Central Nervous System Barriers Research Articles

Metabolite transport across central nervous system barriers.

Metabolomic analysis of cerebrospinal fluid (CSF) is used to improve diagnostics and pathophysiological understanding of neurological diseases. Alterations in CSF metabolite levels can partly be attributed to changes in brain metabolism, but relevant transport processes influencing CSF metabolite concentrations should be considered. The entry of molecules including metabolites into the central nervous system (CNS), is tightly controlled by the blood-brain, blood-CSF, and blood-spinal cord barriers, where aquaporins and membrane-bound carrier proteins regulate influx and efflux via passive and active transport processes. This report therefore provides reference for future CSF metabolomic work, by providing a detailed summary of the current knowledge on the location and function of the involved transporters and routing of metabolites from blood to CSF and from CSF to blood.

The liver and muscle secreted HFE2-protein maintains central nervous system blood vessel integrity

Liver failure causes breakdown of the Blood CNS Barrier (BCB) leading to damages of the Central-Nervous-System (CNS), however the mechanisms whereby the liver influences BCB-integrity remain elusive. One possibility is that the liver secretes an as-yet to be identified molecule(s) that circulate in the serum to directly promote BCB-integrity. To study BCB-integrity, we developed light-sheet imaging for three-dimensional analysis. We show that liver- or muscle-specific knockout of Hfe2/Rgmc induces BCB-breakdown, leading to accumulation of toxic-blood-derived fibrinogen in the brain, lower cortical neuron numbers, and behavioral deficits in mice. Soluble HFE2 competes with its homologue RGMa for binding to Neogenin, thereby blocking RGMa-induced downregulation of PDGF-B and Claudin-5 in endothelial cells, triggering BCB-disruption. HFE2 administration in female mice with experimental autoimmune encephalomyelitis, a model for multiple sclerosis, prevented paralysis and immune cell infiltration by inhibiting RGMa-mediated BCB alteration. This study has implications for the pathogenesis and potential treatment of diseases associated with BCB-dysfunction.

Recent advances in understanding the human host immune response in tuberculous meningitis.

Tuberculous meningitis (TBM), the most severe form of tuberculosis, causes death in approximately 25% cases despite antibiotic therapy, and half of survivors are left with neurological disability. Mortality and morbidity are contributed to by a dysregulated immune response, and adjunctive host-directed therapies are required to modulate this response and improve outcomes. Developing such therapies relies on improved understanding of the host immune response to TBM. The historical challenges in TBM research of limited in vivo and in vitro models have been partially overcome by recent developments in proteomics, transcriptomics, and metabolomics, and the use of these technologies in nested substudies of large clinical trials. We review the current understanding of the human immune response in TBM. We begin with M. tuberculosis entry into the central nervous system (CNS), microglial infection and blood-brain and other CNS barrier dysfunction. We then outline the innate response, including the early cytokine response, role of canonical and non-canonical inflammasomes, eicosanoids and specialised pro-resolving mediators. Next, we review the adaptive response including T cells, microRNAs and B cells, followed by the role of the glutamate-GABA neurotransmitter cycle and the tryptophan pathway. We discuss host genetic immune factors, differences between adults and children, paradoxical reaction, and the impact of HIV-1 co-infection including immune reconstitution inflammatory syndrome. Promising immunomodulatory therapies, research gaps, ongoing challenges and future paths are discussed.

The novel HS-mimetic, Tet-29, regulates immune cell trafficking across barriers of the CNS during inflammation

BackgroundDisruption of the extracellular matrix at the blood–brain barrier (BBB) underpins neuroinflammation in multiple sclerosis (MS). The degradation of extracellular matrix components, such as heparan sulfate (HS) proteoglycans, can be prevented by treatment with HS-mimetics through their ability to inhibit the enzyme heparanase. The heparanase-inhibiting ability of our small dendrimer HS-mimetics has been investigated in various cancers but their efficacy in neuroinflammatory models has not been evaluated. This study investigates the use of a novel HS-mimetic, Tet-29, in an animal model of MS.MethodsNeuroinflammation was induced in mice by experimental autoimmune encephalomyelitis, a murine model of MS. In addition, the BBB and choroid plexus were modelled in vitro using transmigration assays, and migration of immune cells in vivo and in vitro was quantified by flow cytometry.ResultsWe found that Tet-29 significantly reduced lymphocyte accumulation in the central nervous system which, in turn, decreased disease severity in experimental autoimmune encephalomyelitis. The disease-modifying effect of Tet-29 was associated with a rescue of BBB integrity, as well as inhibition of activated lymphocyte migration across the BBB and choroid plexus in transwell models. In contrast, Tet-29 did not significantly impair in vivo or in vitro steady state-trafficking under homeostatic conditions.ConclusionsTogether these results suggest that Tet-29 modulates, rather than abolishes, trafficking across central nervous system barriers.

