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Bicarbonate signalling via G protein-coupled receptor regulates ischaemia-reperfusion injury
The acid–base balance regulates cellular responses, but little has been known about its molecular mechanism. Here, the authors unveil a bicarbonate-sensing GPCR, GPR30, that underlies cerebral ischemia–reperfusion injury by regulating blood flow recovery.
- Airi Jo-Watanabe
- , Toshiki Inaba
- & Takehiko Yokomizo
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Article
| Open Access
Repeated blood–brain barrier opening with a nine-emitter implantable ultrasound device in combination with carboplatin in recurrent glioblastoma: a phase I/II clinical trial
Recent work indicates that drug delivery to the brain can be improved through disruption of the blood brain barrier using low intensity pulsed ultrasound. Here, the authors report a phase I/II clinical trial investigating the combination of a nine-emitter implantable ultrasound device and carboplatin in patients with recurrent glioblastoma.
- Alexandre Carpentier
- , Roger Stupp
- & Ahmed Idbaih
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| Open Access
Non-invasive modulation of meningeal lymphatics ameliorates ageing and Alzheimer’s disease-associated pathology and cognition in mice
Meningeal lymphatic vessels have been associated with amyloid beta clearance, which is considered as a modulation target for Alzheimer’s disease (AD) treatment. Here, the authors show that transcranial light treatment can enhance meningeal lymphatic drainage in aged and AD model mice and improve AD-associated pathology and cognitive function.
- Miao Wang
- , Congcong Yan
- & Feifan Zhou
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| Open Access
The liver and muscle secreted HFE2-protein maintains central nervous system blood vessel integrity
Blood vessel integrity is critical to maintain brain health. Here, the authors show that both the liver and the muscles secrete HFE2, a protein that promotes blood vessel integrity in healthy animals and in an animal model for multiple sclerosis.
- Xue Fan Wang
- , Robin Vigouroux
- & Philippe P. Monnier
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ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells
LRP1 plays a key role in the clearance of Aβ peptides across the blood-brain barrier. Here, the authors report that ANKS1A promotes the LRP1-mediated Aβ clearance in brain endothelium, providing insights into the pathology of Alzheimer’s disease.
- Jiyeon Lee
- , Haeryung Lee
- & Soochul Park
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Article
| Open Access
VE-cadherin in arachnoid and pia mater cells serves as a suitable landmark for in vivo imaging of CNS immune surveillance and inflammation
How the leptomeninges establish CNS compartments with different accessibility to immune cells and immune mediators remains unknown. Here, the authors show junctional localization of VE-cadherin in arachnoid and pia mater cells, which allows to visualize potential barrier properties of the leptomeninges in vivo.
- Josephine A. Mapunda
- , Javier Pareja
- & Britta Engelhardt
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CD98hc is a target for brain delivery of biotherapeutics
New delivery platforms are needed to allow broader application of biotherapeutics for CNS diseases. Here, the authors show enhanced CNS delivery with a transport vehicle engineered to bind CD98hc, a highly expressed target at the blood-brain barrier.
- Kylie S. Chew
- , Robert C. Wells
- & Mihalis S. Kariolis
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Article
| Open Access
Expanded vacuum-stable gels for multiplexed high-resolution spatial histopathology
Emerging high-plex imaging technologies are limited in resolving subcellular biomolecular features. Here, the authors propose a spatial histopathology tool that allows for high-plex protein staining and physical expansion, while retaining the lateral tissue expansion.
- Yunhao Bai
- , Bokai Zhu
- & Sizun Jiang
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| Open Access
Defining diurnal fluctuations in mouse choroid plexus and CSF at high molecular, spatial, and temporal resolution
The choroid plexus (ChP) modulates cerebrospinal fluid (CSF) composition and the blood-CSF barrier. Here the authors show that the ChP is a critical circadian component with time-of-day variations in translation, barrier, and metabolism to alter CSF composition.
- Ryann M. Fame
- , Peter N. Kalugin
- & Maria K. Lehtinen
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The contribution of inflammatory astrocytes to BBB impairments in a brain-chip model of Parkinson’s disease
Astrocytes are implicated in the maintenance of the blood-brain barrier (BBB). This study established a microfluidic BBB chip and found that astrocytes may play a role in cerebrovascular dysfunction in people with Parkinson’s disease.
