones, a globally utilized medicinal plant, exhibits favorable pharmacological effects against depression and tumors. Iridoids derived from V. jatamansi (IRFV) promote recovery following spinal cord injury (SCI). Inflammation and disruption of the blood-spinal cord barrier (BSCB) represent key pathological processes in SCI. However, the specific effects of IRFV on neuroinflammation and BSCB integrity remain unexplored.
Methods and Results: This study aims to elucidate the functional significance and molecular mechanisms by which IRFV modulates neuroinflammation and preserves BSCB function following SCI. Experimental results demonstrated that IRFV treatment significantly enhanced locomotor recovery in SCI models. Moreover, IRFV reduced macrophage infiltration and inhibited inflammatory mediator secretion, effectively attenuating the neuroinflammatory response. IRFV also mitigated BSCB permeability alterations by suppressing tight junction disruption and structural damage. In vitro experiments revealed that IRFV attenuated oxygen-glucose deprivation/reperfusion (OGD/R)-induced endothelial cell damage and tight junction protein degradation, suggesting a potential mechanism for its BSCB protection. Critically, the protective effects of IRFV were abolished upon suppression of the Nrf2/HO-1 pathway, demonstrating its essential role in this process.
Conclusion: In conclusion, our study demonstrates that IRFV treatment activates the Nrf2/HO-1 signaling pathway, thereby suppressing neuroinflammation, mitigating blood-spinal cord barrier damage, and promoting recovery from SCI, thus highlighting its therapeutic potential.

Keywords:  Nrf2/HO-1 signaling pathway; Valeriana jatamansi Jones; blood-spinal cord barrier; neuroinflammation; spinal cord injury

DOI:  https://doi.org/10.3389/fphar.2025.1597719
Front Immunol. 2025 ;16 1636917

TREM-1 as a potential gatekeeper of neuroinflammatory responses: therapeutic validation and mechanistic insights in experimental traumatic brain injury.

Yunsheng Zhang, Yulian Zhang, Hanhan Dang, Chuanpeng Zhang, Kun He, Xu Yang, Zixi Wang, Li Zhang, Yanbing Yu.

   Background: Traumatic brain injury (TBI) triggers a cascade of neuroinflammatory responses mediated by microglial activation, which significantly contributes to secondary brain damage. While triggering receptor expressed on myeloid cells-1 (TREM-1) is a key inflammatory amplifier, its mechanistic role and therapeutic potential in TBI remain elusive. Thus, this study endeavored to elucidate the exact role of TREM-1 in experimental TBI.
Methods: A controlled cortical impact (CCI) model was established in male C57BL/6 mice to induce TBI. The temporal expression profile of TREM-1 was assessed using RNA sequencing and Western blot (WB). The TREM-1 inhibitory peptide LP17 was administered intranasally at 2 hours post-injury (hpi). Neurobehavioral assessments, histological analyses, immunofluorescence (IF), brain water content (BWC) measurement, Evans blue (EB) assays and laser speckle contrast imaging (LSCI) were performed in this study. In vitro experiments using BV2 microglial cells were conducted to investigate the molecular mechanisms underlying TREM-1-mediated inflammation. Spleen tyrosine kinase (SYK) inhibition was achieved using R406, and TREM-1 small interfering RNA (siRNA) and overexpressing plasmids were performed to validate its role in NF-κB signaling and pyroptosis quantified using WB and enzyme-linked immunosorbent assay (ELISA). Quantitative data are expressed as mean ± SD, and group comparisons were made by two-tailed Student's t-tests or one-way ANOVA with Tukey's post hoc test, with P < 0.05 considered statistically significant.
Results: TBI significantly upregulated TREM-1 expression in microglia, peaking at 3 days post-injury (dpi). Intranasal administration of the TREM-1 antagonist LP17 treatment attenuated neuroinflammation, reduced blood-brain barrier disruption, ameliorated cerebral blood flow decrease, promoted synaptic remodeling, and improved functional outcomes. Mechanistically, through its interaction with SYK, TREM-1 triggered the CARD9/NF-κB signaling and induced pyroptosis. SYK inhibition reversed these effects, confirming the necessity of the TREM-1/SYK axis in neuroinflammatory signaling. In vitro studies further demonstrated that TREM-1 overexpression enhanced SYK phosphorylation, NF-κB activation, and pyroptosis, while LP17 or R406 treatment suppressed these responses.
Conclusion: Our finding demonstrates that TREM-1 critically mediates neuroinflammation and synaptic dysfunction after TBI. Pharmacological targeting of TREM-1 attenuates neuroinflammation, reduces cerebral edema, preserves blood-brain barrier integrity, and improves functional recovery. These effects are mediated through suppression of TREM-1-dependent NF-κB signaling and pyroptosis. These results highlight TREM-1 as a promising therapeutic target for TBI.

