Fluids and Barriers of the CNS最新文献

{"title":"Ependymal cilia decline and AQP4 upregulation in young adult rats with syringomyelia.","authors":"Longbing Ma, Sumei Liu, Qingyu Yao, Xinyu Wang, Jian Guan, Fengzeng Jian","doi":"10.1186/s12987-025-00631-2","DOIUrl":"10.1186/s12987-025-00631-2","url":null,"abstract":"<p><strong>Background: </strong>Syringomyelia was a rare condition characterized by the formation of fluid-filled cysts (syrinx) within the spinal cord, resulting in sensory and motor dysfunction. Currently, there was no satisfactory treatment for syringomyelia. Ependymal cells were integral to water transport and may represent a promising therapeutic target.</p><p><strong>Methods: </strong>Induction of syringomyelia occurred in 8-week old female rats followed by histological analyses at 3-, 7-, 14-, 30-, 60-, 180-, and 365-days later. Scanning electron microscope (SEM) and transmission electron microscope (TEM) were performed to visualize cilia on rat central canal membrane cells at 30-day post-induction. Syringomyelia was induced via compression at T12-T13 using a sterile cotton ball. Each rat underwent MRI scanning one day before induction and one day prior to sacrifice. In vivo magnetic resonance imaging (MRI) was utilized to measure syrinx enlargement in eight-week-old syringomyelia rats. Histological Analysis and immunofluorescence staining were performed for changes of cilia, neurons, expression of AQP4 and infiltration of immune cells into spinal tissue.</p><p><strong>Results: </strong>In the current study, the cell junctions between ependymal cells of syringomyelia rats were absent, and the cilia on ependymal cells were reduced significantly on day 30 post syringomyelia. The number of ependymal cells kept increasing lasting for 1-2 months and begin to decrease. Edema and vacuolation in the spinal cord tissue are significant in syringomyelia rats. Furthermore, AQP4 expression was elevated in astrocytes of syringomyelia rats, and IBA1⁺ immune cells infiltrated spinal tissue. Furthermore, neuronal necrosis began in the acute stage of syringomyelia, and reached its peak one month later. Pathological changes in axonal rupture at anterior commissure (connection of the left and right white matter) could be observed in syringomyelia spinal tissue.</p><p><strong>Conclusions: </strong>These findings underscored the significance of cilia on ependymal cells and the evolving microenvironment post-syringomyelia, providing valuable insights for clinical treatment strategies for this condition.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"21"},"PeriodicalIF":5.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491457","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":"Neurogenesis and glial impairments in congenital hydrocephalus: insights from a BioGlue-induced fetal lamb model.","authors":"Dicle Karakaya, Kristin Lampe, Jose L Encinas, Soner Duru, Lucas Peiro, Halil Kamil Oge, Francisco M Sanchez-Margallo, Marc Oria, Jose L Peiro","doi":"10.1186/s12987-025-00630-3","DOIUrl":"10.1186/s12987-025-00630-3","url":null,"abstract":"<p><strong>Background: </strong>Congenital hydrocephalus (HCP) is a prevalent condition, that leads to fetal cerebral ventricle dilation and increased intracranial pressure. It is associated with significant neurological impairments, partly due to the disruption of neurogenesis and gliogenesis. This study aims to investigate alterations in the proliferation and differentiation of neural progenitor cells (NPCs) in a fetal lamb model of obstructive HCP induced by intracisternal BioGlue injection, to identify the potential optimal intervention time for prenatal surgery.</p><p><strong>Methods: </strong>This study involved 22 fetal lambs, divided into control (n = 10) and HCP (n = 12) groups with hydrocephalus induced at approximately 85-90 gestational days. Histological and molecular techniques, including hematoxylin and eosin staining, triple immunofluorescence, Western blot analysis, and RT-qPCR, were utilized to assess changes in NPCs, astrocytes, and oligodendrocytes across three different gestational stages (E105, E125, and E140). The analysis of data was done by using multiple (unpaired) two-sample t-test and was represented as mean and standard deviation.