-
Signal Transduction and Targeted Therapy May 2023Blood-brain barrier (BBB) is a natural protective membrane that prevents central nervous system (CNS) from toxins and pathogens in blood. However, the presence of BBB... (Review)
Review
Blood-brain barrier (BBB) is a natural protective membrane that prevents central nervous system (CNS) from toxins and pathogens in blood. However, the presence of BBB complicates the pharmacotherapy for CNS disorders as the most chemical drugs and biopharmaceuticals have been impeded to enter the brain. Insufficient drug delivery into the brain leads to low therapeutic efficacy as well as aggravated side effects due to the accumulation in other organs and tissues. Recent breakthrough in materials science and nanotechnology provides a library of advanced materials with customized structure and property serving as a powerful toolkit for targeted drug delivery. In-depth research in the field of anatomical and pathological study on brain and BBB further facilitates the development of brain-targeted strategies for enhanced BBB crossing. In this review, the physiological structure and different cells contributing to this barrier are summarized. Various emerging strategies for permeability regulation and BBB crossing including passive transcytosis, intranasal administration, ligands conjugation, membrane coating, stimuli-triggered BBB disruption, and other strategies to overcome BBB obstacle are highlighted. Versatile drug delivery systems ranging from organic, inorganic, and biologics-derived materials with their synthesis procedures and unique physio-chemical properties are summarized and analyzed. This review aims to provide an up-to-date and comprehensive guideline for researchers in diverse fields, offering perspectives on further development of brain-targeted drug delivery system.
Topics: Blood-Brain Barrier; Drug Delivery Systems; Brain; Biological Transport; Pharmaceutical Preparations; Biological Products
PubMed: 37231000
DOI: 10.1038/s41392-023-01481-w -
Annual Review of Neuroscience Jul 2023Astrocyte endfeet enwrap the entire vascular tree within the central nervous system, where they perform important functions in regulating the blood-brain barrier (BBB),... (Review)
Review
Astrocyte endfeet enwrap the entire vascular tree within the central nervous system, where they perform important functions in regulating the blood-brain barrier (BBB), cerebral blood flow, nutrient uptake, and waste clearance. Accordingly, astrocyte endfeet contain specialized organelles and proteins, including local protein translation machinery and highly organized scaffold proteins, which anchor channels, transporters, receptors, and enzymes critical for astrocyte-vascular interactions. Many neurological diseases are characterized by the loss of polarization of specific endfoot proteins, vascular dysregulation, BBB disruption, altered waste clearance, or, in extreme cases, loss of endfoot coverage. A role for astrocyte endfeet has been demonstrated or postulated in many of these conditions. This review provides an overview of the development, composition, function, and pathological changes of astrocyte endfeet and highlights the gaps in our knowledge that future research should address.
Topics: Astrocytes; Blood-Brain Barrier; Central Nervous System; Protein Biosynthesis; Brain
PubMed: 36854317
DOI: 10.1146/annurev-neuro-091922-031205 -
Nature Communications Jul 2023Accumulation of amyloid beta protein (Aβ) in brain vessels damages blood brain barrier (BBB) integrity in cerebral amyloid angiopathy (CAA). Macrophage lineage cells...
Accumulation of amyloid beta protein (Aβ) in brain vessels damages blood brain barrier (BBB) integrity in cerebral amyloid angiopathy (CAA). Macrophage lineage cells scavenge Aβ and produce disease-modifying mediators. Herein, we report that Aβ40-induced macrophage-derived migrasomes are sticky to blood vessels in skin biopsy samples from CAA patients and brain tissue from CAA mouse models (Tg-SwDI/B and 5xFAD mice). We show that CD5L is packed in migrasomes and docked to blood vessels, and that enrichment of CD5L impairs the resistance to complement activation. Increased migrasome-producing capacity of macrophages and membrane attack complex (MAC) in blood are associated with disease severity in both patients and Tg-SwDI/B mice. Of note, complement inhibitory treatment protects against migrasomes-mediated blood-brain barrier injury in Tg-SwDI/B mice. We thus propose that macrophage-derived migrasomes and the consequent complement activation are potential biomarkers and therapeutic targets in CAA.