Keywords:  NF-κB signaling; TREM-1; neuroinflammation; pyroptosis; traumatic brain injury

DOI:  https://doi.org/10.3389/fimmu.2025.1636917
Ageing Res Rev. 2025 Aug 05. pii: S1568-1637(25)00200-4. [Epub ahead of print]112 102854

Is the renin-angiotensin system a friend or foe in neurological diseases? Unveiling its role and therapeutic potential.

Pratyush Porel, Garry Hunjan, Shamsher Singh, Khadga Raj Aran.

  The renin-angiotensin system (RAS), an important regulator of body fluid and cardiovascular homeostasis, is gradually implicated in the pathogenesis of neurological diseases due to its dysregulation. In addition to their traditional functions, components of the RAS, especially angiotensin-II (Ang-II), enhance neuroinflammation, oxidative stress, and neuronal injury. Ang-II exacerbates blood-brain barrier (BBB) disruption, promotes glial activation, and contributes to neurodegeneration via the Angiotensin type 1 (AT1) receptor (AT1R) and causes neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), epilepsy, depression, and anxiety. The angiotensin (1-7) axis mediated by the Mas receptor appears to be neuroprotective, however, as it reverses the negative effects of Ang-II. In experimental models and clinical trials, blocking RAS specifically by angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) has demonstrated promise in reducing neuroinflammation and neuronal damage, especially in stroke and neurodegenerative diseases. In the current era of research, neuropharmacologists have new optimism due to emerging evidence of the promising potential of RAS-modulating drugs, such as ARBs and ACEIs, in the treatment of various neurological diseases. Since RAS imbalance causes neuroinflammation, neuronal damage, and cognitive decline in conditions including AD, PD, and MS, these drugs may offer a new treatment approach. In the current era of neuropharmacology, this technique is novel since it enables more targeted therapies to address the root causes of neurodegeneration. This review explores the molecular pathways of RAS dysregulation in various neurological diseases, highlighting its therapeutic potential and paving the way for future treatment strategies.

Keywords:  Angiotensin receptor blockers; Angiotensin-II; Angiotensin-converting enzyme; Neurological diseases; Renin-angiotensin system

DOI:  https://doi.org/10.1016/j.arr.2025.102854
Autoimmun Rev. 2025 Jul 31. pii: S1568-9972(25)00158-2. [Epub ahead of print]24(11): 103897

Neutrophil extracellular traps and neuropsychiatric lupus: Signaling pathways involved in NET formation and mechanisms affecting the central nervous system.

Xin Guan, Xiaojie He, Lingjuan Liu.

  Neuropsychiatric systemic lupus erythematosus (NPSLE) is a severe complication of systemic lupus erythematosus (SLE) that affects the central or peripheral nervous system. The clinical management of NPSLE faces significant challenges due to the absence of specific diagnostic biomarkers and the lack of standardized, evidence-based diagnostic and therapeutic protocols. Therefore, a comprehensive understanding of the pathogenesis of NPSLE and the exploration of novel therapeutic targets have become urgent priorities in current research. Recent studies have demonstrated that neutrophils and their hallmark product, neutrophil extracellular traps (NETs), play a central role in various pathological processes of NPSLE, with blood-brain barrier (BBB) disruption and the subsequent inflammatory cascade being particularly critical. This paper provides a systematic review of the molecular regulatory network of neutrophils in NPSLE, focusing on the mechanisms by which neutrophils mediate neuroimmune microenvironmental disorders through BBB damage, with the goal of offering a theoretical foundation for the precise diagnosis and treatment of this disease.