</p><p><strong>Results: </strong>HCP led to significant disruptions in the ventricular zone (VZ), with the translocation of NPCs into the intraventricular CSF and formation of periventricular heterotopias. This study revealed an initial surge in the expression of NPC markers (Pax6 and Sox2), which decreased as HCP progressed. Astroglia reaction intensified, as indicated by increased expression of GFAP, vimentin, and aquaporin 4, particularly at later stages of pregnancy (p < 0.001, p < 0.001 and p < 0.001, control and HCP E140, respectively). Myelin formation was also adversely affected, with reduced expression of oligodendrocyte markers (Olig2 and Sox10, p = 0.01 and p = 0.009, control and HCP E140, respectively) and myelin proteins (MOBP, MOG and MBP, p = 0.02, p = 0.049 and p = 0.02 control and HCP E140, respectively).</p><p><strong>Conclusions: </strong>This study contributed to clarify the profound impact of congenital HCP on neurogenesis and gliogenesis in an experimental fetal lamb model. The VZ disruption and altered expression of key neurogenic and glial markers suggested a significant pathological process underlying neurodevelopmental abnormalities. The findings suggested a potential window for prenatal surgical intervention between E105 and E125 in the sheep model, offering new avenues for prenatal therapeutic approaches and improving surgical outcomes in affected fetuses and neonates.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"20"},"PeriodicalIF":5.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491460","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":"The glutathione-dependent neuroprotective activity of the blood-CSF barrier is inducible through the Nrf2 signaling pathway during postnatal development.","authors":"Nathalie Strazielle, Karen Silva, Emmanuel Rault, Cindy Durand, Elodie Saudrais, Pascal Mein, Sandrine Blondel, Anne Denuzière, Jean-François Ghersi-Egea","doi":"10.1186/s12987-025-00622-3","DOIUrl":"10.1186/s12987-025-00622-3","url":null,"abstract":"<p><strong>Background: </strong>Choroid plexuses regulate the exchanges between the blood and the CSF, and provide trophic factors necessary to brain development. They also express detoxifying enzymes that protect the developing brain from harmful substances. Targeting the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathway may enhance the detoxification capabilities of choroid plexuses that are linked to glutathione conjugation, but little is known about mechanisms of enzyme induction in this tissue.</p><p><strong>Methods: </strong>Rat pups were treated with dimethylfumarate and the subcellular localization of Nrf2 was analyzed in the choroidal tissue by confocal imaging. Glutathione-S-transferase (GST) activity was assessed ex vivo in the choroidal tissue, and 1-chloro-2,4-dinitrobenzene, a toxicant and prototypic GST substrate, was used to evaluate in vivo the efficiency of the glutathione-dependent enzymatic barrier function of choroid plexuses. Nrf2 knockout rat pups were used to establish the Nrf2 dependency of GST induction in this tissue.</p><p><strong>Results: </strong>We show an early postnatal expression of Nrf2 in the rat choroidal tissue. Treatment of rat pups with dimethylfumarate triggers Nrf2 nuclear translocation in choroidal epithelial cells. This treatment increases GST activity in choroid plexus, and reduces the blood-to-CSF permeation of 1-chloro-2,4-dinitrobenzene. In Nrf2 knockout rats, the constitutive activity of the choroidal glutathione-dependent detoxifying machinery is maintained, but the efficacy of dimethylfumarate to induce glutathione conjugation in the choroid plexuses is strongly reduced, indicating that dimethylfumarate acts mainly through the Nrf2 signaling pathway.</p><p><strong>Conclusions: </strong>This work shows that the glutathione-dependent detoxifying function of the blood-CSF barrier can be pharmacologically enhanced through the Nrf2 signaling pathway to better protect the neural fluid environment from drug and toxic accumulation during the neonatal period.