Thursday, June 16, 2022

What Cells Form The Blood Brain Barrier

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Issues Surrounding The Bbb

What Exactly Is the Blood Brain Barrier?

Fa Transport Across The Bbb And Effects Of Fa On Bbb Permeability

Fatty acids are key components of membranes and exhibit many biological functions in a variety of tissues, including the key energy source for mitochondrial -oxidation . Cells acquire fatty acids through de novo synthesis, hydrolysis of triglycerides or uptake from exogenous sources . Minimal amount of FA are derived from TG hydrolysis and most cells are dependent upon fatty acid uptake from the peripheral blood . FA from the diet are absorbed by enterocytes in the small intestine and packaged into chylomicrons as TG. The liver also produces very low density lipoprotein , a rich source of endogenously generated TG. Circulating chylomicrons and VLDL particles are hydrolyzed by lipoprotein lipase in the capillary lumen of tissues and the released FA from these lipoproteins may be taken up by tissues in the body . FA that enter into cells are then esterified and stored as TG or transported to the mitochondria for -oxidation. The importance of FA for the developing and adult brain has been recently reviewed . FA transport from blood into parenchymal neurons is much more difficult than other cells since the tight junctions of the BBB severely restrict passage into the brain. FA must first move via transcellular transport across both the luminal and abluminal membranes of the endothelial cells and then across the plasma membrane of the neural cells .

The Bbb Can Be Broken Down By:

  • Hypertension : highblood pressure opens the BBB.
  • Development: the BBB is present, but may be not fully formed at birth.
  • Hyperosmolitity: a high concentration of asubstance in the blood can open the BBB.
  • Microwaves: exposure to microwaves can openthe BBB.
  • Radiation: exposure to radiation can open theBBB.
  • Infection: exposure to infectious agents canopen the BBB.
  • Trauma, Ischemia, Inflammation, Pressure:injury to the brain can open the BBB.
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    Dysfunction Of The Bbb In Cns Disorders

    Disruption of the BBB is observed in many different neurological disorders including MS, stroke, Alzheimer’s disease , epilepsy, and traumatic brain injuries. Functional imaging of human patients and analysis of postmortem brain samples has identified the pathological breakdown of the barrier in different neurological diseases. In addition, work with animal models of disease and with cell culture BBB models has enabled the identification of some of the molecular mechanisms that cause changes to the BBB. This dysfunction can include alterations in many different properties of the BBB including TJs, transporters, transcytosis, and LAM expression. This breakdown can lead to edema, disruption of ionic homeostasis, altered signaling, and immune infiltration that can lead to neuronal dysregulation and, ultimately, degeneration. Although BBB dysfunction is often secondary to the primary insult in these diseases, in some cases, it has been a suggested cause, including MS, epilepsy, and AD .

    Schematic representation of signaling regulating the bloodbrain barrier in health and disease. ICAM, intercellular adhesion molecule MMP, matrix metalloproteinase ROS, reactive oxygen species.

    Esr 1 Marjolein Heymans

    Cerebrovascular and Blood

    In vitro models of the BBB and applications in pharmacological and toxicological screenings

    In my individual project, I am testing different CNS drugs in vitro, which is a term meaning in a test tube and is the opposite of in vivo, which basically means in a living organism. In my experiments, I make use of different types of human and animal cells, characteristic of the BBB, that are put together in such way that they mimic the BBB. This kind of experiments reduce the intensive and direct use of animals, but still gives us the opportunity to study the barrier mechanisms of the BBB. The main goal in this project would be to be able to use these kind of in vitro models to predict drug distribution into the human brain, as well as drug brain toxicity.

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    Associated Conditions And Problems

    The blood-brain barrier is usually effective at keeping foreign or toxic substances out of your central nervous system. Most of the time this is a good thing, but it can pose a problem when developing new drugs for the nervous system. For example, one of the major challenges in treating brain tumors is that it can be difficult to make a medication capable of getting across the blood-brain barrier to reach the cancer. Because of this problem, researchers are developing medicine to try to bypass the blood-brain barrier.