Immaturity of immune cells around the dural venous sinuses contributes to viral meningoencephalitis in neonates.

High neonatal susceptibility to meningitis has been attributed to the anatomical barriers that act to protect the central nervous system (CNS) from infection being immature and not fully developed. However, the mechanisms by which pathogens breach CNS barriers are poorly understood. Using the Armstrong strain of lymphocytic choriomeningitis virus (LCMV) to study virus propagation into the CNS during systemic infection, we demonstrate that mortality in neonatal, but not adult, mice is high after infection. Virus propagated extensively from the perivenous sinus region of the dura mater to the leptomeninges, choroid plexus, and cerebral cortex. Although the structural barrier of CNS border tissues is comparable between neonates and adults, immunofluorescence staining and single-cell RNA sequencing analyses revealed that the neonatal dural immune cells are immature and predominantly composed of CD206hi macrophages, with major histocompatibility complex class II (MHCII)hi macrophages being rare. In adults, however, perivenous sinus immune cells were enriched in MHCIIhi macrophages that are specialized for producing antiviral molecules and chemokines compared with CD206hi macrophages and protected the CNS against systemic virus invasion. Our findings clarify how systemic pathogens enter the CNS through its border tissues and how the immune barrier at the perivenous sinus region of the dura blocks pathogen access to the CNS.

Novel therapeutic delivery for neurodegenerative diseases: Strategies to overcome CNS barriers

The incidence of central nervous system (CNS) diseases is expected to rise significantly due to increasing lifespan and changing population demographics. Among CNS diseases, neurodegenerative diseases (ND’s) entail a significant challenge since they frequently involve neuronal loss and age-related progressive deterioration in brain function. Although the mechanisms and pathogenesis of neuronal disorders including Parkinson's disease (PD), Alzheimer's disease, and Huntington's disease (HD) have been extensively studied, effective treatment strategies remain limited. Drug delivery to the CNS is particularly challenging and poses a significant obstacle in the management of neurodegeneration. The present review focuses on the challenges associated with neuronal disorders, especially concerning the delivery of macro molecules containing proteins and nucleic acid. Additionally, we highlight opportunities to enhance therapeutic delivery for the treatment of ND’s. As our understanding of the biological aspects of ND’s continues to grow, there is a growing potential for therapeutic interventions. Therefore, these delivery strategies play a vital role for the future transition of CNS therapies from research labs to clinical practices.

Implication of Central Nervous System Barrier Impairment in Amyotrophic Lateral Sclerosis: Gender-Related Difference in Patients.

Central nervous system (CNS) barrier impairment has been reported in amyotrophic lateral sclerosis (ALS), highlighting its potential significance in the disease. In this context, we aim to shed light on its involvement in the disease, by determining albumin quotient (QAlb) at the time of diagnosis of ALS in a large cohort of patients. Patients from the university hospital of Tours (n = 307) were included in this monocentric, retrospective study. In total, 92 patients (30%) had elevated QAlb levels. This percentage was higher in males (43%) than in females (15%). Interestingly, QAlb was not associated with age of onset, age at sampling or diagnostic delay. However, we found an association with ALS functional rating scale-revised (ALSFRS-r) at diagnosis but this was significant only in males. The QAlb levels were not linked to the presence of a pathogenic mutation. Finally, we performed a multivariate survival analysis and found that QAlb was significantly associated with survival in male patients (HR = 2.3, 95% CI = 1.2-4.3, p = 0.009). A longitudinal evaluation of markers of barrier impairment, in combination with inflammatory biomarkers, could give insight into the involvement of CNS barrier impairment in the pathogenesis of the disease. The gender difference might guide the development of new drugs and help personalise the treatment of ALS.

