bims-blobar 2025-06-22 papers

bims-blobar

Biomed News

on Blood Brain Barrier Repair

Issue of 2025–06–22
thirty-one papers selected by
Nicolas Rebergue

In Vitro Comparison of Two Python-Based Programs for the Automated Analysis of Tight-Junction Phenotype in Brain Endothelium During Bacterial Infection.
From inserts to chips: microfluidic culture and 3D astrocyte co-culture drive functional and transcriptomic changes in hiPSC-derived endothelial cells.
Different roles of astrocytes in the blood-brain barrier during the acute and recovery phases of stroke.
Iron overload and oxidative stress participated in zinc oxide nanoparticles-induced blood-brain barrier dysfunction.
Dolutegravir Inhibits Autophagy In Vitro in a Mouse Blood-Brain Barrier Model.
Protective effects of alectinib on germinal matrix hemorrhage-induced neonatal brain injury.
Deferoxamine prevents BBB disruption, neuroinflammation and apoptotic changes in early hours of ischemic reperfusion injury.
Novel Insights into the Mechanism and Treatment of Diabetes-Related Brain Complications: Focusing on the Blood-Brain Barrier Impairment.
Role of tight junctions in three-dimensional mechanical model of blood-brain barrier.
DNAJB6: A guardian against neurodegeneration.
Advances in alginate-based nanoformulations: Innovative and effective strategies for targeting and treating brain disorders.
MicroRNA-29a-5p attenuates hemorrhagic transformation and improves outcomes after mechanical reperfusion for acute ischemic stroke.
Microglia Promote Endothelial Cell Activation Through NSUN2-Mediated SQLE m5C Modification in Diabetic Retinopathy.
Propionate ameliorates neural degeneration by modulating mitochondrial fission and fusion in nerve cells.
Genetic deletion of microRNA-15a/16-1 in pericytes stimulates cerebral angiogenesis and promotes functional recovery after ischemic stroke.
Investigation of Poststroke Depression Following a Nucleus Accumbens Infarct in Mice.
Blood-brain barrier permeability in CKD: link with inflammation and cognitive and mood impairment in rats.
Pericyte-glial cell interactions: Insights into brain health and disease.
Carotid endarterectomy and blood-brain barrier permeability in subjects with bilateral carotid artery stenosis.
Retrotransposition-competent L1s are increased in the genomes of individuals with amyotrophic lateral sclerosis.
The protective effect of DMT against neurodegeneration.
Induced neural stem cells ameliorate blood-brain barrier injury by modulating the calcium signaling pathway of astrocyte in cerebral ischemia-reperfusion rats.
The FindMNDBiomarker Program: Protein Changes in Motor Neuron Disease/Amyotrophic Lateral Sclerosis Postmortem Tissue and Biofluids.
A single dose of a vectorized mAb targeting TDP-43 potently inhibits the neuropathology in a model of ALS/FTD.
Microcirculation Dysfunction in Subacute Stroke: The Role of Delayed Capillary Pericyte Loss.
Plasma glial fibrillary acidic protein as a biomarker of blood-brain barrier integrity in patients with occult cerebral small vessel disease.
Bilirubin: a game-changer in alzheimer's therapy? Unveiling its neuroprotective and disease-modifying potential.
Repeated Low-Level Inflammatory Challenge Leads to Alterations in the TNF-CXCL10 Signalling Pathway in Mouse Cerebral Endothelial Cells In Vitro.
Cola acuminata extract's inhibition of NLRP3 inflammasome in THP-1 cells as a potential treatment option for Parkinson's disease.
Distinct behavioural and neurovascular signatures induced by acute and chronic stress in rats.
Applications of artificial intelligence in drug discovery for neurological diseases.

Cell Biochem Funct. 2025 Jun;43(6): e70093

In Vitro Comparison of Two Python-Based Programs for the Automated Analysis of Tight-Junction Phenotype in Brain Endothelium During Bacterial Infection.

Henry D Mauser, Janessa Caroza, Shane Nicole Homez, Alyssa S Arnett, William D Cutts, Daryl W Lam, Justin Thornton, Walter Adams, Brandon J Kim.

  Tight junction complexes are crucial features of brain endothelial cells, as they restrict the paracellular route across the blood-brain barrier. Tight junction disruption has been observed in conjunction with numerous diseases of the CNS. In such cases, the organization or integrity of cell-cell junctions may be analyzed with a variety of automated computer programs that quantitatively assess junction images. Here, we directly compare two previously developed python-based programs-JAnaP and IJOQ- for the semi- or fully automated analysis of tight junctions in human stem cell-derived brain-like endothelial cells. Cells were infected with S. pneumoniae and S. agalactiae to initiate junction disruption, and occludin and ZO-1 were analyzed in mock and infected groups via JAnaP and IJOQ. JAnaP and IJOQ both yielded comparable results for the quantification of tight junction disruption in brain endothelial cells. While JAnaP rendered data at the cellular level and gave more information regarding junction phenotype, IJOQ significantly reduced user time and eliminated potential user bias. Our results suggest that JAnaP and IJOQ are both appropriate for quantifying tight junction integrity in brain endothelial cells, and both may offer distinct advantages depending on their context of use.

Keywords:  blood–brain barrier; fluorescence microscopy; image analysis; tight junction disruption; tight junctions

DOI:  https://doi.org/10.1002/cbf.70093
Fluids Barriers CNS. 2025 Jun 16. 22(1): 58

From inserts to chips: microfluidic culture and 3D astrocyte co-culture drive functional and transcriptomic changes in hiPSC-derived endothelial cells.

Tuuli-Maria Sonninen, Sanni Peltonen, Sara Kälvälä, Hoang-Tuan Nguyen, Marika Ruponen, Prateek Singh, Šárka Lehtonen.

   BACKGROUND: The blood-brain barrier (BBB) exhibits a hurdle for drug delivery and development. In addition, the dysfunction of the BBB has been seen in several neurodegenerative diseases, although the mechanisms remain poorly understood. Thus, improved models are needed for the purposes of disease modelling and drug development. To overcome the constraints of conventional in vitro models, there has been a growing use of human induced pluripotent stem cells (hiPSCs) and organ-on-chip systems. However, the detailed characterization of these models is still mainly missing. We aimed to investigate how different culture platforms alter the functionality and, consequently, the transcriptomic phenotype of hiPSC-derived endothelial cells (ECs).
METHODS: ECs were cultured on a microfluidic BBB chip platform (AKITA plate) or a standard cell culture insert model. Furthermore, we used hiPSC-derived astrocytes in the AKITA plate format to examine their effect on ECs. Astrocytes were cultured under either 2D or 3D conditions. The impact of pore size and culture system was studied using permeability assays and protein expression. Finally, we used single-cell RNA sequencing to analyze transcriptional changes in ECs cultured on insert or AKITA plate, both with and without astrocytes.
RESULTS: First, we tested the impact of different membrane pore sizes in AKITA plate on EC morphology and barrier formation. We demonstrated that the AKITA plate supports confluent monolayer formation, even with higher pore sizes. Secondly, ECs cultured on AKITA plate showed improved barrier function and reduced migration in comparison to ECs cultured on inserts, supported by permeability experiments and transcriptomics. The single-cell RNA sequencing revealed the activation of cholesterol metabolism-related pathways in ECs cultured on an AKITA plate under flow conditions. At last, we discovered that astrocytes require 3D culture to sustain the EC monolayer. Moreover, astrocytes promote a slight shift in transcription levels by upregulating genes associated with EC-astrocyte interactions.
CONCLUSIONS: Complex cell culture systems are becoming accessible; still, additional research into their properties is needed. Our data highlights the importance of the cell environment and its impact on the cellular function and gene expression profiles. Understanding these changes can improve future models and facilitate the development of more physiologically relevant platforms.

Keywords:  Astrocyte; BBB; Co-culture; Endothelial cell; HiPSC; Microfluidic chip; Single-cell RNA sequencing

DOI:  https://doi.org/10.1186/s12987-025-00672-7
Neural Regen Res. 2025 Jun 19.

Different roles of astrocytes in the blood-brain barrier during the acute and recovery phases of stroke.

Jialin Cheng, Yuxiao Zheng, Fafeng Cheng, Chunyu Wang, Jinhua Han, Haojia Zhang, Xin Lan, Chuxin Zhang, Xueqian Wang, Qingguo Wang, Changxiang Li.