    The blood-brain barrier can sometimes also be broken down by injuries and infections. Research shows that strokes and traumatic brain injury can damage the endothelial tissue and cause the blood-brain barrier to open. Researchers have also found that those with early signs of cognitive impairment have a breakdown of the blood-brain barrier. The findings could help to lead to early diagnostic tests for Alzheimers disease and other conditions that cause cognitive impairment.

    Esr 5 Kakogiannos Nikolaos

    The role of G-protein-coupled receptor Gpr126 signalling in the development of the blood-brain barrier

    The complexity of the blood-brain barrier has hampered efforts for drug delivery to the brain for the treatment of various pathological conditions, like cancers and neurodegenerative diseases. To this end, we need to understand the dynamics and molecular mechanisms that drive BBB formation through the identification of new genes. In our laboratory we have focused on a novel gene, Gpr126, which we believe to be important for the development of the BBB. We are trying to describe the role and the molecular mechanism of Gpr126 during the establishment of the BBB.

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    The Blood Brain Barrier

    More than 100 years ago it was discovered that if blue dye was injectedinto the bloodstream of an animal, that tissues of the whole body EXCEPTthe brain and spinal cord would turn blue. To explain this, scientiststhought that a “Blood-Brain-Barrier” which prevents materials fromthe blood from entering the brain existed. More recently, scientists havediscovered much more about the structure and function of theBBB.

    Models To Study The Bbb

    Blood brain barrier and vasogenic edema | Circulatory System and Disease | NCLEX-RN | Khan Academy

    In vitro models of the BBB have proven very effective to study the transport of endogenous macromolecules like fatty acids across the BMEC. They have also been used extensively in pharmaceutical research to study the passage of therapeutic molecules across the BMEC . Several studies have shown that the BMEC lose many of their special properties when removed from their natural environment and show dedifferentiation behaviour. Thus, one potential limitation of in vitro BBB models is that the BMEC may not behave as site-specific specialized endothelial cells in vitro, but rather as common peripheral endothelial cells . In spite of this shortcoming, several successful in vitro models of the BBB have been described . Many of these have used human, bovine, and porcine or rat endothelial cells:

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    Regulation Of The Bbb By Astrocytes

    The persistence of a functional BBB throughout adulthood is maintained and regulated by numerous factors unique to the microniche of the neurovascular unit . AstrocyteBBBEC interactions are known to regulate EC morphology, angiogenesis, and to influence the phenotype of the barrier under physiological and pathological conditions .

    Astrocytes are known to produce factors that modulate endothelial functioning during development and adulthood. One of these pathways is the Hedgehog signaling cascade known to be involved in embryonic morphogenesis, neuronal guidance, and angiogenesis. Astrocytes secrete Sonic Hh , and BBB ECs express the Hh receptor Patched-1, the signal transducer Smoothened , as well as transcription factors of the Gli family. Interestingly, transendothelial electrical resistance and permeability experiments showed that activation of the Hh pathway induced expression of junctional proteins and promoted a BBB phenotype. In addition, mice genetically engineered to lose the signal transducer Smo on ECs had a significant increase in BBB permeability that correlated with a decrease in junctional protein expression and disturbed BMs , supporting the concept that the Hh pathway has a significant influence on BBB function.

    Introduction To The Blood

    The blood-brain barrier is a component of the neurovascular unit and acts as the blood-brain interface, mediating communication between the central nervous system and the periphery. The BBB separates the circulation from the brain, allowing for protection from and transport regulation of serum factors and neurotoxins. The BBB is not just a physical barrier but also acts more selectively as a transport interface , a secretory body, and a metabolic barrier .

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    Tight Junctions And The Blood

    The TJ is an intricate complex of several transmembrane proteins including junctional adhesion molecules , occludin and claudins , and cytoplasmic proteins, such as zonula occludens and cingulin . Some of these components are directly linked to the actin cytoskeleton. For example, the cytoplasmic protein links membrane proteins to actin cytoskeleton to maintain the endotheliums structural and functional integrity . Table 2 provides a detailed description of many junction-associated proteins that play a role in blood-barrier formation/function in Drosophila and vertebrates. The expression and subcellular localization of TJ proteins are modulated by several intrinsic signaling pathways, including those involving calcium, phosphorylation, and G proteins .