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"19"},"PeriodicalIF":5.9,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476418","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":"Alanine and glutathione targeting of dopamine- or ibuprofen-coupled polypeptide nanocarriers increases both crossing and protective effects on a blood-brain barrier model.","authors":"Mária Mészáros, Thi Ha My Phan, Judit P Vigh, Gergő Porkoláb, Anna Kocsis, Anikó Szecskó, Emese K Páli, Nárcisz M Cser, Tamás F Polgár, Gábor Kecskeméti, Fruzsina R Walter, Jens C Schwamborn, Tamás Janáky, Jeng-Shiung Jan, Szilvia Veszelka, Mária A Deli","doi":"10.1186/s12987-025-00623-2","DOIUrl":"10.1186/s12987-025-00623-2","url":null,"abstract":"<p><strong>Background: </strong>Targeting the blood-brain barrier (BBB) is a key step for effective brain delivery of nanocarriers. We have previously discovered that combinations of BBB nutrient transporter ligands alanine and glutathione (A-GSH), increase the permeability of vesicular and polypeptide nanocarriers containing model cargo across the BBB. Our aim was to investigate dopamine- and ibuprofen-coupled 3-armed poly(L-glutamic acid) nanocarriers targeted by A-GSH for transfer across a novel human co-culture model with induced BBB properties. In addition, the protective effect of ibuprofen containing nanoparticles on cytokine-induced barrier damage was also measured.</p><p><strong>Method: </strong>Drug-coupled nanocarriers were synthetized and characterized by dynamic light scattering and transmission electron microscopy. Cellular effects, uptake, and permeability of the nanoparticles were investigated on a human stem cell-based co-culture BBB model with improved barrier properties induced by a small molecular cocktail. The model was characterized by immunocytochemistry and permeability for marker molecules. Nanocarrier uptake in human brain endothelial cells and midbrain organoids was quantified by spectrofluorometry and visualized by confocal microscopy. The mechanisms of cellular uptake were explored by addition of free targeting ligands, endocytic and metabolic inhibitors, co-localization of nanocarriers with intracellular organs, and surface charge modification of cells. The protective effect of ibuprofen-coupled nanocarriers was investigated against cytokine-induced barrier damage by impedance and permeability measurements.</p><p><strong>Results: </strong>Targeted nanoformulations of both drugs showed elevated cellular uptake in a time-dependent, active manner via endocytic mechanisms. Addition of free ligands inhibited the cellular internalization of targeted nanocarriers suggesting the crucial role of ligands in the uptake process. A higher permeability across the BBB model was measured for targeted nanocarriers. After crossing the BBB, targeted dopamine nanocarriers subsequently entered midbrain-like organoids derived from healthy and Parkinson's disease patient-specific stem cells. The ibuprofen-coupled targeted nanocarriers showed protective effects against cytokine-induced barrier damage.</p><p><strong>Conclusion: </strong>BBB-targeted polypeptide nanoparticles coupled to therapeutic molecules were effectively taken up by brain organoids or showing a BBB protective effect indicating potential applications in nervous system pathologies.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"18"},"PeriodicalIF":5.