Formation and function of the meningeal arachnoid barrier around the developing mouse brain.

The arachnoid barrier, a component of the blood-cerebrospinal fluid barrier (B-CSFB) in the meninges, is composed of epithelial-like, tight-junction-expressing cells. Unlike other central nervous system (CNS) barriers, its' developmental mechanisms and timing are largely unknown. Here, we show that mouse arachnoid barrier cell specification requires the repression of Wnt-β-catenin signaling and that constitutively active β-catenin can prevent its formation. We also show that the arachnoid barrier is functional prenatally and, in its absence, a small molecular weight tracer and the bacterium group B Streptococcus can cross into the CNS following peripheral injection. Acquisition of barrier properties prenatally coincides with the junctional localization of Claudin 11, and increased E-cadherin and maturation continues after birth, where postnatal expansion is marked by proliferation and re-organization of junctional domains. This work identifies fundamental mechanisms that drive arachnoid barrier formation, highlights arachnoid barrier fetal functions, and provides novel tools for future studies on CNS barrier development.

Engineered extracellular vesicles for ischemic stroke treatment

Dear Editor, Nanotechnology-based therapeutic strategies have been proven effective in diseases including cancer, infection, inflammation, etc.1Machtakova M. Thérien-Aubin H. Landfester K. Polymer nano-systems for the encapsulation and delivery of active biomacromolecular therapeutic agents.Chem. Soc. Rev. 2022; 51: 128-152Crossref PubMed Google Scholar However, the application of nanotechnology is greatly restricted in the treatment of central nervous system (CNS) disorders due to physiological CNS barriers. For example, the blood-brain barrier (BBB) can be the “Maginot line” for pharmacologically active molecules, blocking them out of the CNS. Besides, the neuroinflammation and non-directional differentiation of neural stem cells (NSCs) during neurological disorders could also affect neuronal activity and even produce fibrotic scars, thus hindering the CNS regeneration process.2Dorrier C.E. Aran D. Haenelt E.A. et al.CNS fibroblasts form a fibrotic scar in response to immune cell infiltration.Nat. Neurosci. 2021; 24: 234-244Crossref PubMed Scopus (55) Google Scholar Synthetic nanocarriers, including liposomes, micelles, and nanoparticles, can be engineered through PEGylation and functional surface ligands to overcome the BBB and achieve CNS-targeted drug delivery.3Terstappen G.C. Meyer A.H. Bell R.D. Zhang W. Strategies for delivering therapeutics across the blood-brain barrier.Nat. Rev. Drug Discov. 2021; 20: 362-383Crossref PubMed Scopus (151) Google Scholar,4Ruan H. Yao S. Wang S. et al.Stapled RAP12 peptide ligand of LRP1 for micelles-based multifunctional glioma-targeted drug delivery.Chem. Eng. J. 2021; 403: 126296Crossref Scopus (14) Google Scholar However, repeated administrations of synthetic nanoparticles may trigger unexpected immune responses and increase the blood clearance rate of nanocarriers. Inspired by nature, we focus on the naturally evolved biologic nanoparticles, such as extracellular vesicles (EVs), which are cell-secreted membrane-derived signaling nanoparticles, to address these issues. EVs contain biologically active molecules like lipids, DNA, RNAs, and proteins as natural intercellular signals, so they could serve as natural nanomedicine carriers.5Kalluri R. LeBleu V.S. The biology, function, and biomedical applications of exosomes.Science. 2020; 367: eaau6977Crossref PubMed Scopus (2627) Google Scholar More importantly, EVs also demonstrate the ability to cross the BBB. Combined with the advantages of low immunogenicity and good biocompatibility, EVs are a promising class of biological nanocarriers that can be engineered to improve the treatment of neurological disorders.6Zhang Z.G. Buller B. Chopp M. Exosomes - beyond stem cells for restorative therapy in stroke and neurological injury.Nat. Rev. Neurol. 2019; 15: 193-203Crossref PubMed Scopus (262) Google Scholar Taking ischemic stroke as an example, due to the limited number of NSCs in the injured area and the restricted neuronal differentiation efficiency, the neural regeneration in the cerebral ischemic region is inhibited.7Faiz M. Sachewsky N. Gascón S. et al.Adult neural stem cells from the subventricular zone give rise to reactive astrocytes in the cortex after stroke.Cell Stem Cell. 2015; 17: 624-634Abstract Full Text Full Text PDF PubMed Google Scholar Thus, a biologically engineered nanomedicine that can transmit NSC recruitment signals and activate their neuronal differentiation ability was designed for ischemic stroke treatment. First, the M2 microglia-derived EVs were used as the core. Then stromal cell-derived factor 1 (SDF-1) was covalently grafted on the surface of EVs through copper-free click chemistry to emit NSC recruitment signals (SDF-1-EVs). When intravenously injected, SDF-1-EVs could cross the BBB and accumulate in the ischemic region (Figure 1A). The immunofluorescent assay (Figure 1B) showed that FITC-labeled SDF-1 could co-localize with Dil-red-labeled EVs, suggesting that SDF-1 was successfully modified on EVs. Besides, the morphology of SDF-1-EVs was in a cup shape with an approximate 120 nm diameter, identical to typical EVs (Figures 1C and 1D). Transwell experiments were carried out to verify the effect of SDF-1-EVs on the recruitment of NSCs. The results revealed that adding SDF-1-EVs in the lower chamber significantly induced NSCs in the upper chamber membrane to migrate to the opposite membrane compared with the control and unmodified EVs groups (Figures 1E and 1F). Additionally, in vitro NSC differentiation assays demonstrated (Figures 1G–1I) that SDF-1-EVs can effectively promote neuronal differentiation (Tuj1+ cells) of NSCs while inhibiting astrocytes (GFAP+) generation. Moreover, the induction effect was similar to the unmodified EVs group, indicating that the modification of SDF-1 did not affect their activity on NSC differentiation while conferring the migratory effect of EVs on NSCs. Next, a transient middle cerebral artery occlusion (tMCAO) mouse model was constructed to simulate clinical ischemic stroke. PBS, EVs, and SDF-1-EVs were intravenously injected respectively. 