   ABSTRACT: Ischemic stroke, a frequently occurring form of stroke, is caused by obstruction of cerebral blood flow, which leads to ischemia, hypoxia, and necrosis of local brain tissue. After ischemic stroke, both astrocytes and the blood-brain barrier undergo morphological and functional transformations. However, the interplay between astrocytes and the blood-brain barrier has received less attention. This comprehensive review explores the physiological and pathological morphological and functional changes in astrocytes and the blood-brain barrier in ischemic stroke. Post-stroke, the structure of endothelial cells and peripheral cells undergoes alterations, causing disruption of the blood-brain barrier. This disruption allows various pro-inflammatory factors and chemokines to cross the blood-brain barrier. Simultaneously, astrocytes swell and primarily adopt two phenotypic states: A1 and A2, which exhibit different roles at different stages of ischemic stroke. During the acute phase, A1 reactive astrocytes secrete vascular endothelial growth factor, matrix metalloproteinases, lipid carrier protein-2, and other cytokines, exacerbating damage to endothelial cells and tight junctions. Conversely, A2 reactive astrocytes produce pentraxin 3, Sonic hedgehog, angiopoietin-1, and other protective factors for endothelial cells. Furthermore, astrocytes indirectly influence blood-brain barrier permeability through ferroptosis and exosomes. In the middle and late (recovery) stages of ischemic stroke, A1 and A2 astrocytes show different effects on glial scar formation. A1 astrocytes promote glial scar formation and inhibit axon growth via glial fibrillary acidic protein, chondroitin sulfate proteoglycans, and transforming growth factor-β. In contrast, A2 astrocytes facilitate axon growth through platelet-derived growth factor, playing a crucial role in vascular remodeling. Therefore, enhancing our understanding of the pathological changes and interactions between astrocytes and the blood-brain barrier is a vital therapeutic target for preventing further brain damage in acute stroke. These insights may pave the way for innovative therapeutic strategies for ischemic stroke.

Keywords:  astrocytes; axon; blood-brain barrier; cytokines; endothelial cells; glial scar; ischemic stroke; phenotype; remodel; vascular

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01417
Ecotoxicol Environ Saf. 2025 Aug;pii: S0147-6513(25)00873-5. [Epub ahead of print]301 118528

Iron overload and oxidative stress participated in zinc oxide nanoparticles-induced blood-brain barrier dysfunction.

Eun-Hye Kim, Seung Mi Baek, Donghyun Kim, Sungbin Choi, Wondong Kim, Yiying Bian, Soroush Tahmasebi, Ok-Nam Bae.

  Since zinc oxide nanoparticles (ZnO-NPs) are widely used, concerns about their potential human health effects are growing. Although ZnO-NPs, due to their nano-size, can cross the blood-brain barrier (BBB) and affect brain function, the potential risk of ZnO-NPs in brain endothelial cells, the major components of the BBB, is largely unknown. In brain endothelial cells (bEnd.3 cells), ZnO-NPs were exposed for 9 h to evaluate the brain endothelial dysfunction and BBB disruption. ZnO-NPs were deposited in the lysosome and promoted ferroptosis in bEnd.3 cells. Increased oxidative stress led to lysosomal dysfunction and cytotoxicity in bEnd cells treated with ZnO-NPs.3 cells. ZnO-NPs induced dysregulated autophagy flux and hyperpermeability via intracellular iron overload in bEnd.3 cells. We developed a putative adverse outcome pathway (AOP) to understand the effects of ZnO-NPs on the function of brain endothelial cells. Our study will help clarify the potential impact and toxicity of ZnO-NPs on the brain endothelium and the BBB.

Keywords:  Blood-brain barrier; Brain endothelial cells; Ferroptosis; Iron overload; Lysosome; Zinc oxide nanoparticles

DOI:  https://doi.org/10.1016/j.ecoenv.2025.118528
FASEB J. 2025 Jun 30. 39(12): e70751

Dolutegravir Inhibits Autophagy In Vitro in a Mouse Blood-Brain Barrier Model.

Chang Huang, Qing Rui Qu, Reina Bendayan.

Despite the effectiveness and tolerability of antiretroviral therapy (ART) in treating HIV infection, integrase strand transfer inhibitors, particularly dolutegravir (DTG)-based ART, have been associated with various brain complications. Our research group has previously reported that DTG disrupts the blood-brain barrier (BBB) by inducing endoplasmic reticulum (ER) stress. To further understand DTG-associated toxicity, this follow-up study assessed autophagy dysfunction, a critical process that is closely linked to ER stress, using primary cultures of mouse brain microvascular endothelial cells as a robust BBB rodent model. We demonstrated that DTG exposure at therapeutically relevant concentrations significantly increased Sqstm/p62, LC3B-I and LC3B-II protein expression, and downregulated autophagy-related genes Ulk1 and Atg14, suggesting an autophagy inhibition as a result of DTG treatment. This study provides new insights into the toxicological mechanisms of DTG and pathogenesis of DTG-associated brain complications.

DOI: https://doi.org/10.1096/fj.202500568RR
Neuroreport. 2025 Jun 13.

Protective effects of alectinib on germinal matrix hemorrhage-induced neonatal brain injury.

Xuhui Yin, Yiheng Wang, Xiaoli Zhang, Xixiao Zhu, Bing-Qiao Zhao.

   OBJECTIVE: This study aimed to investigate the role of alectinib in a neonatal mouse model of germinal matrix hemorrhage (GMH).
METHODS: We induced GMH in postpartum day 5 mouse pups by injecting collagenase into the germinal matrix. Alectinib was administered intraperitoneally after GMH induction. Western blot, immunofluorescence staining, and quantitative PCR were performed to explore the effects of alectinib on oxidative stress, microglial number, proinflammatory cytokines expression, blood-brain barrier (BBB) damage, and cortical neuron loss. Cresyl violet and Prussian blue staining were used to detect the ventricular size, cerebral cortical atrophy, and hemorrhage burden. Novel object recognition and rotarod tests were used to determine the neurological function.
RESULTS: We found that anaplastic lymphoma kinase (ALK) was upregulated in the perihematomal areas following GMH and was presented in endothelial cells. Treatment with alectinib resulted in a reduction in oxidative stress, as shown by decreasing generation of reactive oxygen species, lipid peroxidation, and oxidative DNA at 3 days after GMH. Alectinib also attenuated the number of microglia, levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α, loss of BBB integrity ZO-1 and claudin-5, and disruption of BBB. These effects of alectinib were accompanied by reduced hemorrhage burden, cortical neuron loss and cerebral cortical atrophy, and improved motor coordination, cognitive and memory impairments at 23 days after GMH.
CONCLUSION: Our data revealed that alectinib reduced oxidative stress, microglia number, and BBB permeability, thereby alleviating secondary brain injury in GMH. Therapies that inhibit ALK signaling may confer neuroprotection against GHM.

Keywords:  alectinib; anaplastic lymphoma kinase; blood–brain barrier disruption; cerebral cortical atrophy; germinal matrix hemorrhage; oxidative stress and inflammation

DOI:  https://doi.org/10.1097/WNR.0000000000002180
Neurochem Int. 2025 Jun 13. pii: S0197-0186(25)00082-8. [Epub ahead of print] 106009

Deferoxamine prevents BBB disruption, neuroinflammation and apoptotic changes in early hours of ischemic reperfusion injury.

Rajesh Ugale, Sneha Vatte, Punit Girdhar, Dinesh Anandani.