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457333","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":"Low prevalence of CWH43 variants among Finnish and Norwegian idiopathic normal pressure hydrocephalus patients: a cohort-based observational study.","authors":"Joel Räsänen, Seppo Helisalmi, Sami Heikkinen, Joose Raivo, Ville E Korhonen, Henna Martiskainen, Antti Junkkari, Benjamin Grenier-Boley, Céline Bellenguez, Minna Oinas, Cecilia Avellan, Janek Frantzen, Anna Kotkansalo, Jaakko Rinne, Antti Ronkainen, Mikko Kauppinen, Mikael von Und Zu Fraunberg, Kimmo Lönnrot, Jarno Satopää, Markus Perola, Anne M Koivisto, Valtteri Julkunen, Anne M Portaankorva, Arto Mannermaa, Hilkka Soininen, Juha E Jääskeläinen, Jean-Charles Lambert, Per K Eide, Aarno Palotie, Mitja I Kurki, Mikko Hiltunen, Ville Leinonen, Anssi Lipponen","doi":"10.1186/s12987-025-00625-0","DOIUrl":"10.1186/s12987-025-00625-0","url":null,"abstract":"<p><strong>Background: </strong>Heterozygous CWH43 loss-of-function (LOF) variants have been identified as iNPH risk factors, with 10-15% of iNPH patients carrying these variants in cohorts from the US. Mouse model harboring CWH43 LOF variants display a hydrocephalic phenotype with ventricular cilia alterations. Our aim was to study the effect of CWH43 variants on disease risk and clinical phenotype in Finnish and Norwegian iNPH cohorts.</p><p><strong>Methods: </strong>We analyzed CWH43 LOF frameshift deletions (4:49032652 CA/C, Leu533Ter and 4:49061875 CA/C, Lys696AsnfsTer23) in Finnish iNPH patients from the Kuopio NPH registry (n = 630) and FinnGen (iNPH n = 1 131, controls n = 495 400), and Norwegian iNPH patients from EADB (n = 306). The Kuopio and Norwegian cohorts included possible and probable iNPH patients based on the American-European iNPH guidelines. FinnGen cohort included iNPH patients based on ICD-10 G91.2 with the exclusion of secondary etiologies, and controls having no diagnosis of hydrocephalus.</p><p><strong>Results: </strong>In the Kuopio cohort of Finnish iNPH patients, 2.9% carried CWH43 variants (Leu533Ter 2.1%, Lys696AsnfsTer23 0.8%), with one homozygous Leu533Ter carrier. In FinnGen, 3.1% of iNPH patients carried heterozygous variants (Leu533Ter 2.6%, Lys696AsnfsTer23 0.5%) compared to 2.5% of controls (p = 0.219, OR = 1.23, 95% CI 0.85-1.72), with no effect on disease risk or onset age. Importantly in the FinnGen cohort, none of the 23 compound heterozygote or 59 homozygote individuals had hydrocephalus diagnosis. In the Norwegian iNPH cohort, 5.2% of patients were heterozygous variant carriers (Leu533Ter 3.3%, Lys696AsnfsTer23 2.0%). No differences in clinical phenotype (age, triad symptoms, shunt response, vascular comorbidities) were found between carriers and noncarriers in any cohort. However, 74% of variant-carrying iNPH patients in FinnGen were female, compared to 47% of noncarriers (p = 0.002). Pedigrees indicated no autosomal dominant co-inheritance of iNPH and the CWH43 variants.</p><p><strong>Conclusions: </strong>We studied the iNPH-associated CWH43 LOF variants for the first time on a population-scale. Contrary to previously reported findings in smaller cohorts, our study revealed a low prevalence of these variants in the population-scale Finnish iNPH cohort, with no effect on disease risk of iNPH. The prevalence in the Norwegian iNPH cohort was also low compared to previous studies.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"17"},"PeriodicalIF":5.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413904","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":"Kidins220-deficient hydrocephalus mice exhibit altered glial phenotypes and AQP4 differential regulation in the retina and optic nerve, with preserved retinal ganglion cell survival.","authors":"Jose A Fernández-Albarral, Ana Simón-García, Elena Salobrar-García, Juan J Salazar, Celia López-Menéndez, Luis S M Pajuelo, Jose A Matamoros, Rosa de Hoz, Inés López-Cuenca, Lorena Elvira-Hurtado, Lidia Sanchez-Puebla, Marina P Sánchez-Carralero, Marina Sanz, José M Ramírez, Teresa Iglesias, Ana I Ramírez","doi":"10.1186/s12987-025-00626-z","DOIUrl":"10.1186/s12987-025-00626-z","url":null,"abstract":"<p><p>Hydrocephalus, characterized by ventriculomegaly due to cerebrospinal fluid accumulation in the cerebral ventricles, is a co-morbidity factor in several neurodevelopmental, psychiatric and neurodegenerative diseases. Aquaporin-4 (AQP4) is crucial for brain water homeostasis, with Aqp4 knockout mice showing sporadic ventriculomegaly and increased brain water content. Kinase D interacting substrate of 220 kDa (Kidins220), a transmembrane protein involved in neuronal survival, synaptic activity and neurogenesis, controls