Fluids and Barriers of the CNS最新文献

{"title":"Sleep disorders and Alzheimer's disease: relationship and mechanisms involving neuroinflammation, orexin and Aβ.","authors":"Wenjing Zhang, Tenghong Lian, Mingyue He, Peng Guo, Huiying Guan, Jinghui Li, Jing Qi, Dongmei Luo, Jing Li, Yanan Zhang, Yue Huang, Gaifen Liu, Weijia Zhang, Zijing Zheng, Hao Yue, Zhan Liu, Fan Zhang, Ruidan Wang, Yao Meng, Wei Zhang","doi":"10.1186/s12987-025-00638-9","DOIUrl":"https://doi.org/10.1186/s12987-025-00638-9","url":null,"abstract":"<p><strong>Aims: </strong>Sleep disorders are common in Alzheimer's disease (AD), but the underlying mechanisms are unknown. This study aimed to specifically investigate the relationship between a specific sleep disorder of short sleep duration (SSD) and AD, and related mechanisms involving neuroinflammation, orexin and AD biomarkers in both AD patients and mice.</p><p><strong>Methods: </strong>In part I, total 247 AD patients were consecutively recruited and categorized into AD with SSD (AD-SSD, < 6 h) and AD with no SSD (AD-nSSD, 7-8 h). Comparisons were made between the two groups in cognitive function, neuroinflammatory factors, orexinergic factors and AD biomarkers in cerebrospinal fluid (CSF). The correlations of orexinergic factors with the neuroinflammatory factors and AD biomarkers in CSF from AD-SSD group were investigated. In part II, the spatiotemporal relationships among glial activation, orexin expression, AD pathology, sleep architecture disturbance and cognitive function in 5XFAD mice were dynamically explored and the potential mechanisms underlying their relationships were analyzed.</p><p><strong>Results: </strong>In part I, compared to AD-nSSD group, AD-SSD group exhibited significantly poorer cognitive performance on the Montreal Cognitive Assessment and the Auditory Verbal Learning Test-delayed recall scales, higher orexin A level in CSF and lower β amyloid (Aβ) 42 level in CSF (all P < 0.05). Furthermore, orexin A had a positive correlation with prostaglandin E₂ (PGE₂) (r = 0.322, P = 0.002) and a negative correlation with Aβ42 (r = -0.223, P = 0.027) levels in CSF from AD-SSD group. In part II, compared with WT mice, 5XFAD mice displayed elevated hippocampal glial fibrillary acidic protein level at 3.5 months, increased hippocampal/cortical Chitinase-3-like protein 1 level, hypothalamic orexin A level and sleep architecture disturbance at 4.5 months, elevated insoluble Aβ42 deposition in hippocampus, orexinergic neuronal numbers in lateral hypothalamus, colocalization of their fibers with Aβ in cerebral cortex and cognitive impairment at 5.5 months old (all P < 0.05).</p><p><strong>Conclusion: </strong>SSD in AD is associated with significant cognitive impairment, neuroinflammation, orexin elevation and Aβ deposition. Hippocampal astroglial activation, hypothalamic orexin elevation and sleep architecture disturbance precede Aβ deposition in hippocampus and cognitive impairment in 5XFAD mice.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"62"},"PeriodicalIF":5.9,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain fluid physiology in ischaemic stroke; more than just oedema.","authors":"Kirsten G Coupland, Merce Fuentes Amell, Neil J Spratt","doi":"10.1186/s12987-025-00671-8","DOIUrl":"10.1186/s12987-025-00671-8","url":null,"abstract":"<p><strong>Background: </strong>Cerebrospinal fluid and interstitial fluid dynamics are critical for maintaining homeostasis in the central nervous system. These fluids facilitate waste clearance, micronutrient distribution, and provide a tightly regulated ionic environment. Ischaemic stroke, a leading cause of morbidity and mortality, disrupts this delicate system, compounding the physiological challenges posed by the condition. Despite recent advances in our understanding of the importance of cerebrospinal fluid (CSF) and interstitial fluid (ISF) movement and exchange, the role of this system in stroke pathophysiology remains underexplored.</p><p><strong>Main body: </strong>Emerging evidence indicates that ischaemic stroke acutely alters CSF and ISF movement and exchange, with effects observed at both local and brain-wide levels. In the hyper-acute phase, there is an influx of CSF into perivascular spaces, potentially contributing to early cell swelling. Over time, impaired clearance mechanisms exacerbate ionic and vasogenic oedema, elevating intracranial pressure and further compromising perfusion in the ischaemic penumbra. Mechanistic studies suggest that disruptions in arterial pulsatility, extracellular space microstructure, and aquaporin 4 localisation may underlie these changes. Experimental models have revealed decreased CSF and ISF exchange, movement and outflow in the hours to days following stroke, with implications for waste clearance and secondary injury processes. The interplay between these dynamics and cortical spreading depolarisations, stroke severity, and cerebrovascular physiology adds complexity to understanding the condition's progression.