- A. de Rus Jacquet
- , M. Alpaugh
- & F. Cicchetti
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Functional gene delivery to and across brain vasculature of systemic AAVs with endothelial-specific tropism in rodents and broad tropism in primates
Delivering genes to and across the brain vasculature efficiently and specifically across species remains challenging. Here, the authors show that endothelial-specific AAVs with serotype flexibility enable redosing and transform the brain vasculature into an in vivo biofactory in genetically diverse rodents. In primates, these vectors cross the blood-brain-barrier and show broad tropism.
- Xinhong Chen
- , Damien A. Wolfe
- & Viviana Gradinaru
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Article
| Open Access
Antigen recognition detains CD8+ T cells at the blood-brain barrier and contributes to its breakdown
Blood-brain barrier (BBB) breakdown and immune cell infiltration into the central nervous system are early hallmarks of multiple sclerosis. Here, the authors demonstrate that brain endothelial cells cross-present antigen to CD8+ T cells, thereby preventing their migration and initiating BBB breakdown.
- Sidar Aydin
- , Javier Pareja
- & Britta Engelhardt
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Identification of age-specific gene regulators of La Crosse virus neuroinvasion and pathogenesis
La Crosse Virus predominantly causes encephalitis in children. Here, Basu et al. use transcriptomics and targeted siRNA screening to identify that age-dependent expression of EphrinA2 and Connexin43 by brain capillary endothelial cells is important for neuroinvasion.
- Rahul Basu
- , Sundar Ganesan
- & Iain D. C. Fraser
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Subcellular analysis of blood-brain barrier function by micro-impalement of vessels in acute brain slices
The blood-brain barrier (BBB) tightly and dynamically regulates exchange with the brain. Here, the authors report a brain slice approach to study the native BBB in a highly controlled manner by combining intravascular perfusion and multiphoton microscopy.
- Amira Sayed Hanafy
- , Pia Steinlein
- & Dirk Dietrich
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| Open Access
Reactive astrocytes transduce inflammation in a blood-brain barrier model through a TNF-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin
Inflammation of brain endothelial cells is seen in neurodegenerative conditions and in aging. Here the authors examine the role of astrocytes in blood brain barrier function using an iPSC-derived cell co-culture model.
- Hyosung Kim
- , Kun Leng
- & Ethan S. Lippmann
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Article
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Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure
Using in vivo two-photon imaging, Berthiaume et al. demonstrate how pericyte loss during aging could contribute to deterioration of cerebral blood flow. They also show how pericyte remodeling reduces the deleterious effects of pericyte loss.
- Andrée-Anne Berthiaume
- , Franca Schmid
- & Andy Y. Shih
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Microvascular stabilization via blood-brain barrier regulation prevents seizure activity
The mechanisms underlying epilepsy development are not well understood. Here the authors show that loss of a key component of the so called blood-brain barrier drives seizures in mice and is also lost in humans with treatment resistant epilepsy
- Chris Greene
- , Nicole Hanley
- & Matthew Campbell
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Article
| Open Access
Astrocyte plasticity in mice ensures continued endfoot coverage of cerebral blood vessels following injury and declines with age
Disruption of the blood brain barrier can occur in several diseases. Here the authors show that targeted ablation of astrocytes results in a plasticity mechanism in nearby cells to maintain cerebrovascular coverage, but that this mechanism is impaired in older animals.
- William A. Mills III
- , AnnaLin M. Woo
- & Harald Sontheimer
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Endothelial Unc5B controls blood-brain barrier integrity
The authors show that Netrin-1-Unc5B signaling controls blood-brain barrier integrity by maintaining Wnt/b-catenin signaling and that delivery of antibodies blocking Netrin-1 binding to Unc5B causes transient and size-selective BBB breakdown.
- Kevin Boyé
- , Luiz Henrique Geraldo
- & Anne Eichmann
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Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue
The vascular, cellular and molecular changes underlying sex differences in mood disorders are unclear. Here, the authors show that blood-brain barrier dysfunction modulates anxiety- and depressive-like behaviors in female mice and endothelium-specific changes associated with maladaptive responses compared to resilience to stress.