14 days post-stroke, brains were taken for histological analysis (Figure 1J). Compared with PBS and EVs groups, the significantly higher fluorescent signal of DCX-positive cells in the SDF-1-EVs group indicated that an increased number of immature neurons were migrating toward the ischemic area (Figures 1K and 1N), demonstrating that SDF-1-EVs could efficiently enhance NSC migration and its neuronal differentiation. Moreover, the brain atrophy volume obviously decreased under treatment with SDF-1-EVs (Figures 1L and 1M). The above results all revealed that the biologically engineered SDF-1-EVs exhibited an enhanced therapeutic effect on brain injury. Though EVs can overcome BBB to treat neurological diseases, intravenous administration of EVs is still prone to be quickly cleared by the mononuclear phagocyte system, which is an obstacle to achieving therapeutic drug concentration. Therefore, it is expected to utilize the tissue engineering technique to construct a nanomedicine niche that could serve as the NSC signal transmitter in the specific area of the brain to recruit NSCs and direct their differentiation. Hydrogel microspheres (MSs) prepared using microfluidic techniques are excellent nanomedicine carriers due to their superior injectability, quality controllability, and sustained release.8Zhao Z. Wang Z. Li G. et al.Injectable microfluidic hydrogel microspheres for cell and drug delivery.Adv. Funct. Mater. 2021; 31: 2103339Crossref Scopus (75) Google Scholar By loading SDF-1-EVs into the MSs, the SDF-1-EVs niche ([email protected]) was constructed and stereotactically injected into the intracerebral cavity of the tMCAO model rat. This [email protected] is expected to overcome obstacles of EVs blood clearance and achieve the long-term repair of stroke (Figure 2A). The MSs have a diameter around 200 μm, and they could effectively encapsulate Dil-red-labeled S-EVs (Figure 2B), and the loading efficiency was about 80%. The in vitro release results (Figure 2C) exhibited that S-EVs in [email protected] were slowly released and reached about 46% after 15 days. Besides, [email protected] was co-incubated with NSC in vitro to assess the cytotoxicity of [email protected] It was found that a MS itself had no toxic effect on cell proliferation and exhibited good biocompatibility (Figure 2D). Interestingly, [email protected] was able to promote NSC proliferation, which may be attributed to the function of SDF-1. SDF-1 could promote NSC proliferation in a dose-dependent manner. Also, the growth factors like endothelial growth factor and basic fibroblast growth factor would further enhance the proliferative effect of SDF-1. In vivo studies were performed on the tMCAO model rat. The brain atrophy volume significantly decreased in the [email protected] group compared with the PBS and S-EVs groups, suggesting the importance of MS incorporation (Figures 2E and 2F). Overall, we constructed two different types of engineered EVs as signal transmitters for the recruitment and differentiation induction of NSCs and successfully achieved neural regeneration in the experimental rodent stroke model. We explored the possibility of biologically engineered EVs for neurological disorders treatment using both systemic and local delivery. Systemic therapy exhibits superior clinical compliance, but with the burdens of repeated administration and rapid blood clearance. Although the addition of sustained-release MSs overcomes these defects, the immunogenicity and biocompatibility of MS degradation products remain to be further investigated. Nevertheless, these kinds of engineered EVs therapies, together with related advanced biotechnologies or by itself, show great potential for clinical translation in the diagnosis, monitoring, treatment, and care of not only CNS diseases, but also cardiovascular disease, bone and joint regeneration, cancer, wound healing, and immune disorders.9Zheng D. Ruan H. Chen W. et al.Advances in extracellular vesicle functionalization strategies for tissue regeneration.Bioact. Mater. 2022; https://doi.org/10.1016/j.bioactmat.2022.07.022Crossref Scopus (1) Google Scholar,10Meng F. Li L. Zhang Z. et al.Biosynthetic neoantigen displayed on bacteria derived vesicles elicit systemic antitumour immunity.J. Extracell. Vesicles. 2022; 11: 12289Crossref PubMed Scopus (0) Google Scholar This research was supported by grants from the National Key R&D Program of China (2019YFA0112000), Zhejiang Provincial Natural Science Foundation of China (No. LQ21H300009), National Natural Science Foundation of China (81930051, 82003658, 82202785), and GuangCi Professorship Program of Ruijin Hospital Shanghai Jiao Tong University School of Medicine. The authors declare no competing interests.