    Brain Barriers: A Dynamic Field Yet To Be Discovered


    While the study of brain barriers started already over a century ago, ongoing discoveries and surprising findings indicate that our current knowledge touches only the tip of the iceberg! Technical advancements in biological research allow the investigation of BBB- characteristics, dynamics, and the cellular components in increasing resolution. The compound efforts and ongoing international data-sharing and collaborations among scientists over the past decades have been essential in the scientific advancement in this field. Two up-and-coming topics we are now able to address include the dynamic nature of the barriers, as well as the complex interaction between all the cells involved.

    Brain barriers: a highly dynamic and changing structure

    While in healthy conditions the brain barriers maintain a steady CNS, this does not mean the status quo of the barrier is static. Instead, the barriers are highly dynamic and actively maintained throughout life and adapt to different situations.

    The neurovascular unit: barrier formation through cooperation

    All the cells in the neurovascular unit interact and communicate in order to regulate the barrier properties.

    Interestingly, the pericytes also help the astrocytes to find and surround the blood vessels with their endfeet. The close interdependence of these cells illustrates the critical role of the communication between all the cells involved to form a good blood brain barrier.

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    What Are The Steps In Spermiogenesis

    Spermiogenesis is comprised of four phases. These phases are Golgi phase, Cap phase, Tail phase, and Maturation phase. Following spermiogenesis is spermiation. The spermatozoa are released from the seminiferous tubules to migrate to epididymis where they become fully-differentiated, motile spermatozoa.

    Organization Of A Neurovascular Unit

    A neurovascular unit is organized by complex associations between endothelial cells, extra-cellular matrix, basal lamina, pericytes, closely juxtaposed neurons, and astrocytes . The components of the neurovascular unit maintain dynamic interactions with each other and play an important role in cerebrovascular function . Contact and communications between cells of the neurovascular unit regulate CNS development and synaptic activity and influence permeability properties of the BBB . A major function of the neurovascular unit is to regulate the transport and diffusion properties of brain capillary endothelial cells that compose the BBB .

    Within the neurovascular organization, further modular structures, termed the gliovascular units, are detected where individual astrocytic glia support the function of particular neuronal populations and communicate with associated segments of the microvasculature . Several recent studies have highlighted the importance of this modular organization in disease pathology and the cell-cell interactions that result in modulating the BBB.

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    What Are Glial Cells And What Do They Do

    You’ve likely heard of the gray matter of the brain, which is made up of cells called neurons, but a lesser-known type of brain cell is what makes up the white matter. These are called glial cells.

    Originally, glial cellsalso called glia or neurogliawere believed to just provide structural support. The word glia literally means “neural glue.”

    Relatively recent discoveries have revealed that they perform all kinds of functions in the brain and the nerves that run throughout your body. As a result, research has exploded and we’ve learned volumes about them. Still, much more is left to learn.

    Modulation Of The Bbb Following Hypoxia/ischemia And In Stroke

    2-Minute Neuroscience: Blood-Brain Barrier

    In vivo and in vitro stroke models have shown that cerebral vascular permeability increases in a time- and hypoxia-dependent manner. This leads to a subsequent increase in cerebral edema however, the processes involved in the hypoxia-induced BBB permeability are not completely understood. Work in animal models of stroke has identified that there is a biphasic leakage of the BBB, with an early opening within hours following hypoxia/ischemia, followed by a refractory phase and then a second opening the next day . In addition, analysis in transgenic models has identified that there are stepwise alterations in the BBB, with an increase in transcytosis observed first followed by alterations in the TJs . There are also important changes in ion channel and efflux transporter expression and activity.