- Laurence Dion-Albert
- , Alice Cadoret
- & Caroline Menard
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Drosophila ßHeavy-Spectrin is required in polarized ensheathing glia that form a diffusion-barrier around the neuropil
In the invertebrate CNS, synapses and dendrites are clustered in distinct neuropil areas that are separated from neuronal cell bodies by ensheathing glia (EG). Here, the authors show that Drosophila EG are polarized cells that form an internal diffusion barrier. EG cell polarity requires βHeavy-Spectrin and is needed for normal locomotor behaviour.
- Nicole Pogodalla
- , Holger Kranenburg
- & Christian Klämbt
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| Open Access
Exposure to 16 h of normobaric hypoxia induces ionic edema in the healthy brain
Prolonged hypoxia, which can be due to stroke or ascent to high altitude, can lead to cerebral edema. Here, the authors used a combination of sodium and proton MRI and experimentally induced hypoxic conditions to identify the cause for brain swelling: Ionic edema, an intermediate between cytotoxic and vasogenic edema defined by sodium ion accumulation in extracellular space and an intact endothelium.
- Armin Biller
- , Stephanie Badde
- & Kai Schommer
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Comment
| Open Access
Microglia have a grip on brain microvasculature
Microglia are brain resident immune cells with multiple functions. However, little is known about microglia-vascular interactions. In a recent paper published in Nature Communications, Bisht et al. identify a signalling mechanism that attracts and maintains microglia at the capillary wall. Moreover, they show that microglia regulate capillary vascular tone, playing a more significant role in blood flow regulation than previously thought.
- Kassandra Kisler
- , Angeliki Maria Nikolakopoulou
- & Berislav V. Zlokovic
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NEK1-mediated retromer trafficking promotes blood–brain barrier integrity by regulating glucose metabolism and RIPK1 activation
NEK1 mutations promote lethality early in life and ALS late in life via unknown mechanisms. Here, the authors show that NEK1 mutation disrupts retromer-mediated trafficking and promotes RIPK1 activation, connecting retromer trafficking and metabolism to neuroinflammation by dietary intervention.
- Huibing Wang
- , Weiwei Qi
- & Junying Yuan
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Article
| Open Access
Post-capillary venules are the key locus for transcytosis-mediated brain delivery of therapeutic nanoparticles
Limited understanding of the interactions between nanoparticle drug carriers and the blood-brain barrier underlies many translational failures in treatments of brain disorders. Here the authors use two-photon microscopy in mice to characterize the receptor-mediated transcytosis of nanoparticles at all steps of delivery from the blood to the brain in vivo.
- Krzysztof Kucharz
- , Kasper Kristensen
- & Martin Johannes Lauritzen
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| Open Access
A circadian clock regulates efflux by the blood-brain barrier in mice and human cells
The blood-brain barrier is critical for neural function. Here, the authors show that efflux of xenobiotics through the BBB follows a circadian rhythm in mice and human cells.
- Shirley L. Zhang
- , Nicholas F. Lahens
- & Amita Sehgal
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Article
| Open Access
An original infection model identifies host lipoprotein import as a route for blood-brain barrier crossing
Bacterial and fungal pathogens that cross the blood-brain-barrier (BBB) can cause severe disease. Here, Benmimoun et al. develop a model to study BBB crossing in the developing Drosophila brain and discover Group B Streptococcus factors important for BBB crossing and virulence, one of which, a lipoprotein, they confirm in mice.
- Billel Benmimoun
- , Florentia Papastefanaki
- & Pauline Spéder
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Transplantation of hPSC-derived pericyte-like cells promotes functional recovery in ischemic stroke mice
Pericytes play an essential role in blood brain barrier (BBB) integrity. Here, the authors generate pericyte-like cells (PCs) from human pluripotent stem cells (hPSCs) which display functional properties and also promote BBB recovery in a mouse model of cerebral artery occlusion.
- Jiaqi Sun
- , Yinong Huang
- & Weiqiang Li
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| Open Access
Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis
Traumatic brain injury (TBI) is a serious and poorly understood medical condition. Here, the authors show that TBI induces long-lasting deficits in brain lymphatic drainage. They report that defects in this drainage pathway provoke severe TBI pathogenesis that can be rescued with VEGF-C treatment.
- Ashley C. Bolte
- , Arun B. Dutta
- & John R. Lukens
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| Open Access
Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain
Blood–brain barrier dysfunction occurs in ageing and in neurodegenerative diseases. Here, the authors use scRNA-seq to identify transcriptomic changes in endothelial cell subtypes in the aged mouse brain, some of which may generalize to human and can be reversed by treatment with a GLP-1R agonist.