The interplay between T helper cells and brain barriers in the pathogenesis of multiple sclerosis.

The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) represent two complex structures protecting the central nervous system (CNS) against potentially harmful agents and circulating immune cells. The immunosurveillance of the CNS is governed by immune cells that constantly patrol the BCSFB, whereas during neuroinflammatory disorders, both BBB and BCSFB undergo morphological and functional alterations, promoting leukocyte intravascular adhesion and transmigration from the blood circulation into the CNS. Multiple sclerosis (MS) is the prototype of neuroinflammatory disorders in which peripheral T helper (Th) lymphocytes, particularly Th1 and Th17 cells, infiltrate the CNS and contribute to demyelination and neurodegeneration. Th1 and Th17 cells are considered key players in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis. They can actively interact with CNS borders by complex adhesion mechanisms and secretion of a variety of molecules contributing to barrier dysfunction. In this review, we describe the molecular basis involved in the interactions between Th cells and CNS barriers and discuss the emerging roles of dura mater and arachnoid layer as neuroimmune interfaces contributing to the development of CNS inflammatory diseases.

Novel localization of folate transport systems in the murine central nervous system

BackgroundFolates are a family of B9 vitamins that serve as one-carbon donors critical to biosynthetic processes required for the development and function of the central nervous system (CNS) in mammals. Folate transport is mediated by three highly specific systems: (1) folate receptor alpha (FRα; FOLR1/Folr1), (2) the reduced folate-carrier (RFC; SLC19A1/Slc19a1) and (3) the proton-coupled folate transporter (PCFT; SLC46A1/Slc46a1). Folate transport into and out of the CNS occurs at the blood–cerebrospinal fluid barrier (BCSFB), mediated by FRα and PCFT. Impairment of folate transport at the BCSFB results in cerebral folate deficiency in infants characterized by severe neurological deficiencies and seizures. In contrast to the BCSFB, CNS folate transport at other brain barriers and brain parenchymal cells has not been extensively investigated. The aim of this study is to characterize folate transport systems in the murine CNS at several known barriers encompassing the BCSFB, arachnoid barrier (AB), blood–brain barrier (BBB) and parenchymal cells (astrocytes, microglia, neurons).MethodsApplying immunohistochemistry, localization of folate transport systems (RFC, PCFT, FRα) was examined at CNS barriers and parenchymal sites in wildtype (C57BL6/N) mice. Subcellular localization of the folate transport systems was further assessed in an in vitro model of the mouse AB. Gene and protein expression was analyzed in several in vitro models of brain barriers and parenchyma by qPCR and western blot analysis.ResultsRFC, PCFT, and FRα expression was localized within the BCSFB and BBB consistent with previous reports. Only RFC and PCFT expression was detected at the AB. Varied levels of RFC and PCFT expression were detected in neuronal and glial cells.ConclusionsLocalization of RFC and PCFT within the AB, described here for the first time, suggest that AB may contribute to folate transport between the peripheral circulation and the CSF. RFC and PCFT expression observed in astrocytes and microglia is consistent with the role that one or both of these transporters may play in delivering folates into cells within brain parenchyma. These studies provide insights into mechanisms of folate transport in the CNS and may enhance our understanding of the critical role folates play in neurodevelopment and in the development of novel treatment strategies for disorders of brain folate deficiency due to impaired transporter function.