AQP4 levels in ependymocytes and brain astrocytes. Indeed, Kidins220 deficiency in mice leads to hydrocephalus by downregulating VPS35, a key component of the retromer complex, and targeting AQP4 to lysosomal degradation. Importantly, the ependymal barrier of idiopathic normal pressure hydrocephalus patients shows a similar downregulation of KIDINS220 and AQP4. In addition, pathogenic variants in the KIDINS220 gene are linked to SINO syndrome, a rare disorder characterized by spastic paraplegia, intellectual disability, nystagmus, and obesity associated with hydrocephalus and ventriculomegaly. Given the retina's structural and functional similarities to the brain, we hypothesized that Kidins220 deficiency would affect retinal water regulation. However, the diminished expression of Kidins220 and VPS35 in the retina of Kidins220-deficient hydrocephalus mice, did not cause edema or downregulate AQP4 in Müller cells. Surprisingly, there was an increase in AQP4 levels within this glial cell population. Conversely, AQP4 expression in the optic nerve astrocytes was reduced, as observed in brain astrocytes, suggesting a distinctive adaptive response to hydrocephalus in Müller glia within the Kidins220-deficient retina. Furthermore, we observed phenotypic modifications in retinal glia in Kidins220-deficient hydrocephalus mice. However, we did not find any signs of neuronal damage in the retina. Future studies using OCT and OCTA in SINO syndrome patients with ventriculomegaly will be essential in elucidating the relationship between KIDINS220 pathogenic variants, retinal alterations, papilledema, and visual function.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"16"},"PeriodicalIF":5.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406519","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":"Blood-CSF barrier clearance of ABC transporter substrates is suppressed by interleukin-6 in lupus choroid plexus spheroids.","authors":"Joshua A Reynolds, Lola Torz, Leslie Cummins, Ariel D Stock, Ayal Ben-Zvi, Chaim Putterman","doi":"10.1186/s12987-025-00628-x","DOIUrl":"10.1186/s12987-025-00628-x","url":null,"abstract":"<p><strong>Background: </strong>The choroid plexus (CP) has been recently implicated in the pathogenesis of the neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE). Lupus patients demonstrate increased serum and cerebrospinal fluid (CSF) concentrations of interleukin-6 (IL-6), which can disrupt vital blood-CSF barrier (B-CSFB) functions performed by the CP. However, difficulty accessing this tissue has largely precluded dynamic imaging or evaluation of CP barrier function in vivo.</p><p><strong>Methods: </strong>In this study, explant CP spheroids which replicate the functional and structural properties of the B-CSFB were generated from 12 + week old female MRL/lpr (IL-6 wildtype; IL-6 WT) lupus mice, IL-6 knockout (IL-6 KO) MRL/lpr mice, and congenic control MRL/mpj mice. CP spheroids derived from IL-6 WT MRL/lpr mice were found to synthesize and secrete IL-6, similar to the CP in vivo, whereas the IL-6 KO spheroids did not produce IL-6. Accumulation of different fluorescent tracers within the central CSF-like fluid vacuole of spheroids, modeling brain ventricles, was measured to probe transcellular permeability, paracellular diffusion, and clearance functions of the CP.</p><p><strong>Results: </strong>As shown by blocking the IL-6 receptor in IL-6 WT spheroids or comparing them to IL-6 KO spheroids, IL-6 signaling decreased spheroid clearance of methotrexate, a chemotherapeutic drug employed in the therapy of lupus, and lucifer yellow. This suppression occurred without altering CP epithelial morphology and ultrastructure. Methotrexate and lucifer yellow efflux can occur through ATP-binding cassette (ABC) transporters, including BCRP and MRP1. Cytoplasmic accumulation of the ABC-specific dye fluorescein diacetate was also increased by IL-6. Pharmacologic inhibition of either BCRP or MRP1 in IL-6 KO spheroids was sufficient to recreate the clearance deficits observed in IL-6 WT spheroids. Moreover, CP expression of BCRP was significantly lower in IL-6 WT mice.