3b Blood-Brain Barrier

most energy expensive organs in the human body

brain, liver, GI tract

since the brain does not have significant capacity to store metabolic nutrients, fuel to power the brain is provided on-demand by the _____ and _____ _______

lungs, GI system

the ______ system is crucial in delivering nutrients necessary to maintain normal brain function

vascular

interruption of cerebral blood flow quickly leads to _______ _____

neuronal death

in cardiac arrest, neuronal apotosis begins almost ______; brain damage occurs after about ___ minutes

immediately, 5

blood-brain barrier regulates ________ of the CNS by forming a tightly regulated __________ _____ (NVU)

homeostasis, neurovascular unit

what is included in the NVU

endothelial cells, pericytes, astrocytic endfeet

the BBB prevents what from entering the brain

neurotoxic plasma components, blood cells, pathogens

BBB breakdown and dysfunction leads to

-leakage of harmful blood components into CNS
-cellular infiltration
-aberrant transport and clearance of molecules
-cerebral blood flow reductions
-neurological deficits

barrier layers found at 3 main sites in brain and spinal cord...

1. endothelium of parenchymal microvessels
2. epithelium of choroid plexus secreting CSF
3. arachnoid epithelium

choroid plexus

modified ependymal lining of brain ventricles

arachnoid epithelium

middle layer of meninges forming outer covering of CNS

circumventricular organs (CVOs)

regions of the brain with a "leaky endothelium" allowing relatively free access between blood and neural tissue

where are CVOs usually

neurosecretory brain areas, such as the posterior pituitary gland

BBB proper barrier

created at level of cerebral capillary endothelial cells by tight junction formation

blood-CSF barrier

lies at choroid plexuses in ventricles of the brain

arachnoid barrier

at arachnoid villi that are CSF drainage sites

functions of BBB

1. control molecular traffic, keep out toxins (preserves neural connectivity)
2. contributes to ion homeostasis for optimal neural signaling
2. maintains low-protein environment in CNS; limits proliferation, preserves neural connectivity
4. separates central and peripheral neurotransmitter pools, reduces cross-talk, allows non-synaptic signaling in CNS
5. allows immune surveillance and response with minimal inflammation and cell damage

cerebral endothelial cells

key cells of BBB connected by tight junctions to restrict paracellular transport into the brain

pericytes

partially envelop endothelial cells

astrocyte endfeet

ensheath microvessels' wall

pericytes and astrocytes are important in _______ _____ and _______; astrocytes mediate the connection to _______

barrier induction, maintenance, neurons

the brain endothelium forming the BBB and blood-spinal cord barrier is the largest interface between the _____ and _______ ____

vasculature, nervous system

BBB has shortest ______ _____ to neurons

diffusion distance

why is that important

the pattern of cerebral blood vessels follows the major brain circuits of the brain

under physiological conditions, the human brain receives ___% of the cardiac output and uses ___% of the body's oxygen and glucose

20, 20

neurovascular coupling

cerebral blood vessels supplying the CNS circuits in response to neuronal stimuli by increasing the rate of cerebral blood flow and oxygen delivery

the BBB serves as a ______, ______, _____, and ______ barrier

physical, transport, enzymatic, immunological

leukocytes may ____ the BBB adjacent to, or by modifying tight junctions

cross

solutes may _____ _____ through the cell membrane and cross the endothelium; ________ lipid solubility favors this process

passively diffuse, greater

_______ _______ ____ may intercept some of these passively penetrating solutes and pump them out of the endothelial cell

active efflux carriers

carrier-mediated influx

may be passive or secondarily active, can transport many essential polar molecules such as glucose, AA, and nucleosides into the CNS

receptor mediated transcytosis (RMT)

transport macromolecules such as peptides and proteins across the cerebral endothelium

adsorptive mediated transcytosis (AMT)

induced non-specifically by positively charged macromolecules

tight junction modulation

by surface and intracellular enzymes

the BBB is strengthened by the _______ system as early as in embryonic development

immune

maternal gut microbiota influences the formation of fetal BBB during gestation by upregulating expression of ______ ________ such as claudin-5

TJ proteins

BBB permeability ________ in systemic inflammation, infection, autoimmune disease, injuries, and neurodegenerative diseases

increases

why does BBB permeability increase in these scenarios

pro-inflammatory cytokiines and chemokines, peripheral leukocytes (monocytes), and macrophages enter the brain and exacerbate diseases

t/f: some viruses can directly infect the endothelial cells of the human BBB

true

how do the endothelial cells get infected

-targeting junctional proteins such as JAM-A or transporters such as GLUT1 as entry receptors to get access to the CNS
-viral infections downregulate TJ proteins and promote chemokine production and VCAM-1 expression in the brain endothelial cells, weakening the BBB and allowing entry into the brain
-host immune response limits the spreading of the viruses and attenuates BBB damage

what are the three barriers in the CNS

BBB proper, blood-CSF barrier, arachnoid barrier

which cells form the NVU

endothelial cells, pericytes, astrocytes

functions of the BBB

physical, transport, enzymatic and immunological barrier

transport through the BBB

cell migration, passive diffusion, active efflux, active influx, RMT, AMT, TJ modulation

cerebrovascular coupling

increased cerebral blood flow in response to neuronal activity