lecture 4 Blood Brain Barrier Flashcards
Blood–CSF barriers
Choroid plexus epithelial cells
Arachnoid membrane
Choroid plexus is
main site of entry for Ca2+ into the brain.
What is the blood-brain barrier
A highly selective semi-permeablebarrier separating the circulating blood from the brain and spinal cord
types of cells that make up BBB
Brain endothelial cells, basement membrane, pericytes, astrocytes, neurons
_________ cells that precludes entrance of
substances into the brain
tight-junctioned brain capillary
endothelial
BBB has gaps where
in some sensory (area postrema) and secretory area
______ are responsible for the formation and the maintenance of the BBB
Astrocytes
what are the main Cellular constituents of the BBB (%)
Brain endothelial cells Basement membrane Pericytes Astrocytes Neurons
fenestrations occur in
periphery (a gap)
TJs are one mode of cell-cell adhesion, sealing the ________ between endothelial cells.
aqueous paracellular diffusional pathway
Linked together by a complex of proteins which span the inter-endothelial space creating
Tight Junctions
Individual TJ strands then ____ and tightly associate with strands in the apposing membrane of _____to form paired strands, intercellular distance becomes nonexistent….. “kissing points
laterally,,adjacent cells
what are the 4 main the interaction between integral membrane proteins
Junctional Adhesion Molecules
Occludin
Claudin
Adherence Junctions
Junctional Adhesion Molecules with a single transmembrane domain, was shown to associate laterally with TJ strands, but
not to constitute the strands per se
Zonulae Occludins are ____conditions where BBB breakdowns and TJ can formed wit/without
decreased without
Adherens Junctions______ found in many tissues
Adhesive cell-cell contact
3 main functions of BBB important
Physical:BECs & tight junctions
Transport: Specialized transporters
Metabolic: enzymes
Cadherin dimers form
cell-cell adhesion
____is critical for the normal functioning of cadherins, which have a _____ binding site in their extracellular domain
calcium
_____ is a major constituent of TJ strands
Claudin
Experiment: WT and Cldn 5-/- embryos injected with a
low molecular mass tracer Findings and authotrs hypothesis
WT mice had no tracer from CNS, whereas
Cldn 5-/- mice showed had tracer throughout CNS parenchyma
Authors hypothesis: BBB is loosened in a size-selective manner in Cldn 5-/- mice.
Main molecular traffic routes across the BBB
1) Transcellular Diffusion
2) Transport Proteins
Solute Carriers
ABC Efflux Transporters
3) Trancytosis
Receptor-mediated
Adsorptive
Transcellular diffusion is dependent upon
lipid solubility-High oil/water partitioning coefficient (K)
But NSAIDs, like aspirin, are structurally lipophilic. Why does it have low lipid solubility on this graph?
The majority of NSAIDs circulate as organic anions (at physiological pH). Such that the small neutral (un-ionized) fraction may prove limiting to brain uptake.
Facilitative transporters: allow
solutes to flow downhill with their electrochemical gradient
Facilitative transporters: example
. Cationic amino acid system (Y+) Lysine, arginine, and ornithine
Secondary active transporters:
Ion-coupled transporters and exchangers that do not require ATP
ATP-binding cassette (ABC) efflux transporters are located where
Located on luminal membrane of the BBB
ATP-binding cassette (ABC) efflux transporters function
Use ATP to actively eject a range of substances, including both xenobiotics and endogenous TOXIC molecules
Trancytosis (Receptor-mediated) Primary route of transport for…
essential peptides and signaling molecules
Including insulin, leptin, and transferrin
Trancytosis (Receptor-mediated Requires ligand-receptor binding, followed by
by endocytosis and exocytosis
Ex. Iron-bound transferrin
Trancytosis (Adsorptive-mediated) Primary route of transport for…
Primary route of transport for many plasma proteins
Ex. Albumin
Trancytosis (Adsorptive-mediated) what types of molecules are readly absorbed
Cations b/c BECs carry an overall negative surface charge on their luminal membrane due to heparan sulfate proteoglycans
BBB is formed via complex interactions between (what types of cells) and the basement membrane
endothelial cells, astrocytic endfeet, pericytes
5 molecular routes across the BBB exist
Transcellular diffusion, solute carriers, ABC efflux transporters, and transcytosis (receptor mediated and adsorptive)
BBB breakdown may occur in
many neurological diseases
_______ as well as finding novel ways to disrupt the barrier to allow for penetration of said drugs, is a hurdle facing scientists today
Developing new drugs to cross the BBB,
Trancytosis (Receptor-mediated Requires
endocytosis and exocytosis only No receptor required -
BBB acts as as an enzymatic barrier by
Allows for uptake of neurotransmitter precursors
L-DOPA
Basement membrane / basal lamina Surround ____ and provieds _______
BECs, and structurral support
what can bind to the BM via specific receptors
BECs, astrocytes, and pericytes
Basement membrane is made of
Composition: mixture of different extracellular matrix proteins
Pericytes Named with respect to their
unique localization in the perivascular space of brain vessels
murual cells aka
Pericytes
pericyte : BEC ratio
1:5
pericyte Functions include:
Vessel formation, sprouting, and stabilization
Vessel diameter and CBF
Cross-talk and functional coupling between ___&____ is the result of several signal transduction cascades
pericytes and BECs
neural scars are formed by
pericytes and astrocytes
Pericytes Essential for ___ (4) during angiogenesis
recruitment, proliferation, migration, and attachment
Pericyte-deficient mice
Accumulation of intravenously injected tracers in the brain parenchyma and endothelium
Perivascular endfeet of _____ surround BECs and are contiguous with the basal lamina
astrocytes
____ channel, involved in ion and volume regulation
Aquaporin 4 (AQP4) and Kir4.1 K+
Weakening of the blood-brain barrier may precede, accelerate, or contribute to a number of
neurodegenerative diseases
Examples: BBB breakdown
MS and infiltration of white blood cells, which go on to attack myelin
Stroke, epilepsy
uptake of “vital dye” into parenchyma in ____ epileptic mice
increased
BBB Dysfunction may occur via ABC transporter _______
overexpression
Crossing the BBB Administration of
hyperosmolar agent
Crossing the BBB Receptor-meditated transcytosis thought of as
Trojan-horse method
Magnetic resonance-guided focused ultrasound helps
Locally disrupts BBB, therapeutic agents can be loaded into MBs