</p><p><strong>Conclusions: </strong>In this study, we establish, validate, and apply a CP spheroid model to the study of B-CSFB function in lupus. Our results show that IL-6, a key cytokine increased in NPSLE, can potentially suppress the CP-specific function and expression of BCRP and MRP1. Therefore, IL-6 could affect the CSF clearance of inflammatory substrates (e.g., leukotrienes), the accumulation of which would incite neurotoxicity and promote progression of NPSLE.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"15"},"PeriodicalIF":5.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11816793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398913","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":"Choroid plexus organoids reveal mechanisms of Streptococcus suis translocation at the blood-cerebrospinal fluid barrier.","authors":"Tiantong Zhao, Laura Pellegrini, Bart van der Hee, Jos Boekhorst, Aline Fernandes, Sylvia Brugman, Peter van Baarlen, Jerry M Wells","doi":"10.1186/s12987-025-00627-y","DOIUrl":"10.1186/s12987-025-00627-y","url":null,"abstract":"<p><p>Streptococcus suis is a globally emerging zoonotic pathogen that can cause invasive disease commonly associated with meningitis in pigs and humans. To cause meningitis, S. suis must invade the central nervous system (CNS) by crossing the neurovascular unit, also known as the blood-brain barrier (BBB), or vascularized choroid plexus (ChP) epithelium known as the blood-cerebrospinal fluid barrier (BCSFB). Recently developed ChP organoids have been shown to accurately replicate the cytoarchitecture and physiological functions of the ChP epithelium in vivo. Here, we used human induced pluripotent stem cells (iPSC)-derived ChP organoids as an in vitro model to investigate S. suis interaction and infection at the BCSFB. Our study revealed that S. suis is capable of translocating across the epithelium of ChP organoids without causing significant cell death or compromising the barrier integrity. Plasminogen (Plg) binding to S. suis in the presence of tissue plasminogen activator (tPA), which converts immobilized Plg to plasmin (Pln), significantly increased the basolateral to apical translocation across ChP organoids into the CSF-like fluid in the lumen. S. suis was able to replicate at the same rate in CSF and laboratory S. suis culture medium but reached a lower final density. The analysis of transcriptomes in ChP organoids after S. suis infection indicated inflammatory responses, while the addition of Plg further suggested extracellular matrix (ECM) remodeling. To our knowledge, this is the first study using ChP organoids to investigate bacterial infection of the BCSFB. Our findings highlight the potential of ChP organoids as a valuable tool for studying the mechanisms of bacterial interaction and infection of the human ChP in vitro.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"14"},"PeriodicalIF":5.9,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11812244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390581","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":"Endothelial and neuronal engagement by AAV-BR1 gene therapy alleviates neurological symptoms and lipid deposition in a mouse model of Niemann-Pick type C2.","authors":"Charlotte Laurfelt Munch Rasmussen, Signe Frost Frederiksen, Christian Würtz Heegaard, Maj Schneider Thomsen, Eva Hede, Bartosz Laczek, Jakob Körbelin, Daniel Wüstner, Louiza Bohn Thomsen, Markus Schwaninger, Ole N Jensen, Torben Moos, Annette Burkhart","doi":"10.1186/s12987-025-00621-4","DOIUrl":"10.1186/s12987-025-00621-4","url":null,"abstract":"<p><strong>Background: </strong>Patients with the genetic disorder Niemann-Pick type C2 disease (NP-C2) suffer from lysosomal accumulation of cholesterol causing both systemic and severe neurological symptoms. In a murine NP-C2 model, otherwise successful intravenous Niemann-Pick C2 protein (NPC2) replacement therapy fails to alleviate progressive neurodegeneration as infused NPC2 cannot cross the blood-brain barrier (BBB). Genetic modification of brain endothelial cells (BECs) is thought to enable secretion of recombinant proteins thereby overcoming the restrictions of the BBB. We hypothesized that an adeno-associated virus (AAV-BR1) encoding the Npc2 gene could cure neurological symptoms in Npc2-/- mice through transduction of BECs, and possibly neurons via viral passage across the BBB.