Zlokovic 2008 BBB Flashcards
What molecules can cross the BBB without assistance?
Lipid-soluble molecules via diffusion
What comprises the BBB?
Endothelial cells with tight and adherens junctions
Briefly describe the mechanism of how tight junctions are maintained.
Maintained by claudins and occludins
They are transmembrane proteins that bind with each other to restrict paracellular flow of molecules
How do MMPs relate to the BBB?
It can degrade claudins and occludins and thus open the BBB
These TJ proteins accumulate in astrocytes and neurons, possibly due to autophagy after BBB breakdown
How is occludin related to diseases like AD and MS?
In AD, there is an accumulation of occludin in non-ECs.
In MS, occludin dephosphorylation as well as ZO-1 loss precedes BBB opening
What junctional proteins could be involved in hypertension?
Increased JAM-A can promote hypertension and seen in rodents
What are cytoskeletal proteins involved in maintaining BBB?
ZO-1, Caveolin-1, and Actin
How does ZO-1 stabilize the BBB?
Anchors TJ proteins to cytoskeletons
How is Caveoline-1 involved in BBB maintenance?
Regulates expression of tight and adherens junction proteins like ZO-1 and occludin and VE-cadherin
How is actin involved in BBB maintenance?
Proper actin filament arrangement is crucial for correct localization of junctional proteins
What are the functional difference between tight and adherens junctions?
Tight = Restricts paracellular flow of macromolecules
Adherens = cell-cell adhesion
Briefly describe the molecular mechanism of how adherens junctions are maintained.
By VE-cadherin and PECAM-1
VE-cadherin is linked to the cytoskeleton via catenins
How may VE-cadherin be involved in angiogenesis and vascular repair?
Forms complex with VEGFR, which is involved in angiogenesis and repair
What is the main role of PECAM-1 and how does it relate to diseases?
Main role is for leukocyte migration across BBB
Promotes leukocyte migration into the brain in EAE (MS model) and also in Abeta mediated migration in AD
What are 5 different mechanisms that mediate BBB transport?
- Carrier-mediate transport
- ion transport
- active efflux transport
- receptor-mediated transport
- caveolae-mediated transport
What is carrier-mediated transport and what is responsible for?
Responsible for transporting nutrients to the brain like glucose and vitamins
Different from receptor-mediated transport (for proteins)
How are glucose, ketones, amino acids and vitamins transported into the brain?
Carrier-mediated transport
Glut1, MCT1, L1 and y+ AA transporter, sodium-dep multivitamin transporter, respectively
How does the brain try to compensate for hypoxia?
Through HIF-1 (Hypoxia inducible factor), increases Glut1 transcription
State how Glut-1 relates to AD
Glut-1 protein levels are decreased at the BBB in AD and precedes the conversion to AD
This is not due to brain atrophy
What does MCT-1 do?
Transports ketone and lactate for metabolic use in the brain
What are the types of amino acid transporter and how do they differ?
L1 and y+ transporters
L1 is for neutral essential AAs
y+ for cationic essential and nonessential (eg. L-arginine)
What is endothelial EAATs potentially for?
It may provide net removal of glutamate which prevents excitotoxicity, implicated in MS, ALS, AD
What ion transporters are important and why?
Na+/K+-ATPase uses ATP to maintain high Na+ gradient for Na+-dependent transport
Also sodium-hydrogen exchanger to maintain pH
Provide an example of active efflux.
ABC transporter such as P-gp is important for the removal of toxins and drugs
P-gp also regulates LRP1 expression and thus Abeta clearance
Provide examples of receptor-mediated transport.
What is its implication for drugs?
LDL, insulin, transferrin
Drugs can be conjugated to antibodies against receptors for these to allow brain entry
How is caveolae involved in transport? What else?
It underlies endocytosis and transcytosis by expressing receptors for things like insulin, LDL, transferrin, albumin etc.
It also involves eNOS and calcium influx proteins
How are pericyte-endothelial contacts maintained?
Processes that encircle endothelial cells
Contacts through TJ, AJ, and Gap junctions too
What are some of the roles of pericytes on ECs?
Provide physical stability by coverage
Secrete signals that promote quiescence
What are examples of pericyte-EC signaling and the consequences of disruption?
PDGFRbeta(pericyte) and PDGFbeta (EC)
TGFbeta and receptors
These promote stabilization of BBB -> disrupt then get microhemorrhages
How do pericytes influence angiogenesis?
During development, pericyte migration guides ECs for angiogenesis and later for BBB integrity
What changes are seen in microglial through activation?
At resting state they have thin long processes
When activated becomes ameboid and then to phagocytic form
What are some examples of microvascular pathologies in AD? (3)
String vessels, basement membrane thickening, changes in vessel diameter
What BBB changes are seen in AD and how does it relate to Abeta pathology?
Increased RAGE expression increases Abeta influx, and thus proinflammatory cytokines (TNFalpha, IL6) and ICAM1, generation of ET-1
Blood is also a major source of Abeta
Describe one way we clear Abeta from the brain and body. How is it altered in AD?
LRP1 binds Abeta to clear it to blood and afterwards at the liver for systemic clearance
Some reports on reduced vascular LRP1 in aging and AD brain
Abeta can promote degradation of LRP1
Neuronal LRP1 contributes to Abeta retention though
How may hypercontraction occur in AD?
Via Abeta-mediated contraction due to ET-1 for example.
Alternatively, expression of VSMC transcription factor like MYOCD that induce hypercontractile phenotype
What are vascular risk factors of AD?
Atherosclerosis, age, stroke, hypertension, ischemia, and ApoE4
Describe 1 pathway in which hypoxia/hypoperfusion can affect AD.
Hypoxia downregulates MEOX-2 in BEC -> stabilize expression of MYOCD -> hypercontractile SMCs
Describe a model of how Abeta and BEC changes interplay with AD pathogenesis.
Changes in key receptors like decreased LRP1 and increased RAGE can promote accumulation of Abeta
Abeta can promote vasoconstrictor secretion (ET1) and expression of hypercontractile SMCs or promote inflammatory (TNFalpha, IL6, IL1) conditions through cytokines and ICAMs, and activated microglia. These cooperate to decrease BBB integrity and thus lead to neuronal damage and decreased activity (due to metabolic insufficiency)
Abeta can also recruit microglia and proinflammatory environment