   BACKGROUND: Iron contributes to brain damage in ischemia/reperfusion injury (I/R). Deferoxamine (DFX), an iron chelator, offers neuroprotective action in I/R animal models. However, its underlying mechanism is under investigation. This study aims to investigate effect of DFX on I/R damage led by BBB disruption, neuroinflammation, and apoptosis.
METHODS: In adult male Wistar rats, cerebral ischemia was induced by middle cerebral artery occlusion (MCAO). Rats were treated with vehicle or DFX at 100, 200, and 300 mg/kg doses intraperitoneally (i.p.) at time intervals 1, 2, and 3 h of I/R injury. The neuroprotective effect of DFX was observed using histological staining and behavioural assessment after 24 h of I/R injury. Blood-brain barrier (BBB) integrity was evaluated by Evans blue staining & MMP9 expression. Anti-inflammatory effect of DFX was observed using immunohistochemical analysis whereas, anti-apoptotic effects via mRNA expressions of CREB, caspase-3, BDNF and Bcl-2.
RESULTS: DFX (300 mg/kg) at 1 h of I/R injury ameliorates cerebral infarction, neurological deficits, and beam walk score. Histologically, Hoechst, hematoxylin and eosin (H & E), and cresyl violet stainings showed reduced neuronal death in DFX treated rats. It mitigates BBB disruption as observed with Evans blue staining. Additionally, DFX reduced MMP-9 expression indicative of reduced BBB disruption and improved inflammatory changes (CD86 and CD206). Besides, it inhibits mRNA expression of cleaved caspase-3 and improved expression of BDNF and Bcl-2.
CONCLUSIONS: Our findings, demonstrate that DFX prevents I/R brain damage in early hour (1 h) of I/R injury by reducing BBB disruption, inflammation, and apoptosis. DFX may exhibit potential to act as adjuvant in management of acute ischemic stroke.

Keywords:  Apoptosis; Deferoxamine; Ischemia reperfusion injury; MCAO; Neuroinflammation

DOI:  https://doi.org/10.1016/j.neuint.2025.106009
Aging Dis. 2025 Jun 09.

Novel Insights into the Mechanism and Treatment of Diabetes-Related Brain Complications: Focusing on the Blood-Brain Barrier Impairment.

Caiyi Long, Yueheng Pu, Shunseng Keng, Jiajing Tao, Boxun Zhang, Rensong Yue.

Diabetes mellitus often leads to secondary brain disorders, thus increasing the risk of mortality. The blood-brain barrier (BBB) is a peripheral-central defense mechanism that significantly impacts diabetes-related brain complications. Under hyperglycemic conditions, the BBB undergoes pathological structural alterations, leading to increased permeability and transport dysfunction. Clinically, BBB damage induces diabetes-related brain complications such as cognitive impairment, stroke, and depression. Notably, BBB damage can occur before the onset of disease symptoms in the brain and may serve as a predictor of disease progression and prognosis. Hyperglycemia is the main cause of BBB damage and can induce oxidative stress, inflammatory response, Advanced glycation end products (AGEs) accumulation, and high-mobility group box 1 (HMGB1) signaling axis activation. These factors lead to endothelial dysfunction, disruption of tight junction proteins, loss of pericytes, activation of astrocytes and microglia, disruption of the actin cytoskeleton, alterations in the basement membrane, and an increase in matrix metalloproteinases (MMPs). Collectively, these processes contribute to brain injury in patients with diabetes. Lifestyle interventions and hypoglycemic, antihypertensive, and lipid-lowering agents play therapeutic roles in BBB damage and diabetes-related brain complications. However, the role of some drugs in this context is controversial and remains known only at the animal and cellular levels. Several studies have investigated the therapeutic potential of targeted nanomedicines and natural compounds; however, it remains challenging to translate their research findings to clinical practice. In conclusion, this review highlights the clinical evidence, pathological mechanisms, and existing treatment options for BBB damage in patients with diabetes-related brain complications. It also demonstrates the potential of targeted nanomedicines and natural compounds, providing a foundation for future research.

DOI: https://doi.org/10.14336/AD.2025.0296
J Biomech. 2025 Jun 07. pii: S0021-9290(25)00289-1. [Epub ahead of print]189 112777

Role of tight junctions in three-dimensional mechanical model of blood-brain barrier.

Haifeng Zhu, Guohui Hu.

  The increasing prevalence of central nervous system (CNS) disorders has imposed a significant social and economic burden on healthcare systems. The blood-brain barrier (BBB) presents a major challenge for effective drug delivery to the brain, hindering disease treatment advancements. The BBB consists of various cell types, including microvascular endothelial cells and astrocytes, with tight junctions playing a key role in regulating molecular exchange and maintaining brain homeostasis. However, current research on the mechanical properties of the BBB mainly focuses on individual cellular components or the vasculature as a whole, with limited attention to the mechanical behavior of the tight junctions between these cells. This study develops a three-dimensional (3D) mechanical model of the BBB, incorporating tight junctions as membrane structures within the vessel wall. To simulate stress distribution within the BBB, tight junctions are described by a modified standard linear solid model, while the vessel wall is depicted by the Yeoh model. Parameters of the Yeoh model are optimized using machine learning algorithms based on experimental data. Then finite element simulations are conducted to analyze the stretching process of the BBB, yielding stress distributions and stress-strain relationships that elucidate the mechanical properties of the BBB under tensile conditions. The influences of the cell membrane elastic modulus, elastic modulus of the cytoskeleton and cytoplasmic viscosity in the modified standard linear solid model on the maximum stress in the tight junction at equilibrium are intensively discussed. These findings provide theoretical insights into the understanding of CNS disorders and have potential applications in drug delivery strategies.

Keywords:  Blood–brain barrier; Finite element analysis; Tight junctions; Yeoh model

DOI:  https://doi.org/10.1016/j.jbiomech.2025.112777
Neural Regen Res. 2025 Jun 19.

DNAJB6: A guardian against neurodegeneration.

Jónvá Hentze, Anna Gelman, Tomasz Brudek, Christian Hansen.

   ABSTRACT: Amyloid protein aggregation plays a major role in multiple neurodegenerative diseases and is likely the primary driving force for the progression of most of these diseases. Multiple recent studies have highlighted that the DNAJ homolog subfamily B member 6 (DNAJB6) chaperone is particularly interesting, when it comes to preventing amyloidogenic proteins from aggregating. It has been shown that DNAJB6 can prevent the aggregation of polyglutamine-expanded proteins in models of Huntington's disease. Likewise, it can suppress aggregation of α-synuclein in models of Parkinson's disease and other synucleinopathies. Finally, it has been shown that DNAJB6 can block aggregation of multiple additional amyloid proteins involved in Alzheimer's disease and other tauopathies as well. We believe there is yet much to learn about the protective role of DNAJB6 in the brain, but this focused review summarizes, what we know so far of this chaperone. It describes the biological role of DNAJB6 in the brain and its interaction with Hsp70, with particular emphasis on the studies that show its ability to prevent amyloid protein aggregation in vitro and in vivo. Moreover, recent work on dysregulation of the expression of DNAJB6 in brain clinical tissue is discussed. Finally, we discuss potential therapeutic perspectives as we believe this protein is a promising druggable target.

Keywords:  DNAJB6; aggregation; chaperones; clinical tissues; human brain; neurodegeneration; neurodegenerative diseases; therapeutic target

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01504
Int J Pharm. 2025 Jun 12. pii: S0378-5173(25)00688-X. [Epub ahead of print] 125851

Advances in alginate-based nanoformulations: Innovative and effective strategies for targeting and treating brain disorders.

Ekta Rawat, Suman Sharma, Shweta Vyas, Omar Awad Alsaidan, Devesh U Kapoor, Bhupendra G Prajapati.

  Brain disorders, encompassing neurodegenerative conditions and intracranial neoplasms, present formidable obstacles in the realm of pharmacological delivery due to the existence of athe blood-brain barrier (BBB) and the restricted bioavailability of therapeutic agents. Alginate-derived nanoformulations have emerged as highly promising systems for drug delivery, offering attributes such as biocompatibility, regulated release, and improved targeting efficacies. This review investigates contemporary advancements in alginate-based nanoformulations, with a particular emphasis on their efficacy in surmounting obstacles to successful pharmacological delivery to the brain. Initially, we furnish a comprehensive overview of alginate, underscoring its pertinent properties, biomedical applications, and inherent limitations. Subsequently, the discourse progresses to strategies for nanoformulation, which encompass lipid-based, polymeric, and inorganic methodologies, with a focus on their benefits in relation to cerebral targeting. Moreover, this review entails the therapeutic potential of alginate-based nanoformulations in addressing significant neurological disorders, including Alzheimer's disease, Parkinson's disease, brain tumours, traumatic brain injury, epilepsy, and amyotrophic lateral sclerosis. By amalgamating cutting-edge nanotechnology with the distinctive properties of alginate, these formulations signify a promising pathway for the advancement of efficacious therapies aimed at brain targeting. Additionally, prospective research trajectories and challenges associated with the optimization of alginate-based nanocarriers for clinical applications are also elucidated.