</p><p><strong>Conclusion: </strong>The disruption of CSF and ISF movement and exchange may represent a significant, yet underappreciated contributor to post-stroke pathology. Addressing these alterations could offer novel therapeutic avenues to mitigate secondary damage, improve central nervous system (CNS) homeostasis, and enhance recovery outcomes. Future research must focus on elucidating the precise mechanisms of CSF and ISF movement and exchange disturbance and exploring targeted interventions to restore normal fluid dynamics in the CNS post-stroke.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"60"},"PeriodicalIF":5.9,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12175363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deformation of brain in normal pressure hydrocephalus is more readily associated with slow vasomotion rather than heartbeat related pulsations of intracranial pressure.","authors":"Ronald T Murambi, Henora Chour, Magdalena Kasprowicz, Craig R Vonhoff, Marek Czosnyka, Zofia Czosnyka, Matthias Jaeger","doi":"10.1186/s12987-025-00670-9","DOIUrl":"10.1186/s12987-025-00670-9","url":null,"abstract":"<p><strong>Objective: </strong>Enlarged brain ventricles, compressed parasagittal cerebrospinal fluid spaces, steep callosal angle, dilated sylvian fissures and focal cortical sulcal dilatation are typical imaging features of idiopathic normal pressure hydrocephalus (iNPH). The pathophysiological mechanisms behind these morphological changes are poorly understood, but the hydrodynamic concepts of communicating hydrocephalus suggest that increased heartbeat related intracranial pulsations are involved in ventricular enlargement. In this cross-sectional study we analysed the association between the radiological findings of iNPH and the physiological intracranial pressure (ICP) waveform components.</p><p><strong>Methods: </strong>117 patients with suspected iNPH underwent computerised overnight ICP monitoring with calculation of heartbeat related ICP pulse wave amplitude (calculated in the frequency domain, AMP, and time domain, MWA), amplitude of respiration induced ICP waves (RESP), power of slow vasogenic waves (SLOW), and index of cerebrospinal compensatory reserve (RAP). Radiological morphological data was recorded from computed tomography using Evans Index (EI), frontal occipital horn ratio (FOHR), and disproportionately enlarged subarachnoid space hydrocephalus (DESH) score.</p><p><strong>Results: </strong>The strongest correlation was observed between SLOW and DESH (r = 0.44, p < 0.012). SLOW also correlated with ventricular size as measured with EI (r = 0.23, p = 0.045) and FOHR (r = 0.26, p = 0.037). ICP and RESP also correlated with DESH (r = 0.25, p = 0.037 and r = 0.25, p = 0.038, respectively). AMP and MWA were not correlated with the radiological data.</p><p><strong>Conclusions: </strong>Mainly SLOW showed correlations with the morphological imaging features of iNPH. SLOW is influenced by vasomotion and intracranial compliance. This study suggests that the magnitude of ICP slow wave activity, but not ICP pulse component is related to the size of brain ventricles and DESH in iNPH.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"61"},"PeriodicalIF":5.9,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12175371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circadian misalignment potentiates blood-brain barrier disruption and mitochondria dysregulation in Zika virus infection.","authors":"Timea Teglas, Silvia Torices, Anne Caroline Marcos, Bogusława Orzechowska-Wylęgała, Michal Toborek","doi":"10.1186/s12987-025-00669-2","DOIUrl":"10.1186/s12987-025-00669-2","url":null,"abstract":"<p><strong>Background: </strong>Zika virus (ZIKV) is a mosquito-borne Flavivirus with a strong affinity for the central nervous system (CNS). After infection, ZIKV can cross the blood-brain barrier (BBB) and reach the CNS, causing potential harm to both adult and developing brains.</p><p><strong>Methods: </strong>The current study aims to evaluate how dysregulated circadian rhythms can affect brain infection by ZIKV, as biorhythms regulate essential physiological processes and disrupted circadian clock can contribute to the pathogenesis of multiple disorders. Both ZIKV infection and circadian rhythm alterations have been related to the disruption of the BBB integrity by modulating the expression of the tight junction (TJ) proteins, however, the input of circadian misalignment on ZIKV infection has never been studied in the literature.