Topics: Mice; Animals; Amyloid beta-Peptides; Blood-Brain Barrier; Mice, Transgenic; Cerebral Amyloid Angiopathy; Brain; Macrophages; Alzheimer Disease
PubMed: 37402721
DOI: 10.1038/s41467-023-39693-x -
Fluids and Barriers of the CNS Jun 2023Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is under investigation as a therapeutic modality for neurodegeneration, yet its effects in humans are...
BACKGROUND
Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is under investigation as a therapeutic modality for neurodegeneration, yet its effects in humans are incompletely understood. Here, we assessed physiologic responses to FUS administered in multifocal brain sites of persons with Alzheimer's disease (AD).
METHODS
At a tertiary neuroscience institute, eight participants with AD (mean age 65, 38% F) enrolled in a phase 2 clinical trial underwent three successive targeted BBB opening procedures at 2 week intervals using a 220 kHz FUS transducer in combination with systemically administered microbubbles. In all, 77 treatment sites were evaluated and encompassed hippocampal, frontal, and parietal brain regions. Post-FUS imaging changes, including susceptibility effects and spatiotemporal gadolinium-based contrast agent enhancement patterns, were analyzed using serial 3.0-Tesla MRI.
RESULTS
Post-FUS MRI revealed expected intraparenchymal contrast extravasation due to BBB opening at all targeted brain sites. Immediately upon BBB opening, hyperconcentration of intravenously-administered contrast tracer was consistently observed around intracerebral veins. Following BBB closure, within 24-48 h of FUS intervention, permeabilization of intraparenchymal veins was observed and persisted for up to one week. Notably, extraparenchymal meningeal venous permeabilization and associated CSF effusions were also elicited and persisted up to 11 days post FUS treatment, prior to complete spontaneous resolution in all participants. Mild susceptibility effects were detected, however no overt intracranial hemorrhage or other serious adverse effects occurred in any participant.
CONCLUSIONS
FUS-mediated BBB opening is safely and reproducibly achieved in multifocal brain regions of persons with AD. Post-FUS tracer enhancement phenomena suggest the existence of a brain-wide perivenous fluid efflux pathway in humans and demonstrate reactive physiological changes involving these conduit spaces in the delayed, subacute phase following BBB disruption. The delayed reactive venous and perivenous changes are consistent with a dynamic, zonal exudative response to upstream capillary manipulation. Further preclinical and clinical investigations of these FUS-related imaging phenomena and of intracerebral perivenous compartment changes are needed to elucidate physiology of this pathway as well as biological effects of FUS administered with and without adjuvant neurotherapeutics.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT03671889, registered 9/14/2018.
Topics: Aged; Humans; Alzheimer Disease; Blood-Brain Barrier; Brain; Ultrasonography; Male; Female
PubMed: 37328855
DOI: 10.1186/s12987-023-00447-y -
Nature Immunology Jul 2023Blood protein extravasation through a disrupted blood-brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets....
Blood protein extravasation through a disrupted blood-brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets. However, how blood proteins polarize innate immune cells remains largely unknown. Here, we established an unbiased blood-innate immunity multiomic and genetic loss-of-function pipeline to define the transcriptome and global phosphoproteome of blood-induced innate immune polarization and its role in microglia neurotoxicity. Blood induced widespread microglial transcriptional changes, including changes involving oxidative stress and neurodegenerative genes. Comparative functional multiomics showed that blood proteins induce distinct receptor-mediated transcriptional programs in microglia and macrophages, such as redox, type I interferon and lymphocyte recruitment. Deletion of the blood coagulation factor fibrinogen largely reversed blood-induced microglia neurodegenerative signatures. Genetic elimination of the fibrinogen-binding motif to CD11b in Alzheimer's disease mice reduced microglial lipid metabolism and neurodegenerative signatures that were shared with autoimmune-driven neuroinflammation in multiple sclerosis mice. Our data provide an interactive resource for investigation of the immunology of blood proteins that could support therapeutic targeting of microglia activation by immune and vascular signals.