</p><p><strong>Methods: </strong>Six weeks old Npc2-/- mice were intravenously injected with the AAV-BR1-NPC2 vector. Composite phenotype scores and behavioral tests were assessed for the following 6 weeks and visually documented. Post-mortem analyses included gene expression analyses, verification of neurodegeneration in Purkinje cells, determination of NPC2 transduction in the CNS, assessment of gliosis, quantification of gangliosides, and co-detection of cholesterol with NPC2 in degenerating neurons.</p><p><strong>Results: </strong>Treatment with the AAV-BR1-NPC2 vector improved motor functions, reduced neocortical inflammation, and preserved Purkinje cells in most of the mice, referred to as high responders. The vector exerted tropism for BECs and neurons resulting in a widespread NPC2 distribution in the brain with a concomitant reduction of cholesterol in adjacent neurons, presumably not transduced by the vector. Mass spectrometry imaging revealed distinct lipid alterations in the brains of Npc2-/- mice, with increased GM2 and GM3 ganglioside accumulation in the cerebellum and hippocampus. AAV-BR1-NPC2 treatment partially normalized these ganglioside distributions in high responders, including restoration of lipid profiles towards those of Npc2+/+ controls.</p><p><strong>Conclusion: </strong>The data suggests cross-correcting gene therapy to the brain via delivery of NPC2 from BECs and neurons.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"13"},"PeriodicalIF":5.9,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074454","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":"Age-related cerebral ventriculomegaly occurs in patients with primary ciliary dyskinesia.","authors":"Franziska Eisenhuth, Joy E Agbonze, Adam M R Groh, Jesse M Klostranec, David A Rudko, Jo Anne Stratton, Adam J Shapiro","doi":"10.1186/s12987-024-00614-9","DOIUrl":"10.1186/s12987-024-00614-9","url":null,"abstract":"<p><p>Primary ciliary dyskinesia (PCD) is a genetic disorder causing motile ciliary dysfunction primarily affecting the respiratory and reproductive systems. However, the impact of PCD on the central nervous system remains poorly understood. Rodent models of PCD exhibit marked hydrocephalus leading to early animal mortality, however, most humans with PCD do not develop hydrocephalus for unknown reasons. We hypothesized that patients with PCD exhibit sub-clinical ventriculomegaly related to ependymal motile ciliary dysfunction. We demonstrated highly specific expression levels of known PCD-related genes in human brain multiciliated ependymal cells (p < 0.0001). To assess ventricular size, computed tomography sinus images from patients with PCD (n = 33) and age/sex-matched controls (n = 64) were analysed. Patients with PCD displayed significantly larger ventricular areas (p < 0.0001) and Evans index (p < 0.01), indicating ventriculomegaly that was consistent across all genetic subgroups. Ventricular enlargement correlated positively with increasing age in patients with PCD compared to controls (p < 0.001). Additionally, chart review demonstrated a high prevalence (39%) of neuropsychiatric/neurological disorders in adult PCD patients that did not correlate with degree of ventriculomegaly. Our findings suggest that patients with PCD may have unrecognized, mild ventriculomegaly which correlates with ageing, potentially attributable to ependymal ciliary dysfunction. Further study is required to determine causality, and whether ventricular enlargement contributes to neuropsychiatric/neurological or other morbidity in PCD.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"12"},"PeriodicalIF":5.9,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074452","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}