</p><p><strong>Results: </strong>Infection of brain endothelial cells with ZIKV selectively impacted endothelial permeability and dysregulated the expression of TJ and mitochondrial proteins. Importantly, these effects were potentiated by silencing Bmal1, a critical circadian rhythm gene. These results were then confirmed in vivo in Bmal1 endothelial cell-specific knockout mice, which were infected with ZIKV at 10⁵ PFU (plaque-forming unit) by retro-orbital infusion. ZIKV infection resulted in a marked decrease in claudin-5, occludin, JAM-3, and ZO-1 expression levels in these mice. In addition, ZIKV affected the expression of FIS1 protein levels and the respiratory complexes of II, III, and IV in mice lacking Bmal1 expression in endothelial cells.</p><p><strong>Conclusions: </strong>Findings from this study contribute to a better understanding of the impact of circadian misalignment on the pathology of ZIKV infection in the adult brain.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"57"},"PeriodicalIF":5.9,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12168291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From inserts to chips: microfluidic culture and 3D astrocyte co-culture drive functional and transcriptomic changes in hiPSC-derived endothelial cells.","authors":"Tuuli-Maria Sonninen, Sanni Peltonen, Sara Kälvälä, Hoang-Tuan Nguyen, Marika Ruponen, Prateek Singh, Šárka Lehtonen","doi":"10.1186/s12987-025-00672-7","DOIUrl":"10.1186/s12987-025-00672-7","url":null,"abstract":"<p><strong>Background: </strong>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).</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"58"},"PeriodicalIF":5.9,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12168306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationships between measures of neurovascular integrity and fluid transport in aging: a multi-modal neuroimaging study.","authors":"Ella Rowsthorn, Lachlan Cribb, Benjamin Sinclair, William Pham, Trevor T-J Chong, Stephanie Yiallourou, Marina Cavuoto, Lucy Vivash, Terence J O'Brien, Xingfeng Shao, Danny J J Wang, Meng Law, Matthew P Pase, Ian H Harding","doi":"10.1186/s12987-025-00664-7","DOIUrl":"10.1186/s12987-025-00664-7","url":null,"abstract":"<p><p>Fluid transport in the neurovascular unit is essential for maintaining brain health through nutrient delivery and waste clearance. However, these systems are complex and the inter-dependencies between elements of these systems and how they may change through aging is not well understood. MRI outcomes provide insight into the underlying biological mechanisms of these systems in vivo, including water exchange rate through the neurovascular unit (BBB k_w), enlarged perivascular spaces (ePVS), cerebral blood flow (CBF), free water (FW), and white matter hyperintensities (WMH). To explore the relationships between functional elements of the neurovascular unit, this study investigated relationships between these MRI measures using Bayesian mixed models, and their variation with chronological age or atrophy-related brain age (brainageR) using linear regression. In 132 non-clinical older adults (mean age = 67 years; 68% female), BBB k_w positively associated with CBF (β^ = 0.08, 95% credible interval (CI) = [0.02, 0.15]). FW positively associated with both ePVS (β^ = 0.44, CI = [0.30, 0.63]) and WMH (β^ = 0.13, CI = [0.04, 0.21]). BBB k_w, CBF and ePVS decreased with age, while FW and WMH increased (all p < 0.05). There were no associations with atrophy-related brain age (all p > 0.05). Relationships between FW, ePVS and WMH likely reflect interconnectivity of fluid regulation within different compartments, while the relationship between BBB k_w and CBF indicates a link between neurovascular fluid flow and vessel function. While individual metrics of neurovascular integrity are associated with age, their inter-relationships appear stable, providing a baseline for future research in fluid transport and vascular health in neurodegenerative disease.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"59"},"PeriodicalIF":5.9,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12168365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of valproate on the entry of inert hydrophilic markers and expression of tight junction associated genes in the neonatal brain and choroid plexus of a rat model of epilepsy (GAERS).","authors":"Fiona Qiu, Katarzyna M Dziegielewska, Mark D Habgood, Yifan Huang, Norman R Saunders","doi":"10.1186/s12987-025-00667-4","DOIUrl":"10.1186/s12987-025-00667-4","url":null,"abstract":"<p><strong>Background: </strong>The integrity of blood-brain and blood-cerebrospinal fluid (CSF) barriers is characterised by their ability to restrict transcellular passage of inert, hydrophilic markers of different molecular sizes by tight junctions between barrier forming cells. Compromised barrier integrity has been linked to many pathologies, including epilepsy.