Keywords:  Alginate; Blood brain barrier; Nanoformulations; Neurological disorders; Targeted therapy

DOI:  https://doi.org/10.1016/j.ijpharm.2025.125851
Noncoding RNA Res. 2025 Oct;14 96-106

MicroRNA-29a-5p attenuates hemorrhagic transformation and improves outcomes after mechanical reperfusion for acute ischemic stroke.

Chang-Luo Li, Jin-Kun Zhuang, Zhong Liu, Zhong-Run Huang, Chun Xiang, Qian-Yu Chen, Ze-Xin Chen, Zhong-Song Shi.

   Background: Hemorrhage transformation (HT) following endovascular reperfusion treatment is associated with worse clinical outcomes in acute ischemic stroke patients. MicroRNA (miR) modulates several aspects of cerebral ischemia-reperfusion injury, including blood-brain barrier (BBB) integrity, inflammation, oxidative stress, and apoptosis, significantly impacting cerebral recovery and function. This study investigated the role of astrocytic miR-29a-5p in HT in the transient middle cerebral artery occlusion (MCAO) model and oxygen-glucose deprivation reoxygenation (OGD/R) model of astrocytes.
Methods: MiR-29a-5p expression in the OGD/R astrocyte model was assessed. The astrocyte injury, the expression of A1 and A2 phenotypes of reactive astrocytes, and the regulation of miR-29a-5p target genes were evaluated after the miR-29a-5p intervention. A mechanical reperfusion-induced HT model was established in hyperglycemic rats using 5-h MCAO following reperfusion at 6 h. MiR-29a-5p agomir was administered intravenously before reperfusion. Infarct volume, HT, BBB damage, neurological score, the expression of miR-29a-5p, and its target genes were evaluated.
Results: MiR-29a-5p expression decreased in OGD/R-treated astrocytes and the peri-infarction tissue and blood of the MCAO model. Elevating miR-29a-5p levels reduced astrocyte injury, suppressed neurotoxic A1 astrocyte markers (C3, Fkbp5, and Serping1), while enhanced neuroprotective A2 astrocyte markers (S100a10 and Emp1) in the OGD/R and MCAO models. Intravenous administration of miR-29a-5p agomir increased the expression of miR-29a-5p and reduced infarct volume, reperfusion-induced HT, and BBB breakdown after ischemia, improving neurological outcomes in the MCAO model. Overexpression of miR-29a-5p effectively suppressed the expression of its direct target genes, glycogen synthase kinase 3 beta and aquaporin 4 in the OGD/R and MCAO models.
Conclusions: MiR-29a-5p alleviates astrocyte injury and regulates A1 and A2 astrocyte markers, glycogen synthase kinase 3 beta, and aquaporin 4 in astrocytes subjected to ischemia-reperfusion injury. Astrocytic miR-29a-5p may be a protective target for reducing HT and improving outcomes following mechanical reperfusion in acute ischemic stroke.

Keywords:  Acute ischemic stroke; Astrocyte; Cerebral ischemia-reperfusion injury; Hemorrhagic transformation; MicroRNA; Oxygen-glucose deprivation reoxygenation

DOI:  https://doi.org/10.1016/j.ncrna.2025.05.016
FASEB J. 2025 Jun 30. 39(12): e70742

Microglia Promote Endothelial Cell Activation Through NSUN2-Mediated SQLE m5C Modification in Diabetic Retinopathy.

Tingting Chen, Min Zhou, Yihua Su, Congyao Wang, Wenhui Zhu, Fenfen Yu, Jingwen Huang, Xia Dong, Yan Sun, Lijun Huo, Pengxia Wan.

  To investigate the effect of retinal microglia on the quiescence-activation balance and angiogenesis potential of endothelial cells in diabetic retinopathy (DR). Retinal microglia from diabetic mice were isolated and cocultured with endothelial cells. The quiescence-activation status of endothelial cells was determined by flow cytometry, EdU staining and expressions of activation markers including P21 and CDK1, and the angiogenesis potential was detected by tube formation assays. RNA sequencing was performed to identify the critical gene, which was regulated by inhibiting or overexpressing lentiviruses transfection. The concentration of cholesterol and its effect on the status and function of endothelial cells, as well as the signal pathways activation, were measured. The critical m5C modification related protein was identified using Western blotting and lentiviruses transfection. Retinal microglia isolated from diabetic mice impeded quiescence but promoted the activation of endothelial cells, and then subsequently enhanced the angiogenesis potential of endothelial cells. Besides, the expression of squalene epoxidase (SQLE) was significantly increased in endothelial cells cocultured with retinal microglia isolated from diabetic mice. Inhibiting SQLE expression in endothelial cells restrained their activation levels and angiogenesis potential, and overexpressing SQLE activated endothelial cells to facilitate angiogenesis. Mechanistically, SQLE increased the concentration of cholesterol in endothelial cells, which promoted their activation via the PI3K-AKT signaling pathway. Moreover, NSUN2 increased the m5C modification level of SQLE and increased its stability, increasing the expression of SQLE in endothelial cells cocultured with retinal microglia isolated from diabetic mice. This study provides new perspectives on the interaction between microglia and endothelial cells involved in the pathogenesis of DR and elucidates the detailed mechanism of NSUN2-mediated m5C modification of SQLE to regulate cholesterol metabolism and signaling pathway activation.

Keywords:  SQLE; diabetic retinopathy; endothelial cells; m5C modification; microglia

DOI:  https://doi.org/10.1096/fj.202500302RR
Neurol Res. 2025 Jun 15. 1-10

Propionate ameliorates neural degeneration by modulating mitochondrial fission and fusion in nerve cells.

Song Xi, Tang Lin, Zhang Haiyan, Zeng Shiyue, Qing Qi, Xiong Qiangqiang, Zheng Mingzhi, Luo Liu.

   BACKGROUND: Sporadic global cognitive decline is on the rise, and current drugs exhibit limited efficacy. Propionate, an SCFAs of the human microbiome, exhibits robust neuroprotective effects.
METHODS: We used CCK8 to evaluate neuronal proliferation, DCFH-DA fluorescence probe to quantify ROS production, ELISA to detect IL-1β and IL-6 release, MitoTracker to assess mitochondrial membrane potential, real-time quantitative PCR, and western blotting to analyze DRP1 and anti-Mfn2 protein expression. We also established an in vitro blood-brain barrier model and AD mouse model.
RESULTS: Propionate normalized the mitochondrial membrane potential in glutamate-treated HT22 cells, reversed growth suppression, ROS accumulation, and elevated IL-1 and IL-6 release. Propionate also decreases Drp1 expression and elevates Mfn2 expression via GRP41 receptor binding. In vitro blood-brain barrier models illustrated the potential of propionate to ameliorate glutamate-induced blood-brain barrier damage. In vivo, propionate notably improved the learning and memory capabilities of AD mice and mitigated AD-induced mitochondrial defects.
CONCLUSION: Supplementation with propionate provides neuroprotection against neurodegenerative diseases. Propionate supplementation may provide a novel strategy for early intervention of neurological disorders.

Keywords:  Drp1; Mfn2; Propionate; blood-brain barrier; neural degeneration

DOI:  https://doi.org/10.1080/01616412.2025.2520019
Angiogenesis. 2025 Jun 17. 28(3): 35

Genetic deletion of microRNA-15a/16-1 in pericytes stimulates cerebral angiogenesis and promotes functional recovery after ischemic stroke.

Ping Sun, Yang Xu, Tianqing Xiong, Shun Li, Na Qiu, Chao Zhou, Jiefei Wang, Alexander Chang, Uma R Chandran, Ke-Jie Yin.