- Lei Zhao
- , Zhongqi Li
- & Ho Ko
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| Open Access
Neutrophil extracellular traps released by neutrophils impair revascularization and vascular remodeling after stroke
Following ischemic insult, neovascularization and vascular remodelling play an essential part in the repair of brain damage. Here the authors show that neutrophil extracellular traps serve a detrimental role in the regeneration process, limiting the functional recovery of the brain post injury.
- Lijing Kang
- , Huilin Yu
- & Bing-Qiao Zhao
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Article
| Open Access
Non-Invasive MRI of Blood–Cerebrospinal Fluid Barrier Function
The blood–cerebrospinal fluid barrier (BCSFB) is an important interface for brain homeostasis. Here the authors describe a non-invasive MRI technique for the quantitative assessment of BCSFB function.
- P. G. Evans
- , M. Sokolska
- & J. A. Wells
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| Open Access
Dual microglia effects on blood brain barrier permeability induced by systemic inflammation
Although it is known that microglia respond to injury and systemic disease in the brain, it is unclear if they modulate blood–brain barrier (BBB) integrity, which is critical for regulating neuroinflammatory responses. Here authors demonstrate that microglia respond to inflammation by migrating towards and accumulating around cerebral vessels, where they initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 before switching, during sustained inflammation, to phagocytically remove astrocytic end-feet resulting in impaired BBB function
- Koichiro Haruwaka
- , Ako Ikegami
- & Hiroaki Wake
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First-in-human trial of blood–brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound
MR-focused ultrasound can be used to transiently open the blood-brain barrier (BBB). Here, the authors report the results of a first-in-human trial on four patients with amyotrophic lateral sclerosis (ALS), showing that the procedure reversibly permeabilised the BBB in the motor cortex without complications, and suggest that the procedure could in the future be used to increase drug delivery in ALS patients.
- Agessandro Abrahao
- , Ying Meng
- & Lorne Zinman
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| Open Access
Loss of the transcription factor RBPJ induces disease-promoting properties in brain pericytes
Pericytes are perivascular cells essential for blood-brain barrier maintenance. Here Diéguez-Hurtado et al. show that depletion of the transcription factor RBPJ in pericytes affects their molecular identity and disturbs endothelial cell behaviour, inducing the formation of vascular lesions in the brain.
- Rodrigo Diéguez-Hurtado
- , Katsuhiro Kato
- & Ralf H. Adams
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| Open Access
Cholinergic neural activity directs retinal layer-specific angiogenesis and blood retinal barrier formation
During retinal development, waves of cholinergic neural activity play a role in retinal circuit development. Here, the authors show that this activity also contributes to layer-specific angiogenesis and formation of the blood-retinal barrier.
- G. A. Weiner
- , S. H. Shah
- & J. L. Goldberg
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| Open Access
Targeting the HIV-infected brain to improve ischemic stroke outcome
Here, using the EcoHIV mouse model of infection, Bertrand et al. report that HIV infection contributes to ischemic stroke damage and decreased tissue recovery by disrupting blood–brain barrier integrity and show that antivirals with high CNS penetration can reduce tissue injury and accelerate post-stroke recovery.
- Luc Bertrand
- , Fannie Méroth
- & Michal Toborek
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Article
| Open Access
Japanese encephalitis virus neuropenetrance is driven by mast cell chymase
How Japanese encephalitis virus (JEV) penetrates the blood-brain barrier (BBB) remains unclear. Here, using a genetic mouse model and a virulent JEV strain, the authors show that perivascular mast cells (MC) mediate JEV neuroinvasion and identify the MC-protease chymase as a potential therapeutic target.
- Justin T. Hsieh
- , Abhay P. S. Rathore
- & Ashley L. St. John
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Article
| Open Access
Wnt/β-catenin signaling regulates VE-cadherin-mediated anastomosis of brain capillaries by counteracting S1pr1 signaling
Wnt signaling is known to regulate the formation of the blood-brain barrier. Here Hübner et al. dissect the underlying mechanisms using high resolution live imaging in zebrafish, and find that Wnt regulates anastomosis of angiogenic sprouts in the brain by counteracting sphingosine-1-phosphate receptor signaling.
