The role of the blood–brain barrier
Although the brain constitutes only 2% of body weight, it receives approximately 15% of the blood supply and consumes nearly 20% of the total oxygen and glucose available to the body. In order to supply these essential nutrients for brain function, there must be a consistent and rapid blood supply to the brain in order that the brain cells may function. This is supplied by the cerebral arteries derived from the internal carotid arteries which branch over the surface of the brain and send smaller branches into the deeper subcortical structures. The capillaries are highly branched and it has been calculated that every nerve cell is no more than 40–50 mm from a capillary. Because of the unique dependence of the brain on oxygen and glucose to enable the extensive oxidative metabolism to take place within the nerve cells, it is essential that the composition of nutrients, electrolytes, etc. in the fluid surrounding the brain cells is controlled. The composition of the blood varies to some extent according to the composition of the diet and therefore a mechanism has evolved to ensure that the composition of the extracellular fluid surrounding the brain cells is constant. The extracellular fluid is inequilibrium with the cerebrospinal fluid which fills the four ventricles of the brain, and covers the surface of the brain and the spinal cord. Cerebrospinal fluid is formed from the blood and may be considered as an ultra filtrate of plasma. Thus cerebrospinal fluid contains most of the electrolytes and low molecular weight nutrients but is low in protein. It is formed from a network of capillaries in the ventricles termed the choroids plexus but the cerebral capillaries also contribute to the production of cerebrospinal fluid. The extracellular fluid and the cerebrospinal fluid compartment is separated from the blood by the blood–brain barrier. This is a barrier formed by tight junctions that exist between the endothelial cells lining the capillaries and the epithelial cells at the choroid plexus. Such a barrier prevents the influx of large molecular weight molecules but enables small molecular weight substances such as glucose, amino acids, fatty acids, electrolytes, etc., which are essential for normal brain function, to enter. In addition to the structural nature of the blood–brain barrier, there also exist specific transport sites that assist the transport of glucose and essential amino acids into the extracellular fluid. Thus the blood–brain barrier has both a structural and a metabolic role to play in maintaining homeostasis. Cellular structure of the brain It has been calculated that the human brain contains approximately 10712 neurons of which the cortex probably contains 10710. Such complexity is further magnified by the neuronal interconnections. Structurally the neuronal cell body contains a number of organelles that are characteristic of all cell types. The most important features are the nucleus, which contains the deoxyribonucleic acid (DNA) together with specific proteins that form chromosomes, and which functions to control the synthesis of all molecules within the neuron, and the nucleolus which is involved in ribosome synthesis and in the transfer of ribonucleic acid (RNA) to the cytosol. There is now evidence that the messenger RNA forming specific proteins is targeted to specific parts of the nerve cell. For example, the messenger RNA for microtubule associated protein-2 (MAP-2) targets the dendrites. This provides a mechanism for maintaining the structural integrity and differentiation of the neuron. The mitochondria, as in all types of cells, provides energy to the nerve cell in the form of adenosine triphosphate (ATP). The smooth endoplasmic reticulum is involved in lipid synthesis and in protein glycosylation whereas the rough endoplasmic reticulum is formed from the attachment of ribosomes to the smooth endoplasmic reticulum. These ribosomes are the main sites of membrane protein synthesis.The Golgi apparatus is situated near the nucleus and is responsible for protein glycosylation, membrane assembly and protein sorting. Lysosomes are responsible for the degradation of all types of cellular debris. The plasma membrane surrounds the neuron and consists of a phospholipid bilayer, inserted into which are intrinsic and extrinsic membrane proteins and cholesterol. The plasma membrane provides an impermeable barrier for many large molecular weight and charged molecules. The plasma membrane is transversed by different types of proteins that act as
neurotransmitter receptors and voltage-sensitive ion channels.The cytosol is the fluid compartment of the cell and contains the enzymes responsible for cellular metabolism together with free ribosomes concerned with local protein synthesis. In addition to these structures which are common to all cell types, the neuron also contains specific organelles which are unique to the nervous system. For example, the neuronal skeleton is responsible for monitoring the shape of the neuron. This is composed ofseveral fibrous proteins that strengthen the axonal process and provide a structure for the location of specific membrane proteins. The axonal cytoskeleton has been divided into the internal cytoskeleton, which consists of microtubules linked to filaments along the length of the axon, which provides a track for the movement of vesicular material by fast axonal transport, and the cortical cytoskeleton. The cytoskeleton is found near the axonal membrane and consists of microfilaments linked internally to microtubules and the plasma membrane by a network of filamentous protein that includes the brain-specific protein fodrin. This protein forms attachment sites for integral membrane proteins either by means of the neuronal cell adhesion molecule (N-CAM) or indirectly by means of a specific protein called ankyrin in the case of the sodium channels. This may provide a means whereby the sodium channels are concentrated in the region of the nodes of Ranvier. Thus the cortical cytoskeleton plays a vital role in neuronal function by acting as attachment site for various receptors and ion channels, but also for synaptic vesicles at nerve terminals, thereby providing a mechanism for concentrating the vesicles prior to the release of the neurotransmitter. There is also interest in the involvement of the cytoskeleton in such dgenerative diseases as Alzheimer’s disease whichis characterized by tangles (paired helical filaments). It seems likely that one of the microtubule-associated proteins (tau protein) is an important component of the tangles found in Alzheimer’s disease. Another unique feature of the neuron is the presence of synaptic and coated vesicles. The former are small smooth-coated vesicles 30–100nm in diameter and containing the neurotransmitters. The latter are rough-coated vesicles that contain the protein clathrin. These are thought to be involved in the retrieval and recycling of membrane components including the synaptic vesicles once they have liberated their neurotransmitter into the synaptic cleft.