</p><p><strong>Methods: </strong>Genetic Absence Epilepsy Rat from Strasbourg (GAERS) and Sprague-Dawley (SD) rats between embryonic day 19 and 21-week were administered an injection of radiolabelled sucrose (342 Da) or dextran (70 kDa) intravenously. After 5 min, plasma, CSF and brain samples were collected for radioactivity measurement. Experiments were performed in drug naïve and valproate (an antiseizure medication) exposed animals. Postnatal rats were provided with a valproate diet (20 g/kg), and fetal animals were exposed to the drug via placental transfer from pregnant dams consuming the diet. Brain cortex and choroid plexus transcriptomes from both rat strains were examined and compared for the expression of tight junction associated proteins. Additionally, differential expression analyses were performed on valproate exposed and control postnatal GAERS pups.</p><p><strong>Results: </strong>Brain/plasma and CSF/plasma concentration ratios of 70 kDa dextran were elevated during a specific period of postnatal development (newborn to 13-week-old) in GAERS compared to age-matched SD rats. In contrast, brain and CSF distribution spaces of sucrose, as well as expression of most transcripts for tight junction associated proteins in cortex and choroid plexus were similar between the strains. Long term postnatal or fetal exposure to valproate reduced the elevated apparent brain distribution space of dextran in GAERS to levels similar to SD rats and correlated with some changes in gene expression in the cortex and choroid plexus.</p><p><strong>Conclusions: </strong>Increased apparent brain and CSF distribution spaces of a large hydrophilic molecule, dextran, but not of a smaller marker sucrose in GAERS implied that while the integrity of brain barriers did not appear to be compromised, its phenotype was distinctly different from that of Sprague Dawley rats. Exposure of GAERS to valproate induced a change in brain barriers phenotype to one more similar to that in Sprague Dawley rats. Understanding potential link between this barrier phenotype and postnatal onset of seizures may shed light on common factor(s) affecting development of cerebral blood vessels and neurons, and their relevance to epileptic seizures.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"56"},"PeriodicalIF":5.9,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144283168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting NLRP3 signaling with a novel sulfonylurea compound for the treatment of vascular cognitive impairment and dementia.","authors":"Adnan Akif, Thi Thanh My Nguyen, Langni Liu, Xiaotian Xu, Amol Kulkarni, Jianxiong Jiang, Yang Zhang, Jiukuan Hao","doi":"10.1186/s12987-025-00665-6","DOIUrl":"10.1186/s12987-025-00665-6","url":null,"abstract":"<p><strong>Background: </strong>As a key inflammatory factor, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in neuroinflammation and the progression of neurodegenerative diseases. Dysregulation of NLRP3 signaling can trigger various inflammatory responses in the brain, contributing to the development of neurodegenerative diseases such as ischemic stroke, vascular dementia (VaD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Therefore, the NLRP3 signaling pathway is a promising therapeutic target for the treatment of neurodegenerative diseases, including VaD.</p><p><strong>Methods: </strong>In this study, we investigated the therapeutic effects of a synthetic sulfonylurea NLRP3 inhibitor, AMS-17, in a VaD mouse model using bilateral common carotid artery stenosis (BCAS) and elucidated the underlying mechanisms. All mice were randomly divided into three groups: Sham, VaD + Vehicle, and VaD + AMS-17. Cognitive function was assessed using the Y-maze and Morris water maze (MWM) on the 50th day after BCAS. Brain sections and blood serum samples were collected for biomarker analysis and immunohistochemistry. Neurodegeneration, expressions of the molecules involved in the NLRP3 signaling pathways, tight junction proteins, and myelination were assessed using western blotting and immunofluorescence (IF). The levels of Interleukin-1 beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-4 (IL-4) in the blood were measured using ELISA.</p><p><strong>Results: </strong>AMS-17 treatment improved cognitive function, enhanced blood-brain barrier (BBB) integrity, and promoted remyelination in VaD mice. Additionally, AMS-17 reduced neurodegeneration and decreased the expression of NLRP3 and its associated proteins, Apoptosis-associated speck-like protein (ASC), and cleaved caspase-1 in the brain. It also lowered pro-inflammatory TNF-α and IL-1β levels, while increasing the anti-inflammatory IL-4 level in the blood.</p><p><strong>Conclusions: </strong>The findings of this study provide the first promising evidence for the use of AMS-17 in VaD treatment in mice. This study introduces AMS-17 as a novel chemical scaffold with NLRP3 inhibitory activity, which can be further developed for the treatment of VaD in humans.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"55"},"PeriodicalIF":5.