4.9 Blood Brain Barrier Flashcards
Describe the anatomy of the areas in between blood and the central nervous system
-the pia mater is the inner layer that covers tissues in CNS
-the arachnoid is the outer layer that forms a protective barrier with tight junctions
-the subarachnoid space is the area in between the pia mater and the arachnoid
-the subarachnoid space contains cerebrospinal fluid (CFS) which cushions the CNS
-the choroid plexus is made up of the choroidal epithelium and the choroidal capillary. The choroid plexus produces the CSF which flows through the ventricles into the subarachnoid space
What are the 3 different ways that systemic circulation can cross into central nervous system tissue
-via the intracerebral capillary (which is the primary route)
-via the extracerebral capillary (where blood can enter into the subarachnoid space and contents of the blood can diffuse from csf to cns)
-via the choroidal capillary where components of the plasma pass into the choroid epithelium which can then filter substances into the csf
What are the 3 barriers protecting the brain from the blood
Blood-CNS : entry at the intracerebral capillaries, protected by the blood brain barrier, with tight junctions in the endothelial cells, the biggest and primary route
Blood-CSF : entry at choroidal capillaries/choroidal epithelium, protected by tight endothelial junctions
Brain-CSF : entry at extracerebral capillaries, protected by arachnoid barrier
What is the blood brain barrier (BBB)
The blood brain barrier is at the barrier between the blood and the central nervous system. It protects entry at the intracerebral capillaries. It is a selectively permeable membrane which restricts the passage of cells and molecules from the blood to the CNS in order to maintain brain and spinal cord homeostasis.
Describe why immune cell interaction with the BBB is limited
The brain acts as an immune privileged site, meaning that the brain takes care of its own immune system via microglia which mop up any unwanted cells.
Neutrophil infiltration into the brain is low, this is because there is a low expression of leukocyte binding proteins like JAMs in the tight junctions.
This is so as not to have any inflammatory cytokines crossing into the CNS as any brain inflammation would be deadly. As a result of all this, very few diseases pass into the brain from the blood.
Describe some similarities and differences in concentrations between plasma and CSF
The pH is very similar, but glucose is reduced in the CSF and almost no proteins and very few amino acids cross over.
Describe the different functions of the BBB
-Maintains ionic composition optimal for synaptic signalling.
-Keeps central and peripheral neurotransmitter pools separate. Plasma glutamate levels can be high, glutamate is neurotoxic so needs to be kept from crossing bbb
-Prevents plasma proteins detrimental to neural function (can cause cellular activation and apoptosis) from entering.
-Protects the brain from neurotoxic substances circulating in the blood.
-BBB has low passive permeability, hence active transport allows for the passage of essential nutrients (e.g glucose) and metabolites
Describe the BBB as a part of the neurovascular unit
The BBB is a key part of the neurovascular unit. Pericytes, microglia, astrocytes and nerve terminals are closely associated with the endothelium in the bbb and play supporting roles in barrier induction, maintenance and function. Barrier function is not fixed and can be modulated and regulated by other cells in the neurovascular unit.
What are circumventricular organs
Circumventricular organs are organs with in the brain that do not have a BBB. Their endothelial cells have pores and fenestrations. They allow a more direct communication between the blood and the brain. CVOs either have a role in sensory detection or secretion, they provide a bridge between CNS and peripheral circulation.
What are some sensory and secretory circumventricular organs
sensory CVOs: subfornical organ and area postrema
secretory CVOs: pineal gland and posterior pituitary gland
What are the 2 types of junctions that cerebral endothelial cells have
Tight junctions - cement adjacent cells and prevent the paracellular movement of solutes
Adherens junctions - provide structural integrity and attachment
Describe the structure of a cerebral endothelial tight junctions
Claudins and occludins span the intercellular cleft. Junctional adhesion molecules (JAMs) and tight junction proteins link to cytoplasmic scaffolding proteins (Z01,2 and 3 on the apical side), these JAMs potentially serve as a binding point for leukocytes.
Describe the structure of cerebral endothelial adherins junctions
V-E cadherins adhesion molecules span the intercellular cleft and are anchored to the cytoskeleton by scaffolding proteins called catenins.
How does the brain obtain a constant supply of energy
Normal brain function requires a constant supply of energy (ATP) derived from the metabolism of glucose and oxygen. Oxygen and CO2 can diffuse across the BBB but glucose can not. So there is a GluT glucose transporter. It is both on membranes.
What is the purpose of transporter proteins in endothelial brain cells
Endothelial cells use cellular transporters to dynamically regulate influx of nutrients and efflux of metabolic waste and toxins between the blood and the brain parenchyma
What are the different mechanisms through which nutrients and waste products move between the blood and brain parenchyma
-lipid soluble molecules moving across the membrane passively
-ABC efflux transporters intercept some of the lipid soluble molecules and pump them back out, active ATP dependent
-transport proteins (e.g GluT) carrying substances like glucose, amino acids and nucleosides
-receptor mediated endocytosis (e.g for insulin and transferrin) and adsorptive endocytosis (e.g for albumin and other plasma proteins), requires protein to be positively charged, but there are very low levels of this endocytosis
What are the occaisions in which some immune cells enter the brian
-In normal conditions some immune-competent cells penetrate by the process of diapedesis directly through the cytoplasm of endothelial cells
-In pathological states opening of tight junctions also allows paracellular entry
Generally describe CNS disorders
CNS disorders can be vascular derived or neural derived. Many disorders result in BBB dysfunction, but the breakdown of BBB can be the cause or the effect of the disorder. It is often not known if the BBB is the primary or secondary pathology
Describe multiple sclerosis in relation to the BBB
Areas of the CNS that have been infiltrated with inflammatory cells due to BBB disruption. These infiltrating leukocytes initiate an autoimmune response against the oligodendrocytes.
Describe the connection between epilepsy and BBB dysfunction
A seizure activates cycles leading to BBB dysfunction where neuron astrocyte interactions are abnormal. Astrocyes are potential targets for therapies to interrupt the cycle.
What is the connection between BBB and neurodegeneration in conditions like alzheimers
Cognitive function further declines as BBB permeability increases. Neurodegeneration is exacerbated by the linked process of BBB disruption and neuroinflammation.
Describe the challenge the BBB provides to therapeutic drugs attempting to pass through
You want a lipophillic drug in order to pass through the membrane. But even then the ATP binding cassete proteins transporters (ABC transporters) will take the drug back out.There are many different types of these efflux transporters that can be selective for different types of drugs.
You also want the drugs not to be bound to plasma proteins and alternative routes of entry into the CNS.