Although the brain constitutes only 2% of body weight, it receives approximately 15% of the blood supply and consumes nearly 20% of the total oxygen and glucose available to the body. In order to supply these essential nutrients for brain function, there must be a consistent and rapid blood supply to the brain in order that the brain cells may function. This is supplied by the cerebral arteries derived from the internal carotid arteries which branch over the surface of the brain and send smaller branches into the deeper subcortical structures. The capillaries are highly branched and it has been calculated that every nerve cell is no more than 40–50 mm from a capillary. Because of the unique dependence of the brain on oxygen and glucose to enable the extensive oxidative metabolism to take place within the nerve cells, it is essential that the composition of nutrients, electrolytes, etc. in the fluid surrounding the brain cells is controlled. The composition of the blood varies to some extent according to the composition of the diet and therefore a mechanism has evolved to ensure that the composition of the extracellular fluid surrounding the brain cells is constant. The extracellular fluid is inequilibrium with the cerebrospinal fluid which fills the four ventricles of the brain, and covers the surface of the brain and the spinal cord. Cerebrospinal fluid is formed from the blood and may be considered as an ultra filtrate of plasma. Thus cerebrospinal fluid contains most of the electrolytes and low molecular weight nutrients but is low in protein. It is formed from a network of capillaries in the ventricles termed the choroids plexus but the cerebral capillaries also contribute to the production of cerebrospinal fluid. The extracellular fluid and the cerebrospinal fluid compartment is separated from the blood by the blood–brain barrier. This is a barrier formed by tight junctions that exist between the endothelial cells lining the capillaries and the epithelial cells at the choroid plexus. Such a barrier prevents the influx of large molecular weight molecules but enables small molecular weight substances such as glucose, amino acids, fatty acids, electrolytes, etc., which are essential for normal brain function, to enter. In addition to the structural nature of the blood–brain barrier, there also exist specific transport sites that assist the transport of glucose and essential amino acids into the extracellular fluid. Thus the blood–brain barrier has both a structural and a metabolic role to play in maintaining homeostasis. Cellular structure of the brain It has been calculated that the human brain contains approximately 10712 neurons of which the cortex probably contains 10710. Such complexity is further magnified by the neuronal interconnections. Structurally the neuronal cell body contains a number of organelles that are characteristic of all cell types. The most important features are the nucleus, which contains the deoxyribonucleic acid (DNA) together with specific proteins that form chromosomes, and which functions to control the synthesis of all molecules within the neuron, and the nucleolus which is involved in ribosome synthesis and in the transfer of ribonucleic acid (RNA) to the cytosol. There is now evidence that the messenger RNA forming specific proteins is targeted to specific parts of the nerve cell. For example, the messenger RNA for microtubule associated protein-2 (MAP-2) targets the dendrites. This provides a mechanism for maintaining the structural integrity and differentiation of the neuron. The mitochondria, as in all types of cells, provides energy to the nerve cell in the form of adenosine triphosphate (ATP). The smooth endoplasmic reticulum is involved in lipid synthesis and in protein glycosylation whereas the rough endoplasmic reticulum is formed from the attachment of ribosomes to the smooth endoplasmic reticulum. These ribosomes are the main sites of membrane protein synthesis.The Golgi apparatus is situated near the nucleus and is responsible for protein glycosylation, membrane assembly and protein sorting. Lysosomes are responsible for the degradation of all types of cellular debris. The plasma membrane surrounds the neuron and consists of a phospholipid bilayer, inserted into which are intrinsic and extrinsic membrane proteins and cholesterol. The plasma membrane provides an impermeable barrier for many large molecular weight and charged molecules. The plasma membrane is transversed by different types of proteins that act as
neurotransmitter receptors and voltage-sensitive ion channels.The cytosol is the fluid compartment of the cell and contains the enzymes responsible for cellular metabolism together with free ribosomes concerned with local protein synthesis. In addition to these structures which are common to all cell types, the neuron also contains specific organelles which are unique to the nervous system. For example, the neuronal skeleton is responsible for monitoring the shape of the neuron. This is composed ofseveral fibrous proteins that strengthen the axonal process and provide a structure for the location of specific membrane proteins. The axonal cytoskeleton has been divided into the internal cytoskeleton, which consists of microtubules linked to filaments along the length of the axon, which provides a track for the movement of vesicular material by fast axonal transport, and the cortical cytoskeleton. The cytoskeleton is found near the axonal membrane and consists of microfilaments linked internally to microtubules and the plasma membrane by a network of filamentous protein that includes the brain-specific protein fodrin. This protein forms attachment sites for integral membrane proteins either by means of the neuronal cell adhesion molecule (N-CAM) or indirectly by means of a specific protein called ankyrin in the case of the sodium channels. This may provide a means whereby the sodium channels are concentrated in the region of the nodes of Ranvier. Thus the cortical cytoskeleton plays a vital role in neuronal function by acting as attachment site for various receptors and ion channels, but also for synaptic vesicles at nerve terminals, thereby providing a mechanism for concentrating the vesicles prior to the release of the neurotransmitter. There is also interest in the involvement of the cytoskeleton in such dgenerative diseases as Alzheimer’s disease whichis characterized by tangles (paired helical filaments). It seems likely that one of the microtubule-associated proteins (tau protein) is an important component of the tangles found in Alzheimer’s disease. Another unique feature of the neuron is the presence of synaptic and coated vesicles. The former are small smooth-coated vesicles 30–100nm in diameter and containing the neurotransmitters. The latter are rough-coated vesicles that contain the protein clathrin. These are thought to be involved in the retrieval and recycling of membrane components including the synaptic vesicles once they have liberated their neurotransmitter into the synaptic cleft.
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