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of cerebrospinal fluid secretion facilitated by serotonergic and noradrenergic receptors in the rat choroid plexus.","authors":"Beatriche L Edelbo, Annette B Steffensen, Eszter O Revesz, Søren N Andreassen, Nanna MacAulay","doi":"10.1186/s12987-025-00666-5","DOIUrl":"10.1186/s12987-025-00666-5","url":null,"abstract":"<p><strong>Background: </strong>The intracranial pressure (ICP) increases at night, partly due to an elevated rate of cerebrospinal fluid (CSF) secretion, which may have therapeutic implications for pressure-related disorders. With similar diurnal regulation in nocturnal rodents and diurnal humans, the diurnally fluctuating CSF dynamics may be governed by nightly shifts in central neuromodulators.</p><p><strong>Method: </strong>We determined the CSF secretion rate in rats upon modulation by melatonin, serotonin, and noradrenaline in association with transcript and protein analysis of choroid plexus receptors.</p><p><strong>Results: </strong>The CSF secretion rate was unaffected by melatonin administration, but was reduced with central delivery of serotonin or noradrenaline. The latter produced only a brief surge in the CSF secretion rate upon systemic delivery. The neuromodulators may thus act on the luminal side of the choroid plexus on the selection of serotonergic and adrenergic receptors expressed in this tissue, some of which displayed diurnal regulation.</p><p><strong>Conclusion: </strong>Diurnally fluctuating central serotonin and noradrenaline levels and/or diurnal fluctuation in choroid plexus adrenergic receptor expression may contribute to the diurnal shift in human and rodent CSF secretion rate. These signaling pathways could thus potentially be harnessed to create pharmacological modulation of the CSF secretion rate in pathological conditions of elevated ICP.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"54"},"PeriodicalIF":5.9,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteome profile differences among human, monkey, and mouse brain microvessels and cultured brain microvascular endothelial cells.","authors":"Haruka Kumabe, Takeshi Masuda, Shingo Ito, Tomomi Furihata, Akiko Toda, Masayuki Mogi, Norie Araki, Sumio Ohtsuki","doi":"10.1186/s12987-025-00650-z","DOIUrl":"10.1186/s12987-025-00650-z","url":null,"abstract":"<p><strong>Background: </strong>The blood-brain barrier (BBB) expresses transporters, receptors, and tight junction proteins that regulate the exchange of substances between the blood and brain. The differences in the expression of these proteins in the BBB among different species and cultured BBB model cells should be clarified to interpret the BBB function in model animals and cells. This study aimed to elucidate species differences among humans, monkeys, and mice and in vitro-in vivo differences in the BBB proteome using deep proteomic analysis.</p><p><strong>Methods: </strong>Brain microvessels (BMVs) were isolated from frozen cerebral cortices of human and monkey and frozen mouse cerebrums. BMVs and cultured brain microvascular endothelial cells (BMECs), such as hCMEC/D3, HBMEC/ciβ, and primary BMECs, were analyzed via data-independent acquisition using liquid chromatography-mass spectrometry.</p><p><strong>Results: </strong>Proteomics identified 7,149-8,274 proteins in the BMV fractions and 6,657-7,534 proteins in the brain lysates. Comparative analysis revealed distinct proteomic profiles among the three species, with the human profile being more similar to that of monkeys than that of mice. The expression profile of the solute carrier organic anion transporter family was found to vary among mouse, monkey, and human BMVs. The expression levels of SLC22A6/Slc22a6 and SLC22A8/Slc22a8 were higher in mice than in monkeys and humans, whereas SLC43A3/Slc43a3 expression levels were lower in mice. The expression of amino acid transporters, such as SLC7A5 and SLC3A2/Slc3a2, was higher in BMVs, whereas that of SLC1A5/Slc1a5 and SLC38A9/Slc38a9 was higher in cultured BMECs. MFSD2A/Mfsd2a and SLC27A1/Slc27a1 were highly expressed in BMVs. The expression of tight junction proteins, particularly the claudin family, varied between BMVs and cultured BMECs and among cell lines. Specifically, the expression of claudin-5 was higher in BMVs, and claudin-11 expression was higher in cultured BMECs.</p><p><strong>Conclusions: </strong>Deep proteomic analysis revealed species-specific differences in transport-related proteins in the BBB. Furthermore, in vitro and in vivo differences were observed in the transporter and claudin protein expression. This study provides a BBB proteome profile dataset and offers insights for a comprehensive understanding of BBB protein expression across species and between in vivo and in vitro conditions.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"53"},"PeriodicalIF":5.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12124085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}