(4) Blood-Brain Barrier

Blood-brain barrier

specialized, highly selective interface between the blood and the central nervous system that protects neural tissue and maintains the brain’s internal environment

Blood-brain barrier main goals

• Protect from harmful substances

• Maintain precise ion concentrations

• Regulate nutrient entry

• Prevent uncontrolled neurotransmitter fluctuations

• Block pathogens

• Maintain CNS immune privilege

3 structural components of BBB

1. endothelial cells

2. basement membrane

3. astrocyte end-feet

Endothelial cell structure

continuous capillaries with tight junctions, no fenestrations, and minmal pinocytosis

Endothelial tight junction composition

• Claudin-5

• Occludin

• Junctional adhesion molecules

eliminate large spaces between cells, forcing substances to cross through cells rather than between them

Basement membrane

A thick, continuous extracellular matrix beneath endothelial cells.

Basement membrane functions

• Provides structural support

• Adds an additional diffusion barrier

• Regulates molecular passage

Astrocyte end-feet

Astrocytes extend “foot processes” that wrap around ~98–99% of the capillary surface.

Astrocyte end-feet functions

• Induce and maintain tight junction formation

• Regulate blood flow via release of vasoactive molecules (e.g., NO)

• Provide metabolic support (e.g., lactate shuttle)

• Signal to endothelial cells when to upregulate transporters

Pericytes

support cells located within the capillary basement membrane

Pericyte functions

• Regulate capillary diameter

• Stabilize endothelial walls

• Control angiogenesis

• Maintain BBB integrity

• Involved in repair after injury

Results of pericyte loss

hallmark of diabetic microangiopathy & contributes to diabetic retinopathy and neurodegeneration

What molecules diffuse freely across the BBB?

lipid-soluble molecules pass easily

What transporters are required for BBB?

• GLUT1 → glucose

• LAT1 → amino acids (esp. essential aa’s)

• Monocarboxylate transporters → lactate, ketones

• Nucleoside transporters

BBB efflux pumps

actively remove harmful substances

• P-glycoprotein (P-gp) — pumps drugs/toxins out of the brain.

What does it mean that the brain is “immunoprivileged”?

very limmited movement of:

• Proteins

• Peptides

• Immune cells

Circumventricular organs

regions where BBB is absent; some brain areas need direct access to blood for monitoring

Area postrema

circumventricular organ detecting toxins and triggering vomiting

Median eminence

circumventricular organ controlling hypothalamic hormone release

Neurohypophysis (posterior pituitary)

circumventricular organ releasing ADH and oxytocin

Pineal gland

circumventricular organ releasing melatonin into circulation

Subfornical organ

circumventricular organ controlling fluid balance, detects angiotensin II

BBB development

• Begins forming in utero.

• Achieves functional maturity shortly after birth.

• Astrocytes are critical for maturation.

BBB regulation

Controlled by:

• Astrocytes

• Pericytes

• Endothelial signaling

• Shear stress

• Neuronal activity

Factors that increase BBB tightness

• Glucocorticoids

• Normal neuronal activity

• Astrocytic support

• Anti-inflammatory signals

Result of factors disrupting the BBB

Disruption allows proteins, immune cells, and fluid to leak into brain tissue → edema & seizures.

Clinical significance of BBB limiting drug delivery

Many drugs cannot cross:

• Chemotherapeutics

• Large antibiotics

• Monoclonal antibodies

• Dopamine (this is why Parkinson’s treatment gives L-DOPA, which crosses via LAT1)

BBB breakdown contribution to MS

immune cells enter CNS → demyelination

BBB breakdown contribution to meningitis

bacterial inflammation opens tight junctions

BBB breakdown contribution to stroke

ischemia → capillary leak → cerebral edema

BBB breakdown contribution to Alzheimer’s

reduced clearance of β-amyloid

BBB breakdown caused by trauma

local barrier disruption → swelling

BBB breakdown caused by sepsis

inflammatory cytokines weaken barrier

Mannitol therapeutic use

osmotic BBB disruption for chemo entry

Focused ultrasound therpauetic use

temporarily opens BBB

Nanoparticle carriers therapeutic use

receptor-mediated entry used for experimental drug delivery methods