  Stroke is a leading cause of mortality and disability globally. Despite advancements in acute stroke therapies, patient outcomes with ischemic stroke remain suboptimal. Understanding its molecular mechanisms is crucial for developing effective treatments. Angiogenesis actively contributes to post-stroke functional recovery and improves long-term survival in stroke patients. Pericytes are essential for maintaining vascular stability and promoting angiogenesis. We hypothesized that microRNA-15a/16-1 in pericytes significantly modulates post-stroke angiogenesis and neurological recovery. Using a pericyte-specific miR-15a/16-1 conditional knockout (cKO) mouse model, we found that genetic deletion of miR-15a/16-1 in pericytes enhances angiogenesis, promotes cerebral blood flow recovery, and improves sensorimotor and cognitive outcomes following ischemic stroke. Mechanistically, RNA sequencing identified several novel targets of miR-15a/16-1, including Pappa2, Fgf9, Islr, and Ccr2. Interestingly, Pappa2, Fgf9, and Islr function as secreted proteins. Luciferase reporter assays demonstrated that miR-15a/16-1 directly binds and suppresses Pappa2, Fgf9, Islr, and Ccr2 activity in cultured pericytes. In vivo and in vitro assays further confirmed that miR-15a/16-1 silencing in pericytes significantly elevates the protein levels of Pappa2, Fgf9, Islr, and Ccr2 and enhances endothelial cell proliferation, migration, and tube formation under ischemic conditions. These findings suggest that targeting miR-15a/16-1 in pericytes offers a promising therapeutic strategy for enhancing stroke recovery by promoting neurovascular repair and reducing brain damage.

Keywords:  Angiogenesis; Functional recovery; Ischemic stroke; Pericytes; miR-15a/16-1

DOI:  https://doi.org/10.1007/s10456-025-09987-3
Stroke. 2025 Jun 19.

Investigation of Poststroke Depression Following a Nucleus Accumbens Infarct in Mice.

Jonathan Bouchard, Béatrice Daigle, Adeline Collignon, Vincent St-Arnault, Luisa Bandeira Binder, Laura Menegatti Bevilacqua, Véronique Rioux, Laurence Dion-Albert, Manon Lebel, Martin Lévesque, Michèle Desjardins, Caroline Ménard.

   BACKGROUND: Poststroke depression (PSD) affects ≈33% of individuals 1 year after a stroke. Blood-brain barrier (BBB) dysfunction in the nucleus accumbens (NAc), a hub for emotional processing, reward, and mood regulation, has been linked to stress-induced depressive-like behaviors in male mice. Neurovascular alterations were also observed in postmortem tissue samples from men with a diagnosis of major depression. Thus, we aimed to investigate if BBB changes in the NAc could contribute to PSD pathophysiology.
METHODS: Stereotaxic injection of ET-1 (endothelin-1), a potent vasoconstrictor, was performed in the NAc of male mice to create a focal brain stroke, and then, infarct size and localization were assessed and quantified. We subsequently evaluated transcriptomic and morphological effects of the infarct on BBB-related genes and cells in the NAc, particularly those known to be altered after stress exposure in mice or human depression. BBB integrity was assessed with a dextran dye, and magnetic resonance imaging scans were conducted before versus after the injection of Gadovist, a contrast agent. Last, a battery of behavioral tests related to depressive- and anxiety-like behaviors was performed to determine if an infarct in the NAc is sufficient to induce a PSD-like phenotype.
RESULTS: Following ET-1 injection, ≈50% of the total lesion was observed in the NAc leading to BBB hyperpermeability in this brain area. BBB gene expression was impacted by ET-1, and also surgery alone and profiles were differentially regulated throughout time up to 14 days. Gliosis in the NAc was observed with increased reactivity of astrocytes and microglia. The effect of ET-1 on PSD-like symptoms was limited. However, body weight, sociability, and activity were affected by surgery with a more pronounced impact of ET-1 on social interactions compared with naive animals.
CONCLUSIONS: While no clear PSD phenotype was observed following an ET-1-induced stroke in the NAc of male mice, our study shed light on the technical complexity of focal lesions in deep brain structures, an understudied phenomenon occurring in humans. We provide technical insights for the development of a mouse model of deep brain lesions, characterize its impact at molecular, cellular, and behavioral levels, and highlight the need to control for vascular alterations when performing stroke surgeries.

Keywords:  behavior; blood-brain barrier; depression; disease models, animal; gene expression

DOI:  https://doi.org/10.1161/STROKEAHA.125.050839
Behav Brain Res. 2025 Jun 11. pii: S0166-4328(25)00280-3. [Epub ahead of print] 115693

Blood-brain barrier permeability in CKD: link with inflammation and cognitive and mood impairment in rats.

Mickaël Bobot, Amandine Bruyat, Laurent Thomas, Samantha Fernandez, Alexandre Brodovitch, José Boucraut, Stéphane Burtey, Vincent Nail, Benjamin Guillet, Guillaume Hache.

  Chronic kidney disease (CKD) is associated with cognitive impairment. CKD is associated with increased permeability of the blood-brain barrier (BBB), resulting in increased cognitive impairment in animals and in humans. The aim of this study is to describe the inflammatory profile in blood and cerebro-spinal fluid (CSF) during a CKD model induced by adenine rich diet (ARD) in rats, in relation to BBB permeability and to explore the cognitive and mood impairment phenotypes. ARD rats displayed a 5-fold increase in BBB permeability, quantified with brain 99mTc-DTPA SPECT/CT isotopic imaging, without alteration of brain perfusion. CKD is associated with increased PDGFRß levels in CSF (445±85.6 vs. 303±104.9pg/mL, p=0.03), suggesting pericyte dysfunction, but not with CSF levels of inflammatory cytokines, despite increased systemic inflammation. Neurobehavioural evaluation highlighted that ARD rats had impairment of short-term spatial memory, social memory and depressive features but not anxiety. In conclusion, CKD induces systemic inflammation and BBB permeability associated with pericyte dysfunction and alteration of memory and depressive features in rats. BBB disruption seems to be a crucial mechanism involved in cognitive and mood impairment during CKD.

Keywords:  Blood-brain barrier; Chronic kidney disease; Cognitive impairment; Cytokines; Depression; Imaging

DOI:  https://doi.org/10.1016/j.bbr.2025.115693
Neural Regen Res. 2025 Jun 19.

Pericyte-glial cell interactions: Insights into brain health and disease.

Ali Sepehrinezhad, Ali Gorji.

   ABSTRACT: Pericytes are multi-functional mural cells of the central nervous system that cover the capillary endothelial cells. Pericytes play a vital role in nervous system development, significantly influencing the formation, maturation, and maintenance of the central nervous system. An expanding body of studies has revealed that pericytes establish carefully regulated interactions with oligodendrocytes, microglia, and astrocytes. These communications govern numerous critical brain processes, including angiogenesis, neurovascular unit homeostasis, blood-brain barrier integrity, cerebral blood flow regulation, and immune response initiation. Glial cells and pericytes participate in dynamic and reciprocal interactions, with each influencing and adjusting the functionality of the other. Pericytes have the ability to control astrocyte polarization, trigger differentiation of oligodendrocyte precursor cells, and initiate immunological responses in microglia. Various neurological disorders that compromise the integrity of the blood-brain barrier can disrupt these communications, impair waste clearance, and hinder cerebral blood circulation, contributing to neuroinflammation. In the context of neurodegeneration, these disruptions exacerbate pathological processes, such as neuronal damage, synaptic dysfunction, and impaired tissue repair. This article explores the complex interactions between pericytes and various glial cells in both healthy and pathological states of the central nervous system. It highlights their essential roles in neurovascular function and disease progression, providing important insights that may enhance our understanding of the molecular mechanisms underlying these interactions and guide potential therapeutic strategies for neurodegenerative disorders in future research.

Keywords:  brain; inflammation; neuroprotection; neurovascular function; therapeutic targets

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01472
Chin Neurosurg J. 2025 Jun 17. 11(1): 12

Carotid endarterectomy and blood-brain barrier permeability in subjects with bilateral carotid artery stenosis.

Changyu Lu, Chenyu Zhu, Wenjie Li, Huan Zhu, Qihang Zhang, Tong Liu, Tongyu Yang, Yan Zhang.