Astrocytes regulate vascular endothelial responses to simulated deep space radiation in a human organ-on-a-chip model.

Central nervous system (CNS) damage by galactic cosmic ray radiation is a major health risk for human deep space exploration. Simulated galactic cosmic rays or their components, especially high Z-high energy particles such as 56Fe ions, cause neurodegeneration and neuroinflammation in rodent models. CNS damage can be partially mediated by the blood-brain barrier, which regulates systemic interactions between CNS and the rest of the body. Astrocytes are major cellular regulators of blood-brain barrier permeability that also modulate neuroinflammation and neuronal health. However, astrocyte roles in regulating CNS and blood-brain barrier responses to space radiation remain little understood, especially in human tissue analogs. In this work, we used a novel high-throughput human organ-on-a-chip system to evaluate blood-brain barrier impairments and astrocyte functions 1-7 days after exposure to 600 MeV/n 56Fe particles and simplified simulated galactic cosmic rays. We show that simulated deep space radiation causes vascular permeability, oxidative stress, inflammation and delayed astrocyte activation in a pattern resembling CNS responses to brain injury. Furthermore, our results indicate that astrocytes have a dual role in regulating radiation responses: they exacerbate blood-brain barrier permeability acutely after irradiation, followed by switching to a more protective phenotype by reducing oxidative stress and pro-inflammatory cytokine and chemokine secretion during the subacute stage.

Neuroimmune signaling at the brain borders.

The central nervous system (CNS) has been viewed as an immunologically privileged site, but emerging works are uncovering a large array of neuroimmune interactions primarily occurring at its borders. CNS barriers sites host diverse population of both innate and adaptive immune cells capable of, directly and indirectly, influence the function of the residing cells of the brain parenchyma. These structures are only starting to reveal their role in controlling brain function under normal and pathological conditions and represent an underexplored therapeutic target for the treatment of brain disorders. This review will highlight the development of the CNS barriers to host neuro-immune interactions and emphasize their newly described roles in neurodevelopmental, neurological, and neurodegenerative disorders, particularly for the meninges.

The role of neutrophils in the dysfunction of central nervous system barriers

Leukocyte migration into the central nervous system (CNS) represents a central process in the development of neurological diseases with a detrimental inflammatory component. Infiltrating neutrophils have been detected inside the brain of patients with several neuroinflammatory disorders, including stroke, multiple sclerosis and Alzheimer’s disease. During inflammatory responses, these highly reactive innate immune cells can rapidly extravasate and release a plethora of pro-inflammatory and cytotoxic factors, potentially inducing significant collateral tissue damage. Indeed, several studies have shown that neutrophils promote blood-brain barrier damage and increased vascular permeability during neuroinflammatory diseases. Recent studies have shown that neutrophils migrate into the meninges and choroid plexus, suggesting these cells can also damage the blood-cerebrospinal fluid barrier (BCSFB). In this review, we discuss the emerging role of neutrophils in the dysfunction of brain barriers across different neuroinflammatory conditions and describe the molecular basis and cellular interplays involved in neutrophil-mediated injury of the CNS borders.

