Blood Brain Barrier Flashcards
Describe visually what blood brain barrier damage of mice infected with virus by Evan’s blue dye exclusion tests
Inclusion of blue colour dye n the brain indicated the increase permeability or damage of BBB.
Why do we need the BBB?
CNS neurons are intolerant to the fluctuations of metabolites, proteins and immune mediators present in the peripheral blood
Several amino acids such as glutamate are active as NTs and their conc in the extracellular space of the brain must be tightly regulated
Common plasma proteins such as serum albumin have been implicated in the provocation of epileptic seizures through the downstream alteration in astrocyte activity through downstream alteration in astrocyte activity induced by direct interaction with astrocyte TGFbeta Receptor-2 (TGFbR2)
Immune cells and inflammatory mediators may have destructive actions in the CNS
What is the barrier?
Non-fenestrated barrier endothelium of the blood brain vessels
Describe the lining of the BBB
Brain vessels are lined by continuous endothelial cells (ECs) that lack the small pores called fenestrated a found in vessels of many other tissues and organs
Importantly the tight junctions that join the ECs don’t permit leakage of even very small solute molecules, giving the ECs control of everything of everything that crosses the barrier
What gives the endothelial cells control over everything that crosses the barrier
Tight junctions that join the ECs don’t permit leakage of even very small solute molecules
Describe the choroidal capillary ultra structure
Fenestrated non-barrier endothelium typical of endocrine glands, small intestine and the renal glomerulus
Describe the dealing of the barrier
‘Tight’ junctions seal the barrier
The effective sealing of the gap between contiguous endothelial cells is maintained by extremely impermeable zonular occludes e belt-like tight junctions that completely seal the space between the ECs
Continuous endothelium and sealing tight junctions of the CNS blood vessels enables….
Them to act as. Continuous membrane
The tight junctions between BBB endothelial cells leads to …..
High endothelial electrical resistance and low paracellular permeability
The electrical resistance is in the range of 1500-2000 ohms/cm2 (pail vessels) compared to 3-33 ohms/cm2 in other tissues
Permeability of the BBB to different classes of small molecules is similar to that of….
An intact phospholipid membrane
What type of molecules can get through
Hydrophobic eg o2, co2, n2, steroid hormones
How do amino acids transported across
Active transport
Glucose crosses by….
Facilitated diffusion on the Glut-1 transporter
CNS endothelial cells have …… than non barrier vessels
Greater volume fraction of mitochrondria in their cytoplasm than those of non-barrier vessels, to meet the greater energy demands of the ATP driven active transport systems
Specific macromolecules such as carrier proteins are …..
Selectively transferred by receptor-mediated endocytosis and transcytosis
Where are Glut-1 and Glut 3
Glucose transporters
Glut-1 is present on the plasma membranes of retinal neurons, glia and the vascular endothelial cells at the Blood Retinal Barrier
Glut-3 is neuron-specific and absent from the endothelium
Glut-1 is expressed by ….
Retinal neurons, glia and by vascular endothelial cells at the BRB
What permits selective transport of carrier proteins
Receptor-mediated endocytosis
Transcytosis can deliver..
Essential macromolecules such as carrier proteins, or therapeutic antibodies, across the BB in a biologically active state
In receptor-mediated transcytosis, macromolecules internalised by RME at the apical surface are re-routed from early recycling endoscopes to the base-lateral surface in biologically intact form
Intravascular horseradish peroxidase MW 35-40K is…
Confined to the endosomal system of the endothelium of retinal capillary
What are caveolae
pecialised cholesterol-rich microdomains of the plasma membrane, related to ‘lipid rafts’ in a wide variety of cells. However, when first described in endothelial cells by Palade et al over 40 years ago, they were interpreted as transport vesicles because of their spherical shape and the fact that due to their small size (60-80nM), their continuity with the cell surface was often not obvious. (see notes)
Caveolae often create apparent multi-chambered compartments at the luminal surface of vascular endothelial cells that have been associated with pathological activity of vascular endothelial growth factor (VEGF). However, they are present under normal conditions in retinal and choroidal vessels of the eye.
Caveolae of ten create
Apparent multi-chambered compartments at the luminal surface of vascular endothelial cells that have been associated with pathological activity of vascular endothelial GF (VEGF). However, they are present under normal conditions in retinal and choroidal vessels of the eye
Where are caveolae predominantly located
At the albuminal plasma membrane of the endothelium in the brain and retinal vessels, but if they operated transcytosis there should e equivalent numbers on each side of the cell. The tracer HRP within the vessel lumen in this type of preparation is washed out by perfusion fixation showing that caveolae do not internalise the protein
Caveolae in an endothelial cell process show…
Tight clustering around a mitochondrion consistent with their role in locating ATP dependent ion pumps in a protected micro environment at the surface of constantly moving cells