   BACKGROUND: The increased permeability of the blood-brain barrier (BBB) is related to the occurrence and development of diseases such as acute ischemic stroke, chronic ischemia, or small vessel disease. Patients with carotid artery stenosis have chronic ischemia. The exact effect of carotid endarterectomy on the blood-brain barrier is still unclear. The aim of the study was to assess the effect of carotid endarterectomy on basic perfusion parameters and permeability surface area-product (PS).
METHODS: The study included a total of 17 subjects (13 men), of which bilateral carotid artery stenosis was greater than 70%. All patients underwent unilateral carotid endarterectomy. Differences in the following computed tomography perfusion (CTP) parameters were compared before and after operation: cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP), and PS. PS acquired by CTP is used to measure the permeability of the BBB to contrast material.
RESULTS: Before surgery, the operative side exhibited significantly lower CBF (p = 0.001) and prolonged MTT (p = 0.002) and TTP (p = 0.001) compared to the nonoperative side, while PS and CBV showed no significant differences. After carotid endarterectomy, only the operative side demonstrated improvements, with CBV increasing by 9.4%, MTT decreasing by 20.3%, TTP decreasing by 14.1%, and PS decreasing by 27.5% (all p < 0.01). No significant changes were observed on the nonoperative side.
CONCLUSIONS: Carotid endarterectomy augmented BBB permeability can be controlled by carotid endarterectomy in patients with carotid artery stenosis.

Keywords:  Blood–brain barrier; Carotid artery stenosis; Carotid endarterectomy; Computed tomography perfusion; Permeability surface

DOI:  https://doi.org/10.1186/s41016-025-00398-3
Exp Biol Med (Maywood). 2025 ;250 10575

Retrotransposition-competent L1s are increased in the genomes of individuals with amyotrophic lateral sclerosis.

Abigail L Pfaff, Sulev Kõks.

  An individual's genetics contributes to their risk of developing amyotrophic lateral sclerosis (ALS); however, there is still a large proportion of the heritability of ALS to be understood. Part of this missing heritability may lie in complex variants, such as the long interspersed element 1 (L1) retrotransposon, which have yet to be evaluated. The majority of L1 insertions in the human genome are no longer able to retrotranspose, but to date 279 retrotransposition-competent (RC) L1s have been reported. Many RC-L1s are polymorphic for their presence/absence; therefore, each individual will have a different number and complement of RC-L1s. These elements have been hypothesized to be involved in disease processes by multiple mechanisms such as somatic mutation by retrotransposition, the triggering of neuroinflammation and DNA damage. We hypothesize that L1s may influence disease development either through their effects on endogenous genes or through the properties that enable them to retrotranspose. Whole genome sequencing data from the New York Genome Center ALS consortium were used to characterize L1 variation identifying 2,803 polymorphic L1 elements and association analysis was performed in European individuals (ALS/ALS with other neurological disorder (ALSND) n = 2,653, controls n = 320). There were no individual L1 elements associated with disease, but we did identify a significant increase in the number of RC-L1s in ALS/ALSND genomes (p = 0.01) and the presence of ≥46 RC-L1s showed the most significant association (OR = 1.09 (1.02-1.16), p = 0.01) with disease. Analysis of individual L1s and their association with age at onset and survival identified one L1 whose presence was significantly associated with a lower age at onset (52.7 years) compared to homozygous absent individuals (59.2 years) (padj = 0.009). Our study has identified novel genetic factors for both disease risk and age at onset in ALS providing further evidence for the role of L1 retrotransposons in neurodegenerative diseases.

Keywords:  L1; amyotrophic lateral sclerosis; genetics; neurodegeneration; retrotransposons

DOI:  https://doi.org/10.3389/ebm.2025.10575
Int Rev Neurobiol. 2025 ;pii: S0074-7742(25)00025-X. [Epub ahead of print]181 395-420

The protective effect of DMT against neurodegeneration.

Ede Frecska, Attila Kovács, Attila Szabo.

  This paper explores the therapeutic potential of DMT in neuroprotective strategies, particularly concerning ischemia-reperfusion injury (IRI) and neurodegenerative disorders. Besides its potent serotonin receptor actions, DMT is also an endogenous agonist of the sigma-1 receptor (Sig-1R). Sigma receptors are a unique family of proteins with high expression in the brain and spinal cord and have been involved in the etiology, symptom course and treatment of several central nervous system disorders. Our previous theoretical and experimental work strongly suggest that targeting sigma (and serotonin) receptors via DMT may be particularly useful for treatment in a number of neurological conditions like stroke, global brain ischemia, Alzheimer's disease, and amyotrophic lateral sclerosis. In this article, we briefly overview the function of Sig1-R in cellular bioenergetics with a focus on the processes involved in IRI and summarize the results of our previous preclinical (in vitro and in vivo) DMT studies aiming at mitigating IRI and related cellular neuropathologies. We conclude that the effect of DMT may involve a universal role in cellular protective mechanisms suggesting therapeutic potentials against different components and types of IRIs emerging in local and generalized brain ischemia after stroke or cardiac arrest. The multiple neuroprotective mechanisms facilitated by DMT may position it as a model molecule for developing pharmacological treatments for neurodegenerative disorders.

Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Brain ischemia; Dimethyltryptamine; Ischemia-reperfusion injury; Neurodegenerative disorders; Neuroprotection; Serotonin; Sigma-1 receptor; Stroke

DOI:  https://doi.org/10.1016/bs.irn.2025.04.010
Front Cell Dev Biol. 2025 ;13 1611226

Induced neural stem cells ameliorate blood-brain barrier injury by modulating the calcium signaling pathway of astrocyte in cerebral ischemia-reperfusion rats.

Xueyun Liang, Chuanshang Cao, Ningmei Liu, Dongmei Chen, Ting Liu, Haibin Ma, Jiaxin Liu, Taojuan Wu, Jianguo Niu.

   Background: Neural stem cells offer new hope for ischemic stroke patients on the basis of their potential to reverse neurological sequelae, but it is still difficult to obtain sufficient neural stem cells in the clinic. We induced human placental mesenchymal stem cells to neural stem cells (iNSCs), the therapeutic effects and possible mechanisms of iNSCs in ischemic stroke were observed in this study.
Results: Transplanted iNSCs improved neurological deficits, increased the integrity of blood-brain barrier (BBB) structure and its related proteins expression level in middle cerebral artery occlusion/reperfusion (MCAO/R) rats. The in vitro study demonstrated that iNSCs treatment inhibited Ca2+ influx in oxygen-glucose deprived (OGD)-damaged astrocytes. Additionally, iNSCs downregulated the expression level of pCaMK-II, increased the expression level of superoxide dismutase, and inhibited the expression of caspase 9 in both brain of MCAO/R rats and OGD-damaged astrocytes.
Conclusion: iNSCs transplantation improved BBB function by modulating calcium signaling pathway of astrocyte in MCAO/R rats, which proved iNSCs may be a new promising neural stem cells origin for the treatment of cerebral ischemia-reperfusion injury.

Keywords:  BBB; astrocytes; calcium signaling pathways; cerebral ischemia-reperfusion; induced neural stem cells

DOI:  https://doi.org/10.3389/fcell.2025.1611226
Ann Neurol. 2025 Jun 20.

The FindMNDBiomarker Program: Protein Changes in Motor Neuron Disease/Amyotrophic Lateral Sclerosis Postmortem Tissue and Biofluids.

Gabrielle L Adler, Matthew C Kiernan, Rachel H Tan.

OBJECTIVE: Biomarkers of disease pathogenesis are critically needed for amyotrophic lateral sclerosis (ALS) to facilitate diagnosis and patient stratification into appropriate therapeutic trials. Proteomic studies offer significant potential to advance this, but reproducibility across laboratories is a key component toward identifying protein changes that can be translated into clinical applications.
METHODS: A combined analysis of 25 proteomic studies in human ALS biospecimens was performed to identify proteins consistently altered in ALS postmortem tissue, cerebrospinal fluid, or blood, as well as across primary regions of ALS pathology and peripheral biofluids. We consolidated these datasets into a user-friendly database "FindMND Biomarker," which is an accessible search tool that allows users to quickly determine how often, and in which biospecimen types, their proteins of interest are dysregulated in patients with ALS.
RESULTS: Our combined analysis identified 1,458 altered proteins in ALS, and revealed consistent dysregulation in mitochondrial, cytoplasmic, and RNA binding proteins in primary and later affected regions of ALS pathology. Remarkable consistency in the direction and dysregulation of chitinases and gelsolin proteins were observed across ALS biofluids. Comparisons of postmortem tissue and biofluids reinforce several known protein changes, and highlighted novel proteins of interest that may drive disease pathogenesis.
INTERPRETATION: The biospecimen type in which protein dysregulation is most consistently identified provides important insight into disease, and whether these represent potential measures of disease pathogenesis or systemic changes. By streamlining proteins by reproducibility and biospecimen type, FindMNDBiomarker is a useful resource that provides new mechanistic insights, and facilitates the prioritization of ALS-associated proteins for further validation and investigation. ANN NEUROL 2025.