- Kathleen Hübner
- , Pauline Cabochette
- & Wiebke Herzog
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Article
| Open Access
Blood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound
Magnetic resonance-guided focused ultrasound with injected microbubbles has been used to temporarily open the blood–brain barrier (BBB) in animal models of Alzheimer's disease (AD). Here, the authors use this technology to non-invasively open the BBB in 5 patients with mild-to-moderate AD in a phase I trial, and show that the procedure is safe.
- Nir Lipsman
- , Ying Meng
- & Sandra E. Black
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Article
| Open Access
Reactive astrocytic S1P3 signaling modulates the blood–tumor barrier in brain metastases
When brain metastases form, the blood–brain barrier morphs into the blood–tumor barrier (BTB), surrounded by neuroinflammatory response. Here, the authors show that S1P3 is upregulated in neuroinflammatory response in highly BTB permeable lesions, and modulation of S1P3 could impact BTB permeability.
- Brunilde Gril
- , Anurag N. Paranjape
- & Patricia S. Steeg
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Article
| Open Access
Cotransporter-mediated water transport underlying cerebrospinal fluid formation
Osmotic forces do not suffice to explain the rate of cerebrospinal fluid (CSF) production. Here, the authors show that the Na+/K+/2Cl− cotransporter in the choroid plexus contributes substantially to CSF production via its inherent ability to cotransport water.
- Annette B. Steffensen
- , Eva K. Oernbo
- & Nanna MacAulay
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Article
| Open Access
EGFL7 reduces CNS inflammation in mouse
Endothelial cells release extracellular matrix components that regulate inflammation. Here the authors demonstrate that the extracellular matrix component epidermal growth factor-like protein 7 regulates inflammation in experimental autoimmune encephalomyelitis in the mouse.
- Catherine Larochelle
- , Timo Uphaus
- & Frauke Zipp
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Article
| Open Access
Glycaemic control boosts glucosylated nanocarrier crossing the BBB into the brain
There are only a few examples of nanocarriers that can transport bioactive substances across the blood-brain barrier. Here the authors show that by rapid glycaemic increase the accumulation of a glucosylated nanocarrier in the brain can be controlled.
- Y. Anraku
- , H. Kuwahara
- & K. Kataoka
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Article
| Open Access
Blood-brain-barrier spheroids as an in vitro screening platform for brain-penetrating agents
In vitroblood-brain barrier (BBB) models are crucial tools for screening brain-penetrating compounds. Here the authors develop a self-assembling BBB spheroid model with superior performance to the standard transwell BBB model, and use their platform to identify cell-penetrating peptides that can cross the BBB.
- Choi-Fong Cho
- , Justin M. Wolfe
- & Sean E. Lawler
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Article
| Open Access
Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior
There is concern about potential long-term effects of antibiotics on children’s health. Here Leclercqet al. show, in mice, that low doses of penicillin during late pregnancy and early life induce lasting effects on the offspring, including alterations in gut microbiota, brain cytokine levels and behaviour.
- Sophie Leclercq
- , Firoz M. Mian
- & John Bienenstock
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| Open Access
Rapid endothelial cytoskeletal reorganization enables early blood–brain barrier disruption and long-term ischaemic reperfusion brain injury
Matrix metalloproteinases (MMPs) released from infiltrating immune cells are a major contributor to blood-brain barrier (BBB) breakdown following stroke. Here, the authors identify an early, MMP-independent BBB breakdown mechanism caused by rapid cytoskeletal rearrangements in endothelial cells, which could be inhibited by ADF.
- Yejie Shi
- , Lili Zhang
- & Jun Chen
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Article
| Open Access
dNP2 is a blood–brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis
Most of the cell penetrating peptides can transport therapeutic agents across plasma membranes but barely across the blood-brain barrier. Here the authors develop a peptide that can enter the brain, and show that its fusion to immunomodulatory protein ctCTLA-4 is effective in a mouse model of multiple sclerosis.
- Sangho Lim
- , Won-Ju Kim
- & Je-Min Choi
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Article
| Open Access
Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood–brain barrier
A key event during metastasis to the brain is the migration of cancer cells through the blood–brain barrier (BBB). Here the authors show that cancer-cell-derived extracellular vesicles promote metastasis by promoting BBB breaching.
- Naoomi Tominaga
- , Nobuyoshi Kosaka
- & Takahiro Ochiya
A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease