Different Cell Types in the CNS Two Flashcards
What are three reasons why astrocytes would make a good target during neurological diseases?
1) astrocytes serve as a protective/supportive role in the brain therefore there loss would be bad
2) Astrocytic cells are the major origin of the most aggresive brain tumors (Gliablastoma / astroglioma) (WE would want to control astrocyte proliferation)
3) Inflammatory mediators produced by astrocytes may be detrimental to neuronal cell health and exacerbate damage (Anti-inflam stratagies)
What is the triad function fo astrocytes?
1) BBB intergrity control
2) Neuronal homeostasis or synaptic function
3) Various aspects of neuronal inflammation
Describe the vasculature of the brain with reference to neurons
The brain is densely packed with vasculature and no neuron is less than 200 mM away from blood vessels
What comprises the neurovasculature unit?
Endothelial cells
Pericytes
Astrocyte foot processes
Perivascular macrophages (Microglia)
Some of the large vasculature also have smooth muscle actin cells
What is the BBB/
The Physiology of tight junctions in the endothelium of the neurovascular unit
What is a consistant feature of all endothelium?
They are polarised, having a apical and basolateral faces that are completely different.
What can occur within the neurovascular unit?
Cells of the neurovascular unit can communicate
What is found between endothelial cells?
Tight junctions
What is the function of tight junctions?
Tight junction structures comprise of a family of proteins that help seal the vessel forming a selectively permeable barrier to solutes, small molecules, cells (bacteria and leukocytes)
What are proteins that may occur in tight junctions?
Occludins Claudins Zona occludins 1 (cytoplasmic) Cadherins JAMS (Junctional Adhesion Molecules)
What is crucial of the tight junction molecules?
These proteins expression controls the BBB. They are expressed at a very high level to prevent unwanted passage.
In normal vasculature during inflammation passage of inflammation related cells, ECF occurs easily, is this the case in the brain?
No, Tight junctions prevent the ease of inflammation. Therefore inflammation occurs very differently in the brain thus preventing constant brain swelling. Its tightly regulated.
Within the tight junctions what are the two classes of molecules and their proteins?
Tight junction molecules = Claudins and occludins
(Adherins jucntion) Junctional adhesion molecules = JAMS, ZO-1 , Cadherins
How do the tight junction molecules work?
Like velcro
Within the tight junctions list some binding combination example and how they are regulated?
Claudings bind to claudins
Occludins bind to Occludins
ZO-1 control these cytoplasmically
What proteins are found in the Adherins junctions?
PECAM= CD31 VE-Cadherin = CD144
Only found in the bottom of the cleft and are considered back up for the tight junctions molecules
Describe what endothelial cells do?
They are on the the brains defences:
They control what goes into the brain and what comes out (waste).
Control both transcellular and paracellular routes.
How does transcellular transport occur in the endothelium?
Passive diffusion
Transporters
Vesicle transcytosis
Do leukocytes enter the brain?
The BBB tight junctions exclude leukocytes 99% of the time, exceptions are made during injury, stroke, neurodegenerative diseases.
What cells can cause inflammation?
Neurons
AStorcytes
Microglia
Endothelial cells
When brain cells cause inflammation what do they release?
Cytokines = IL-1 , TNFa Chemokines= IL-8, MCP-1, MIPIa, Chemokines (CCLs) and complex chemokines (CXCLs)
What does inflammation lead to the activation of and damage to?
The neurovascular unit and BBB
What are the functions of the cytokines and chemokines released by brain cells?
Cytokines (TNFa and IL-1) activate pericytes and endothelial cells.
Chemokines recruit leukocytes
What happens to released chemokines?
These molecules are either produced soluble or expressed on the cell surface, to attract the leukocytes
How are chemokines expressed on the cell surface?
The expression of chemokines changes the phenotypic expression of proteins attracting leukocytes (upregulation of adhesion molecules on endothelial cell surface)
How do leukocytes cross the blood brain barrier?
Firstly endothelial cells must express adhesion molecules then the process goes:
1) Attatchment
2) Rolling /TETHERING
3) Strong adhesion
4) Diapedesis / Extravasation (either transcellular or paracellular route)
How do cells go via the paracellular route?
They either have enzymes on their surface which degrade the tight junction proteins or contact the cell to change its protein expression
How do cells go via the endothelial transcellular route?
The endothelial cell envaginates around the cell and expells it out the other side
What are the two most important endothelial - leukocyte adhesion molecules?
CD106 = VCAM-1 CD54 = ICAM-1
Why are VCAM-1 and ICAM-1 most important in leukocyte migration?
Block these and you block 90% of leukocyte migration during neuroinflammation
In a slice preparation, what indicates neuroinflammation is occurring?
High levels of VCAM and ICAM expression.
Apically, ie into blood
What must the immune cell express in order to interact with the ICAM or VCAM
Interacting molecule to possible adhere to ICAM or VCAM
once recruited they are drawn closer to form stronger interactions
What are some examples of endothelial CAM expressed during neuroinflammation?
ICAM-1 VCAM-1 E-Selectin P-Selectin CD99 CD31
Of the CAM expressed by endothelial cells which are unique and how?
ICAM-1
VCAM-1
E-Selectin
P-Selectin
Are unique in that they are only expressed by endothelial cells and have heterodimic interaction
CD99
CD31
Have homodimic interaction i.e bind to the same proteins on the leukocytes therefore arent unique to endothelium
What proteins are expressed on leukocytes to interact with CAMs
LFA-1 interact with ICAM (unique to leukocyte)
VLA-4 interact with VCAM (unique to leukocyte)
etc