Taking Advantages of Blood-Brain or Spinal Cord Barrier Alterations or Restoring Them to Optimize Therapy in ALS?

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that still lacks an efficient therapy. The barriers between the central nervous system (CNS) and the blood represent a major limiting factor to the development of drugs for CNS diseases, including ALS. Alterations of the blood–brain barrier (BBB) or blood–spinal cord barrier (BSCB) have been reported in this disease but still require further investigations. Interestingly, these alterations might be involved in the complex etiology and pathogenesis of ALS. Moreover, they can have potential consequences on the diffusion of candidate drugs across the brain. The development of techniques to bypass these barriers is continuously evolving and might open the door for personalized medical approaches. Therefore, identifying robust and non-invasive markers of BBB and BSCB alterations can help distinguish different subgroups of patients, such as those in whom barrier disruption can negatively affect the delivery of drugs to their CNS targets. The restoration of CNS barriers using innovative therapies could consequently present the advantage of both alleviating the disease progression and optimizing the safety and efficiency of ALS-specific therapies.

Mycobacterium tuberculosis Infection Induces BCSFB Disruption but No BBB Disruption In Vivo: Implications in the Pathophysiology of Tuberculous Meningitis.

Central nervous system (CNS) tuberculosis is the most lethal and devastating form among the diseases caused by Mycobacterium tuberculosis. The mechanisms by which M. tuberculosis bacilli enter the CNS are still unclear. However, the BBB and the BCSFB have been proposed as possible routes of access into the brain. We previously reported that certain strains of M. tuberculosis possess an enhanced ability to cause secondary CNS infection in a mouse model of progressive pulmonary tuberculosis. Here, we evaluated the morphostructural and molecular integrity of CNS barriers. For this purpose, we analyzed through transmission electron microscopy the ultrastructure of brain parenchymal microvessels and choroid plexus epithelium from animals infected with two mycobacterial strains. Additionally, we determined the expression of junctional proteins and cytokines by immunological techniques. The results showed that the presence of M. tuberculosis induced disruption of the BCSFB but no disruption of the BBB, and that the severity of such damage was related to the strain used, suggesting that variations in the ability to cause CNS disease among distinct strains of bacteria may also be linked to their capacity to cause direct or indirect disruption of these barriers. Understanding the pathophysiological mechanisms involved in CNS tuberculosis may facilitate the establishment of new biomarkers and therapeutic targets.

Breaching Brain Barriers: B Cell Migration in Multiple Sclerosis.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) known for the manifestation of demyelinated lesions throughout the CNS, leading to neurodegeneration. To date, not all pathological mechanisms that drive disease progression are known, but the clinical benefits of anti-CD20 therapies have put B cells in the spotlight of MS research. Besides their pathological effects in the periphery in MS, B cells gain access to the CNS where they can contribute to disease pathogenesis. Specifically, B cells accumulate in perivascular infiltrates in the brain parenchyma and the subarachnoid spaces of the meninges, but are virtually absent from the choroid plexus. Hence, the possible migration of B cells over the blood–brain-, blood–meningeal-, and blood–cerebrospinal fluid (CSF) barriers appears to be a crucial step to understanding B cell-mediated pathology. To gain more insight into the molecular mechanisms that regulate B cell trafficking into the brain, we here provide a comprehensive overview of the different CNS barriers in health and in MS and how they translate into different routes for B cell migration. In addition, we review the mechanisms of action of diverse therapies that deplete peripheral B cells and/or block B cell migration into the CNS. Importantly, this review shows that studying the different routes of how B cells enter the inflamed CNS should be the next step to understanding this disease.