DOI: https://doi.org/10.1002/ana.27300
Mol Ther. 2025 Jun 14. pii: S1525-0016(25)00477-0. [Epub ahead of print]

A single dose of a vectorized mAb targeting TDP-43 potently inhibits the neuropathology in a model of ALS/FTD.

Greg Del Val, Florence Gauye, Mickaël Audrain, Sébastien Menant, Monisha Ratnam, Elodie Chevalier, Romain Ollier, Daisy Bhatia, Tamara Seredenina, Tariq Afroz, Andrea Pfeifer, Marie Kosco-Vilbois, Damien Nevoltris.

TAR DNA binding protein-43 (TDP-43)-mediated pathology is a hallmark of devastating neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Thus, monoclonal antibodies (mAbs) are being developed to target the pathological forms of this protein. To improve mAb exposure within the central nervous system, a potent anti-TDP-43 mAb, ACI-5891, was generated as a vectorized full-length antibody (vmAb) and evaluated for brain delivery using adeno-associated virus 9 (AAV9). Among the expression cassettes explored, the selected construct utilized an internal ribosome entry site (IRES), which produced high expression yields in vitro (>200 mg/L) with comparable quality, binding and functional properties to the conventionally produced mAb. A single intracisternal administration of vmAb ACI-5891 demonstrated a broad brain distribution and sustained expression (i.e., months) in the serum, cerebrospinal fluid and brain of mice. In a mouse model of ALS/FTD, treatment with a vmAb reduced the amount of pathological phospho-TDP-43 in neurons by 58% and 68% when expressed either using a ubiquitous promoter or a brain-selective promoter, respectively. This innovative approach sufficiently delivers effective immunotherapy with a single dose and illustrates the enormous potential of using vectorized antibodies to target neuropathology, including TDP-43 in patients suffering from ALS, FTD and other TDP-43 proteinopathies.

DOI: https://doi.org/10.1016/j.ymthe.2025.06.026
Aging Dis. 2025 Jun 06.

Microcirculation Dysfunction in Subacute Stroke: The Role of Delayed Capillary Pericyte Loss.

Yiya Xu, Chao Chen, Jilin Weng, Ting Chen, Yingchao He, Zhiwei Song, Yinzhou Wang.

Post-recanalization microcirculation dysfunction is common and significantly contributes to poor outcomes in ischemic stroke. Pericytes have been shown to mediate the "no-reflow" phenomenon by constricting capillaries in experimental stroke models, implicating their critical role in early microcirculation dysfunction. However, little is known about the long-term fate of pericytes and their contribution to sustained microcirculation dysfunction in prolonged period of time. We conducted repeated longitudinal observations of pericyte fate and function, as well as blood flow dynamics across multiple vascular segments, using two-photon imaging in PDGFRβ-tdTomato mice subjected to transient middle cerebral artery occlusion (tMCAO) over a 14-day period. Multivariate analysis was performed to identify imaging features independently associated with capillary perfusion on day 14. Types of pericyte death were assessed using immunohistochemistry and Western blot analysis. Fasudil and the RIPK1 inhibitor necrostatin-1 were administered to modulate pericyte dysfunction and survival during the acute and subacute phases of stroke. Outcomes were evaluated by total capillary perfusion, infarct volume, blood brain barrier (BBB) integrity, and neurological function over 14 days. Pericyte loss observed on day 7 post-stroke was independently associated with impaired microcirculation perfusion, as indicated by a reduction in total capillary volume. While fasudil treatment alone improved microcirculation perfusion on day 3, it did not alter pericyte fate or improve outcomes by day 14. Necroptosis was found to contribute to delayed pericyte loss in the ischemic penumbra. Combined therapy with fasudil and necrostatin-1 effectively prevented delayed pericytes loss and improved both microcirculation perfusion and neurological outcomes on day 14. Delayed pericyte loss contributes to irreversible microcirculation dysfunction in the subacute phase of stroke. Targeting pericyte dysfunction and necroptosis following recanalization represents a promising therapeutic strategy for enhance stroke recovery.

DOI: https://doi.org/10.14336/AD.2025.0197
Am J Transl Res. 2025 ;17(5): 3476-3484

Plasma glial fibrillary acidic protein as a biomarker of blood-brain barrier integrity in patients with occult cerebral small vessel disease.

Peiqi Ma, Guangwei Gu, Lu Liu, Youmeng Wang, Juluo Chen.

   OBJECTIVE: To investigate the association between plasma glial fibrillary acidic protein (GFAP) levels and blood-brain barrier (BBB) integrity in patients with occult cerebral small vessel disease (CSVD).
METHODS: This retrospective study included patients with occult CSVD (CSVD group, n = 68) and age-matched individuals without CSVD (control group, n = 61). Demographic and clinical characteristics were compared between groups. Cognitive function was assessed using the Montreal Cognitive Assessment-B (MoCA-B). Plasma GFAP levels were measured, and all participants underwent sequential magnetic resonance imaging (MRI) to evaluate BBB integrity. Patients were stratified based on total MRI burden of CSVD into moderate/severe and none/mild load groups. Risk factors associated with moderate/severe CSVD load were analyzed.
RESULTS: The prevalence of hyperlipidemia was significantly higher in the CSVD group than in the control group (P = 0.020), and MoCA-B scores were significantly lower. In the CSVD group, plasma GFAP levels were negatively correlated with total cholesterol (r = -0.281, P = 0.020) and low-density lipoprotein (r = -0.282, P = 0.020), as well as with MoCA-B scores (r = -0.440, P = 0.0002). MRI analysis revealed that brain regions showing significant correlations with elevated plasma GFAP levels exhibited BBB disruption and cortical thinning.
CONCLUSION: Elevated plasma GFAP levels are associated with cognitive impairment and BBB disruption in patients with occult CSVD. GFAP may serve as a potential biomarker for evaluating BBB integrity in this population.

Keywords:  Glial fibrillary acidic protein; blood-brain barrier; case-control study; cerebral small vascular disease; hyperlipidemias

DOI:  https://doi.org/10.62347/MBFD3367
Metab Brain Dis. 2025 Jun 16. 40(6): 224

Bilirubin: a game-changer in alzheimer's therapy? Unveiling its neuroprotective and disease-modifying potential.

Ramandeep Kaur Sidhu, Yukti Mittal, Khadga Raj Aran.

  Alzheimer's disease (AD) is a neurological disease characterised by amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTS), oxidative stress, and neuroinflammation resulting in cognitive decline. Bilirubin is considered to be a by-product of heme metabolism and has emerged as a powerful endogenous antioxidant with significant neuroprotective activities. This article focuses on the multidirectional role of bilirubin in AD, underlining its capability to alleviate oxidative stress, reduce neuroinflammation, inhibit Aβ fibrillation and tau hyperphosphorylation, and maintain synaptic and mitochondrial function. The antioxidant activity of bilirubin, which involves the bilirubin-biliverdin redox cycle, scavenges ROS and promotes cellular defence mechanisms. In addition, bilirubin modulates inflammatory signalling pathways like NF-κB and TLR4 to downregulate pro-inflammatory cytokine release. It also induces Aβ clearance and prevents tau pathology by controlling kinase and phosphatase function, thus ensuring neuronal integrity. Despite its therapeutic promise, the role of bilirubin in AD is multifaceted, with reports from studies being conflicting regarding its levels in patients. While physiological levels have neuroprotective properties, higher levels are neurotoxic, and this emphasizes the requirement for accurate therapeutic dosing. The challenges of blood-brain barrier (BBB) permeability, heterogeneity in bilirubin metabolism, and the absence of large-scale clinical trials need to be overcome to apply preclinical observations to clinical applications. Future studies must aim at maximising bilirubin-based treatments, such as bilirubin analogues, HO-1 inducers, and nanocarrier systems, in addition to non-pharmacological methods such as dietary and lifestyle changes. Standardisation of bilirubin assessment and determining its potential as a diagnostic biomarker are also critical. Overall, bilirubin is a potential therapeutic target for AD, but additional research is necessary to optimize its potential while minimising risks.