Keywords:  Blood-brain barrier; Low-density granulocytes; Neuropsychiatric lupus; Neutrophil extracellular traps; Neutrophils

DOI:  https://doi.org/10.1016/j.autrev.2025.103897
Neuropharmacology. 2025 Aug 04. pii: S0028-3908(25)00333-8. [Epub ahead of print] 110625

Brain-invading monocytes promote seizure-associated cognitive deficits and neurodegeneration.

Soheila Pourkhodadad, Wenyi Wang, Ray Dingledine, Nicholas H Varvel.

  Seizure-associated cognitive comorbidities can substantially reduce the quality of life in people with epilepsy. Neuroinflammation is an invariant feature of all chronic neurologic diseases, including epilepsy, and acute brain insults, including status epilepticus (SE). The generalized seizures of SE trigger a robust inflammatory response involving astrocytosis, erosion of the blood-brain barrier (BBB), activation of brain-resident microglia, and recruitment of blood-borne C-C chemokine receptor type 2 positive (CCR2+) monocytes into the brain. We have demonstrated that blocking monocyte recruitment into the brain via global Ccr2 knockout or systemic CCR2 antagonism with a small molecule alleviates multiple deleterious pathologies induced by SE, including BBB damage, microgliosis, and neuronal damage, following pilocarpine-induced SE. This study aimed to determine if fleeting CCR2 antagonism improves SE-associated cognitive impairments in the long term. Here, we show that brief antagonism of CCR2 after SE prevents the working memory deficit in the Y-maze and retention memory in the novel object recognition test, but does not attenuate anxiety-like behavior in the open field arena. Notably, CCR2 antagonism was neuroprotective in the cortex and the CA1 region of the hippocampus. Neuronal numbers in the CA1 hippocampus, but not the cortex, correlated with retention memory. Our results indicate that blood-borne monocytes are a viable therapeutic cellular target for preventing cognitive comorbidities and neurodegeneration associated with seizures.

Keywords:  CCR2 antagonist; Inflammation; chemokines; co-morbidities; cognition; disease prevention; epilepsy; monocyte; status epilepticus

DOI:  https://doi.org/10.1016/j.neuropharm.2025.110625
J Extracell Biol. 2025 Aug;4(8): e70078

Multiomics Profiling of Extracellular Vesicles Supports Their Involvement in Endothelial Senescence-Associated Vascular Dysfunction.

Ryan E Hogans, Yun Lin, Gabriela Grigorean, Ana Cristina Grodzki, Rachel R Mizenko, Anne Knowlton, Randy P Carney, Angie Gelli, Pamela J Lein.

  Dysfunction of vascular endothelium is characteristic of many aging-related diseases, including Alzheimer's disease (AD) and AD-related dementias (ADRD). Although it is widely posited that endothelial cell dysfunction contributes to the pathogenesis and/or progression of AD/ADRD, it is not clear how. A plausible hypothesis is that intercellular trafficking of extracellular vesicles (EVs) from senescent vascular endothelial cells promotes vascular endothelial cell dysfunction. To test this hypothesis, we compared the expression of proteins and miRNAs in EVs isolated from four sets of genetically identical early passage non-senescent (EP) versus late passage senescent (SEN) primary human coronary artery endothelial cells (HCAECs) derived from four donors. Proteomics and miRNA libraries constructed from these EV isolates were evaluated using FunRich gene ontology analysis to compare functional enrichment between EP and SEN endothelial cell EVs (ECEVs). Replicative senescence was associated with altered EV abundance and contents independent of changes in EV size. Unique sets of miRNAs and proteins were differentially expressed in SEN-ECEVs, including molecules related to cell adhesion, barrier integrity, receptor signalling, endothelial-mesenchymal transition and cell senescence. miR-181a-5p was the most upregulated miRNA in SEN-ECEVs, increasing >5-fold. SEN-ECEV proteomes supported involvement in several pro-inflammatory pathways consistent with senescence and the senescence-associated secretory phenotype (SASP). These data indicate that SEN-ECEVs are enriched in bioactive molecules implicated in senescence-associated vascular dysfunction, blood-brain barrier impairment, and AD/ADRD pathology. These observations suggest involvement of SEN-ECEVs in the pathogenesis of vascular dysfunction associated with AD/ADRD.