Topics: Mice; Animals; Microglia; Multiomics; Blood-Brain Barrier; Alzheimer Disease; Fibrinogen
PubMed: 37291385
DOI: 10.1038/s41590-023-01522-0 -
The EMBO Journal Sep 2023Accumulating evidence indicates that gut microbiota dysbiosis is associated with increased blood-brain barrier (BBB) permeability and contributes to Alzheimer's disease...
Accumulating evidence indicates that gut microbiota dysbiosis is associated with increased blood-brain barrier (BBB) permeability and contributes to Alzheimer's disease (AD) pathogenesis. In contrast, the influence of gut microbiota on the blood-cerebrospinal fluid (CSF) barrier has not yet been studied. Here, we report that mice lacking gut microbiota display increased blood-CSF barrier permeability associated with disorganized tight junctions (TJs), which can be rescued by recolonization with gut microbiota or supplementation with short-chain fatty acids (SCFAs). Our data reveal that gut microbiota is important not only for the establishment but also for the maintenance of a tight barrier. Also, we report that the vagus nerve plays an important role in this process and that SCFAs can independently tighten the barrier. Administration of SCFAs in App mice improved the subcellular localization of TJs at the blood-CSF barrier, reduced the β-amyloid (Aβ) burden, and affected microglial phenotype. Altogether, our results suggest that modulating the microbiota and administering SCFAs might have therapeutic potential in AD via blood-CSF barrier tightening and maintaining microglial activity and Aβ clearance.
Topics: Mice; Animals; Blood-Brain Barrier; Gastrointestinal Microbiome; Alzheimer Disease; Amyloid beta-Peptides; Microbiota; Fatty Acids, Volatile
PubMed: 37427561
DOI: 10.15252/embj.2022111515 -
Nature Communications Jun 2023Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimer's...
Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimer's disease. The Norrin/FZD/TSPAN12 pathway activates WNT/β-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD-selective ligand Norrin. Here, we develop L6-F4-2, a non-lipidated, FZD-specific surrogate which significantly improves subpicomolar affinity versus native Norrin. In Norrin knockout (Ndp) mice, L6-F4-2 not only potently reverses neonatal retinal angiogenesis deficits, but also restores BRB and BBB function. In adult C57Bl/6J mice, post-stroke systemic delivery of L6-F4-2 strongly reduces BBB permeability, infarction, and edema, while improving neurologic score and capillary pericyte coverage. Our findings reveal systemic efficacy of a bioengineered FZD-selective WNT surrogate during ischemic BBB dysfunction, with potential applicability to adult CNS disorders characterized by an aberrant blood-brain barrier.
Topics: Mice; Animals; Blood-Brain Barrier; Frizzled Receptors; Retina; Blood-Retinal Barrier; Wnt Signaling Pathway
PubMed: 37268690
DOI: 10.1038/s41467-023-37689-1 -
Nature Neuroscience Mar 2024Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID,...
Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood-brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog. Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.
Topics: Humans; Blood-Brain Barrier; Post-Acute COVID-19 Syndrome; Endothelial Cells; Leukocytes, Mononuclear; COVID-19; Cognitive Dysfunction; Inflammation; Mental Fatigue
PubMed: 38388736
DOI: 10.1038/s41593-024-01576-9 -
International Journal of Molecular... May 2023The blood-brain barrier (BBB) is a complex network of tightly regulated cells and transport proteins that separate the circulating blood from the brain tissue [...].
The blood-brain barrier (BBB) is a complex network of tightly regulated cells and transport proteins that separate the circulating blood from the brain tissue [...].
Topics: Blood-Brain Barrier; Brain; Biological Transport; Carrier Proteins
PubMed: 37298209
DOI: 10.3390/ijms24119261 -
Nature Communications Aug 2023Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization...
Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TV). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATV) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATV demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATV that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TV as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.
Topics: Animals; Mice; Tissue Distribution; Brain; Blood-Brain Barrier; Antibodies; Engineering; Macaca fascicularis
PubMed: 37598178
DOI: 10.1038/s41467-023-40681-4