Keywords:  Alzheimer’s disease; Bilirubin; Neuroinflammation; Neuroprotection; Oxidative stress

DOI:  https://doi.org/10.1007/s11011-025-01653-3
J Neurochem. 2025 Jun;169(6): e70130

Repeated Low-Level Inflammatory Challenge Leads to Alterations in the TNF-CXCL10 Signalling Pathway in Mouse Cerebral Endothelial Cells In Vitro.

Megan Ritson, Dong Xia, Caroline Wheeler-Jones, Helen B Stolp.

  The mechanism by which chronic systemic inflammation contributes to cerebral endothelial dysfunction and neurological disorders is unclear, although endothelial inflammatory signalling is considered a cornerstone of this process. Here, we have performed transcriptomic analysis of published RNASeq datasets and identified consistent upregulation of the Tumour Necrosis Factor-C-X-C Motif Chemokine Ligand 10 (TNF-CXCL10) signalling pathway in mouse cerebral endothelial cells following a single inflammatory challenge. We subsequently investigated the effects of repeated low-level inflammation on the modulation of this pathway in a mouse cerebral endothelial cell line, analysing the effect on markers of endothelial cell activation and changes in cellular function, as a potential mechanism underlying the cerebrovascular response to low-level systemic inflammation. Mouse cerebral endothelial cells (bEnd.3) were exposed to hour-long treatments with phosphate buffered saline (PBS), a single low concentration of TNF (0.5 ng/mL), repeated low-concentration TNF (0.5 ng/mL, 1 h × 4 days) or a single cumulative concentration of TNF (2.0 ng/mL). RNA and protein were extracted 4 and 24 h after the final treatment for analysis of gene/protein expression using qRT-PCR and western blotting. Repeated inflammatory challenge significantly upregulated both Intercellular Adhesion Molecule 1 (ICAM1) and CXCL10 at the mRNA and protein levels. Signal transducer and activator of transcription 1 (STAT1) and phosphorylated-STAT1 (pSTAT1) protein levels were also increased at 4 and 24 h. Differentially, tumor necrosis factor receptor-associated factor 2 (TRAF2) and Interferon gamma (IFNγ) gene expression were decreased at 4 h, returning to control levels at 24 h. Functional analysis revealed significant increases in endothelial cell proliferation and apoptosis in the presence of repeated TNF exposure. CXCL10 knockdown with small interfering RNA (siRNA) reduced mean caspase 3/7 activity induced by the repeated inflammatory paradigm. These data suggest an upregulation of the TNF-CXCL10 pathway in response to low-level repetitive inflammation in mouse cerebral endothelial cells. Modulation of this pathway may represent a broad therapeutic target for neurovascular disease.

Keywords:  apoptosis; cerebrovascular; endothelium; inflammation; proliferation

DOI:  https://doi.org/10.1111/jnc.70130
Metab Brain Dis. 2025 Jun 19. 40(6): 229

Cola acuminata extract's inhibition of NLRP3 inflammasome in THP-1 cells as a potential treatment option for Parkinson's disease.

Brice Ayissi Owona, Viviane Ndam Ngoungoure, Jordas Tchana Tchamba, Frederic Nico Njayou, Paul Fewou Moundipa.

  Neuroinflammation has been described as one of the multiple clinical manifestations of Parkinson's and Alzheimer's diseases (PD and AD). Moreover, it was reported that amyloid-β deposition is associated with cognitive decline in PD. Here, Cola acuminata (CA) extract was used to inhibit NLRP3 inflammasome in THP-1 macrophages in vitro. CA showed significant anti-inflammatory effect by inhibiting nitric oxide (NO) release from cells after stimulation with LPS and Nigericin. Phagocytosis of amyloid-β by THP-1 cells showed that at 100 µg/ml, CA increases phagocytic activity of macrophages in vitro. Moreover, activation of NLRP3 inflammasome and subsequent treatment with CA showed a reduction of IL1-β and IL-18 cytokines release in ELISA assay. Furthermore, NLRP3, caspase-1, IL1-β and NF-kB expressions were significantly inhibited at the gene and protein levels as shown by RTqPCR and western blot assays respectively. Interestingly, colocalization analysis of activated inflammasome confirmed our results suggesting that CA disaggregates inflammasome assembly. Mass spectrometry analysis of CA has identified epicatechin, catechin, chlorogenic acid, quercetin and stigmasterol known as inflammasome inhibitors among the extract chemical constituents. Together, our results indicate that CA can inhibit inflammasome activation in macrophage, thereby opening future perspectives for PD treatment.

Keywords:   Cola acuminata ; Anti-inflammatory; NF-kappaB; NLRP3 inflammasome; Parkinson’s disease

DOI:  https://doi.org/10.1007/s11011-025-01628-4
Behav Brain Res. 2025 Jun 16. pii: S0166-4328(25)00293-1. [Epub ahead of print] 115706

Distinct behavioural and neurovascular signatures induced by acute and chronic stress in rats.

Daniela M Simões, José Carreira, Alexandre Henriques, Rita Gaspar, Eliane S Sanches, Filipa I Baptista, Ana Paula Silva.

  Stress is a contributing factor for several mood disorders, including depression and anxiety which are associated with significant changes in behavioural and cellular domains. Additionally, sex differences in the prevalence of these neuropsychiatric disorders are well established. Emerging evidence suggests that stress is linked to cerebrovascular diseases and that blood-brain barrier (BBB) dysfunction contributes to the development and exacerbation of neuropathology and neuroinflammation. Despite these interesting findings, very little attention has been given to the effect of both acute and chronic stress (unpredictable chronic mild stress-uCMS) on the link between behavioural and BBB alterations. In this study we used the open field and forced swimming tests (FST) to evaluate locomotor activity, anxiety- and depressive-like behaviours in male and female Wistar rats. Western blotting or ELISA were used to quantify the levels of different proteins related to BBB components and neuroinflammation in the prefrontal cortex. We found that acute stress induced anxiety only in males, whereas uCMS had no effect. Additionally, acute stress decreased immobility time in the FST pointing to a coping strategy in both sexes. In contrast, uCMS increased immobility time only in males, indicating depressive-like behaviour. Additionally, both types of stress had no major impact on TNF-α, GFAP and C3/C3aR proteins. Nevertheless, acute stress significantly reduced occludin and VEGF protein levels in both sexes, highlighting significant alterations in the neurovasculature. Concerning uCMS, there was an upregulation in claudin-5 protein levels only in females suggesting a possible compensatory mechanism of the BBB in response to a prolonged situation of stress. In conclusion, acute and uCMS induce distinct behavioural and biochemical profiles, particularly affecting BBB proteins.

Keywords:  Acute stress; Unpredictable chronic mild stress; behaviour; blood-brain barrier; neuroinflammation

DOI:  https://doi.org/10.1016/j.bbr.2025.115706
Neurotherapeutics. 2025 Jun 17. pii: S1878-7479(25)00102-3. [Epub ahead of print] e00624

Applications of artificial intelligence in drug discovery for neurological diseases.

Sean Ekins, Thomas R Lane.

  Neurological disease encompasses over 1000 disorders, exacts a massive human health and financial toll as well as being a story of extremes. At one end are diseases that are complex and heterogeneous affecting millions, while at the other there are monogenic and rare diseases, with a handful of individuals. What are absent are drugs that can treat or cure the disease. Discovering these is challenging, held back by extreme costs to develop them or in some cases by the limited understanding of the diseases. After decades of drug discovery research there is now considerable data available which can be used to help develop novel compounds more strategically. This includes high throughput screening data with targets, crystal structures of proteins implicated in neurological diseases and adjacent data such as properties of molecules like blood brain barrier permeability as well as an array of in vitro and in vivo toxicity endpoints valuable for any drug targeting the central nervous system. While computational tools have been developing and applied to neurological diseases for decades, we are now in the age of machine learning and artificial intelligence (AI). This promises the potential to expedite the identification and discovery of new molecules. Whether by using individual computational techniques or complex end-to-end approaches, scientists can narrow the molecules they make and test as well as study more targets or diseases which might have been out of reach previously. This review highlights the many different applications of AI potentially enabling new discoveries and treatments for neurological diseases.

Keywords:  Artificial intelligence; Machine learning; Neurological diseases

DOI:  https://doi.org/10.1016/j.neurot.2025.e00624