Keywords:  endothelial cells; extracellular vesicles; miRNAseq; proteomics; senescence

DOI:  https://doi.org/10.1002/jex2.70078
Int J Inflam. 2025 ;2025 8670048

Netrin-1: Dual Roles in Neuroinflammation and Neurodegenerative Disease Dynamics.

Hadiseh Farahani, Ali Ganji, Ghasem Mosayebi, Mohsen Ebrahimi Monfared, Ali Ghazavi.

  Netrin-1, a central axonal guidance molecule discovered for its role in neuronal development, is also essential in neurodegenerative diseases. Netrin-1 inhibits leukocyte migration and inflammation-related tissue damage outside the central nervous system. Therefore, it can be viewed as a potential biomarker for inflammatory activity in neurodegenerative diseases. Recent studies highlight the dual roles of Netrin-1 in neuroinflammation and neurodegenerative diseases. In the context of neurodegeneration, Netrin-1 demonstrates both protective and harmful effects. This review highlights recent advancements in research regarding the dual roles of Netrin-1 in neuroinflammation and neurodegeneration. We discuss its involvement in protecting the blood-brain barrier (BBB) and regulating immune cell migration and its effects on various neurodegenerative diseases. A greater understanding of the multifunctionality of Netrin-1 could potentially be employed in developing new treatment modalities.

Keywords:  Netrin-1; Parkinson's disease; multiple sclerosis; neurodegenerative diseases; neuroinflammation

DOI:  https://doi.org/10.1155/ijin/8670048
Theranostics. 2025 ;15(15): 7327-7345

Neutrophil extracellular traps aggravate neuronal apoptosis and neuroinflammation via neddylation after traumatic brain injury.

Xu Zhang, Jianye Xu, Yonggang Fan, Guihong Shi, Bo Chen, Anni Wang, Yanlin Zhu, Lei Li, Haoran Jia, Dilmurat Gheyret, Jinchao Wang, Yiyao Cao, Shenghui Li, Xin Chen, Jianning Zhang, Shu Zhang.

  Rationale: Neddylation, akin to ubiquitination, regulates various cellular processes by attaching neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) to target proteins. Its specific role in traumatic brain injury (TBI) remains poorly defined. Neutrophil extracellular traps (NETs), which accumulate at injury sites in TBI models, are linked to poor outcomes, yet the connection between NETs and neddylation remains unclear. Methods: We analyzed contused brain tissues from TBI patients and mice subjected to controlled cortical impact (CCI) using Western blotting, immunofluorescence, and immunohistochemistry. Neddylation was inhibited using MLN4924, a small-molecule NEDD8-activating enzyme (NAE) inhibitor. We conducted short-term neurobehavioral tests, Fluoro-Jade C staining, TUNEL assay, and Evans blue extravasation. Additionally, co-immunoprecipitation (Co-IP) and mass spectrometry were employed to explore the mechanisms of neddylation post-TBI. Results: Neddylation increased in neurons during the acute phase of TBI. Inhibition of neddylation with MLN4924 reduced neuronal death, mitigated proinflammatory polarization of microglia, and maintained the integrity of the blood-brain barrier (BBB). MLN4924 treatment also decreased cerebral lesion volume and improved short-term neurological outcomes. NETs induced neuronal neddylation and apoptosis, while MLN4924 rescued neurons from NET-induced apoptosis. Mechanistically, NETs promoted NEDD8 binding to the ubiquitin ligase TRIM56, facilitating STING K63-linked ubiquitination and activating the NF-kB pathway, leading to neuroinflammation and neuronal death. Conclusions: Our study revealed that NETs trigger neuronal death and neuroinflammation via neddylation. We propose that inhibiting neddylation could offer therapeutic benefits in TBI.

Keywords:  MLN4924; NEDD8; Neddylation; Neutrophil extracellular traps; traumatic brain injury

DOI:  https://doi.org/10.7150/thno.111512