    Molecular Alterations of the Tight Junctions

    Changes in junctional structure formation or stability are now known to involve up-regulation in vascular endothelial growth factor , and inhibition of VEGF attenuates the hypoxia-induced increase in BBB permeability . In addition, hypoxia increases nitric oxide release by ECs and inhibition of NO synthase reduces the effect of hypoxia on cell permeability. Although the exact mechanisms involved in the VEGF- and NO-mediated changes in EC permeability are still being investigated, some reports have shown that NO may directly modify the TJ proteins by nitrosylation or nitrosation.

    MMPs and the BBB

    Modulation of Channels and Transporters

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    A New Atlas Of Cells That Carry Blood To The Brain

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    While neurons and glial cells are by far the most numerous cells in the brain, many other types of cells play important roles. Among those are cerebrovascular cells, which form the blood vessels that deliver oxygen and other nutrients to the brain.

    Those cells, which comprise only 0.3 percent of the brains cells, also make up the blood-brain barrier, a critical interface that prevents pathogens and toxins from entering the brain, while allowing critical nutrients and signals through. Researchers from MIT have now performed an extensive analysis of these difficult-to-find cells in human brain tissue, creating a comprehensive atlas of cerebrovascular cell types and their functions.

    We think this might be a very promising route because the cerebrovasculature is much more accessible for therapeutics than the cells that lie inside the blood-brain barrier of the brain, says Myriam Heiman, an associate professor in MITs Department of Brain and Cognitive Sciences and a member of the Picower Institute for Learning and Memory.

    A comprehensive atlas

    Organic Anion Transporting Polypeptide

    Organic anion transporting polypeptides are members of the solute carrier organic anion transporter family . The OATPs accommodate the transport of a wide variety of amphipathic solutes, including bile salts, anionic peptides, steroid conjugates, thyroid hormones and an increasing number of pharmaceutical drugs and xenobiotics . Members of the OATP family, of which there are currently 11 known to be expressed in humans , share a great deal of amino acid sequence identity and transport solutes in a sodium independent manner .

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    Why Do We Need It

    The purpose of the bloodbrain barrier is to protect against circulating toxins or pathogens that could cause brain infections, while at the same time allowing vital nutrients to reach the brain.

    Its other function is to help maintain relatively constant levels of hormones, nutrients and water in the brain fluctuations in which could disrupt the finely tuned environment.

    So what happens if the bloodbrain barrier is damaged or somehow compromised?

    One common way this occurs is through bacterial infection, as in meningococcal disease. Meningococcal bacteria can bind to the endothelial wall, causing tight junctions to open slightly. As a result, the bloodbrain barrier becomes more porous, allowing bacteria and other toxins to infect the brain tissue, which can lead to inflammation and sometimes death.

    Its also thought the bloodbrain barriers function can decrease in other conditions. In multiple sclerosis, for example, a defective bloodbrain barrier allows white blood cells to infiltrate the brain and attack the functions that send messages from one brain cell to another. This causes problems with how neurons signal to each other.

    Insulin Signaling Within Cells Of The Blood


    There is not a cell type in the CNS that we are aware of that does not express the insulin receptor. In mice, the expression of the insulin receptor gene is most abundant in endothelial cells, about two times greater than astrocytes, with neurons falling in close behind in terms of RNA expression levels1 . This same expression pattern was not observed in samples from human tissue . Instead, expression of the insulin receptor is more evenly distributed between the cell types. Insulin interacts with receptors on neurons and glial cells , endothelial cells , and pericytes to elicit various physiological effects, some of which are highlighted in Figure 1. The insulin receptor exists in two isoforms, an A and B form, due to differences in splicing of the subunit, resulting in different binding affinities to insulin and insulin-like growth factor . However, until recently, the ability to detect these two isoforms by immunological methods in vivo in different cell types has been a challenge. With the advances in single cell RNA sequencing and a novel in situ RT-PCR/FISH assay , we expect a growth in the knowledge of expression pattern of these isoforms and alterations in human disease within specific cell types and regional variations. The insulin receptor can also form heterodimers with the IGF-1 receptor and can have varying post-translational modifications leading to further diversity of insulin action .

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