Neuroimmune Crosstalk Between the Peripheral and the Central Immune System in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by the degeneration and death of motor neurons. Systemic neuroinflammation contributes to the pathogenesis of ALS. The proinflammatory milieu depends on the continuous crosstalk between the peripheral immune system (PIS) and central immune system (CIS). Central nervous system (CNS) resident immune cells interact with the peripheral immune cells via immune substances. Dysfunctional CNS barriers, including the blood–brain barrier, and blood–spinal cord barrier, accelerate the inflammatory process, leading to a systemic self-destructive cycle. This review focuses on the crosstalk between PIS and CIS in ALS. Firstly, we briefly introduce the cellular compartments of CIS and PIS, respectively, and update some new understanding of changes specifically occurring in ALS. Then, we will review previous studies on the alterations of the CNS barriers, and discuss their crucial role in the crosstalk in ALS. Finally, we will review the moveable compartments of the crosstalk, including cytokines, chemokines, and peripheral immune cells which were found to infiltrate the CNS, highlighting the interaction between PIS and CIS. This review aims to provide new insights into pathogenic mechanisms and innovative therapeutic approaches for ALS.

Ureaplasma-Driven Neonatal Neuroinflammation: Novel Insights from an Ovine Model

Ureaplasma species (spp.) are considered commensals of the adult genitourinary tract, but have been associated with chorioamnionitis, preterm birth, and invasive infections in neonates, including meningitis. Data on mechanisms involved in Ureaplasma-driven neuroinflammation are scarce. The present study addressed brain inflammatory responses in preterm lambs exposed to Ureaplasma parvum (UP) in utero. 7 days after intra-amniotic injection of UP (n = 10) or saline (n = 11), lambs were surgically delivered at gestational day 128–129. Expression of inflammatory markers was assessed in different brain regions using qRT-PCR and in cerebrospinal fluid (CSF) by multiplex immunoassay. CSF was analyzed for UP presence using ureB-based real-time PCR, and MRI scans documented cerebral white matter area and cortical folding. Cerebral tissue levels of atypical chemokine receptor (ACKR) 3, caspases 1-like, 2, 7, and C–X–C chemokine receptor (CXCR) 4 mRNA, as well as CSF interleukin-8 protein concentrations were significantly increased in UP-exposed lambs. UP presence in CSF was confirmed in one animal. Cortical folding and white matter area did not differ among groups. The present study confirms a role of caspases and the transmembrane receptors ACKR3 and CXCR4 in Ureaplasma-driven neuroinflammation. Enhanced caspase 1-like, 2, and 7 expression may reflect cell death. Increased ACKR3 and CXCR4 expression has been associated with inflammatory central nervous system (CNS) diseases and impaired blood–brain barrier function. According to these data and previous in vitro findings from our group, we speculate that Ureaplasma-induced caspase and receptor responses affect CNS barrier properties and thus facilitate neuroinflammation.

Markers of Cerebrovascular Injury, Inflammation, and Plasma Lipids Are Associated with Alzheimer's Disease Cerebrospinal Fluid Biomarkers in Cognitively Normal Persons.

Alzheimer's disease (AD) is a multifactorial process that takes years to manifest clinically. We propose that brain-derived indicators of cerebrovascular dysfunction and inflammation would inform on AD-related pathological processes early in, and perhaps prior to neurodegenerative disease development. Define the relationship between cerebrospinal fluid (CSF) markers of cerebrovascular dysfunction and neuroinflammation with AD CSF biomarkers in cognitively normal individuals. Analytes were measured from CSF and plasma collected at baseline from two randomized control trials. We performed Pearson correlation analysis (adjusting for age, sex, APOE haplotype, and education) between markers of central nervous system (CNS) barrier disruption, cerebrovascular dysfunction, CSF inflammatory cytokines and chemokines, and plasma lipid levels. We then developed a statistical prediction model using machine learning to test the ability of measured CSF analytes and blood lipid profiles to predict CSF AD biomarkers (total tau, phospho-tau (181), Aβ42) in this clinical population. Our analysis revealed a significant association between markers of CNS barrier dysfunction and markers of cerebrovascular dysfunction, acute inflammatory responses, and CSF inflammatory cytokines. There was a significant association of blood lipid profiles with cerebrovascular injury markers, and CSF inflammatory cytokine levels. Using machine learning, we show that combinations of blood lipid profiles, CSF markers of CNS barrier disruption, cerebrovascular dysfunction and CSF inflammatory cytokines predict CSF total tau, p-tau, and, to a lesser extent, Aβ42 in cognitively normal subjects. This suggests that these parallel pathological processes may contribute to the development of AD-related neuropathology in the absence of clinical manifestations.