lecture 4 Blood Brain Barrier

Question 1

Blood–CSF barriers

Answer 1

Choroid plexus epithelial cells

Arachnoid membrane

Question 2

Choroid plexus is

Answer 2

main site of entry for Ca2+ into the brain.

Question 3

What is the blood-brain barrier

Answer 3

A highly selective semi-permeablebarrier separating the circulating blood from the brain and spinal cord

Question 4

types of cells that make up BBB

Answer 4

Brain endothelial cells, basement membrane, pericytes, astrocytes, neurons

Question 5

_________ cells that precludes entrance of

substances into the brain

Answer 5

tight-junctioned brain capillary

endothelial

Question 6

BBB has gaps where

Answer 6

in some sensory (area postrema) and secretory area

Question 7

______ are responsible for the formation and the maintenance of the BBB

Answer 7

Astrocytes

Question 8

what are the main Cellular constituents of the BBB (%)

Answer 8

Brain endothelial cells
Basement membrane
Pericytes
Astrocytes
Neurons

Question 9

fenestrations occur in

Answer 9

periphery (a gap)

Question 10

TJs are one mode of cell-cell adhesion, sealing the ________ between endothelial cells.

Answer 10

aqueous paracellular diffusional pathway

Question 11

Linked together by a complex of proteins which span the inter-endothelial space creating

Answer 11

Tight Junctions

Question 12

Individual TJ strands then ____ and tightly associate with strands in the apposing membrane of _____to form paired strands, intercellular distance becomes nonexistent….. “kissing points

Answer 12

laterally,,adjacent cells

Question 13

what are the 4 main the interaction between integral membrane proteins

Answer 13

Junctional Adhesion Molecules
Occludin
Claudin
Adherence Junctions

Question 14

Junctional Adhesion Molecules with a single transmembrane domain, was shown to associate laterally with TJ strands, but

Answer 14

not to constitute the strands per se

Question 15

Zonulae Occludins are ____conditions where BBB breakdowns and TJ can formed wit/without

Answer 15

decreased without

Question 16

Adherens Junctions______ found in many tissues

Answer 16

Adhesive cell-cell contact

Question 17

3 main functions of BBB important

Answer 17

Physical:BECs & tight junctions
Transport: Specialized transporters
Metabolic: enzymes

Question 18

Cadherin dimers form

Answer 18

cell-cell adhesion

Question 19

____is critical for the normal functioning of cadherins, which have a _____ binding site in their extracellular domain

Answer 19

calcium

Question 20

_____ is a major constituent of TJ strands

Answer 20

Claudin

Question 21

Experiment: WT and Cldn 5-/- embryos injected with a

low molecular mass tracer Findings and authotrs hypothesis

Answer 21

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.

Question 22

Main molecular traffic routes across the BBB

Answer 22

1) Transcellular Diffusion
2) Transport Proteins
Solute Carriers
ABC Efflux Transporters
3) Trancytosis
Receptor-mediated
Adsorptive

Question 23

Transcellular diffusion is dependent upon

Answer 23

lipid solubility-High oil/water partitioning coefficient (K)

Question 24

But NSAIDs, like aspirin, are structurally lipophilic. Why does it have low lipid solubility on this graph?

Answer 24

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.

Question 25

Facilitative transporters: allow

Answer 25

solutes to flow downhill with their electrochemical gradient

Question 26

Facilitative transporters: example

Answer 26

. Cationic amino acid system (Y+) Lysine, arginine, and ornithine

Question 27

Secondary active transporters:

Answer 27

Ion-coupled transporters and exchangers that do not require ATP

Question 28

ATP-binding cassette (ABC) efflux transporters are located where

Answer 28

Located on luminal membrane of the BBB

Question 29

ATP-binding cassette (ABC) efflux transporters function

Answer 29

Use ATP to actively eject a range of substances, including both xenobiotics and endogenous TOXIC molecules

Question 30

Trancytosis (Receptor-mediated) Primary route of transport for...

Answer 30

essential peptides and signaling molecules | Including insulin, leptin, and transferrin

Question 31

Trancytosis (Receptor-mediated Requires ligand-receptor binding, followed by

Answer 31

by endocytosis and exocytosis | Ex. Iron-bound transferrin

Question 32

Trancytosis (Adsorptive-mediated) Primary route of transport for...

Answer 32

Primary route of transport for many plasma proteins | Ex. Albumin

Question 33

Trancytosis (Adsorptive-mediated) what types of molecules are readly absorbed

Answer 33

Cations b/c BECs carry an overall negative surface charge on their luminal membrane due to heparan sulfate proteoglycans

Question 34

BBB is formed via complex interactions between (what types of cells) and the basement membrane

Answer 34

endothelial cells, astrocytic endfeet, pericytes

Question 35

5 molecular routes across the BBB exist

Answer 35

Transcellular diffusion, solute carriers, ABC efflux transporters, and transcytosis (receptor mediated and adsorptive)

Question 36

BBB breakdown may occur in

Answer 36

many neurological diseases

Question 37

_______ as well as finding novel ways to disrupt the barrier to allow for penetration of said drugs, is a hurdle facing scientists today

Answer 37

Developing new drugs to cross the BBB,

Question 38

Trancytosis (Receptor-mediated Requires

Answer 38

endocytosis and exocytosis only No receptor required -

Question 39

BBB acts as as an enzymatic barrier by

Answer 39

Allows for uptake of neurotransmitter precursors | L-DOPA

Question 40

Basement membrane / basal lamina Surround ____ and provieds _______

Answer 40

BECs, and structurral support

Question 41

what can bind to the BM via specific receptors

Answer 41

BECs, astrocytes, and pericytes

Question 42

Basement membrane is made of

Answer 42

Composition: mixture of different extracellular matrix proteins

Question 43

Pericytes Named with respect to their

Answer 43

unique localization in the perivascular space of brain vessels

Question 44

murual cells aka

Answer 44

Pericytes

Question 45

pericyte : BEC ratio

Answer 45

1:5

Question 46

pericyte Functions include:

Answer 46

Vessel formation, sprouting, and stabilization | Vessel diameter and CBF

Question 47

Cross-talk and functional coupling between ___&____ is the result of several signal transduction cascades

Answer 47

pericytes and BECs

Question 48

neural scars are formed by

Answer 48

pericytes and astrocytes

Question 49

Pericytes Essential for ___ (4) during angiogenesis

Answer 49

recruitment, proliferation, migration, and attachment

Question 50

Pericyte-deficient mice

Answer 50

Accumulation of intravenously injected tracers in the brain parenchyma and endothelium

Question 51

Perivascular endfeet of _____ surround BECs and are contiguous with the basal lamina

Answer 51

astrocytes

Question 52

____ channel, involved in ion and volume regulation

Answer 52

Aquaporin 4 (AQP4) and Kir4.1 K+

Question 53

Weakening of the blood-brain barrier may precede, accelerate, or contribute to a number of

Answer 53

neurodegenerative diseases

Question 54

Examples: BBB breakdown

Answer 54

MS and infiltration of white blood cells, which go on to attack myelin Stroke, epilepsy

Question 55

uptake of “vital dye” into parenchyma in ____ epileptic mice

Answer 55

increased

Question 56

BBB Dysfunction may occur via ABC transporter _______

Answer 56

overexpression

Question 57

Crossing the BBB Administration of

Answer 57

hyperosmolar agent

Question 58

Crossing the BBB Receptor-meditated transcytosis thought of as

Answer 58

Trojan-horse method

Question 59

Magnetic resonance-guided focused ultrasound helps

Answer 59

Locally disrupts BBB, therapeutic agents can be loaded into MBs