Blood-Brain Barrier

Brain capillary endothelial cells lack fenestrations and have very few pinocytic vesicles. They are connected by complex tight junctions composed of claudins (especially claudin-5), occludin, and JAM proteins, anchored to the cytoskeleton by ZO-1 and ZO-2. A continuous basement membrane surrounds the endothelium. Pericytes embed in this membrane. Astrocyte end-feet cover ~99% of the abluminal surface and induce barrier properties through Wnt and Sonic hedgehog signaling. Together, these components form the neurovascular unit.

Lipophilic small molecules (oxygen, CO₂, ethanol, anesthetics, many psychiatric drugs) diffuse passively. Glucose enters via GLUT1; amino acids via LAT1; choline, lactate, and other essentials each have specific transporters. Receptor-mediated transcytosis carries transferrin, insulin, and leptin across. Tight junctions exclude paracellular diffusion of even small ions. Charged or large molecules are largely excluded. Active efflux by ABCB1 (P-glycoprotein) and ABCG2 actively pumps many xenobiotics back to blood, further restricting drug entry.

Acute stroke disrupts BBB within hours, allowing edema; this is why tPA carries hemorrhage risk in large infarcts. Bacterial meningitis breaches the barrier, enabling antibiotic penetration that would not occur otherwise. Multiple sclerosis lesions show focal BBB disruption visible on contrast MRI. Brain tumors form abnormal vessels with leaky barriers. Traumatic brain injury, severe hypertension, and inflammation also open the barrier. BBB disruption is sometimes therapeutic — focused ultrasound with microbubbles transiently opens the barrier for drug delivery.

Most molecules cross the BBB poorly. Small lipophilic drugs cross best — psychiatric drugs are designed for this. Charged or polar drugs (most antibiotics, many chemotherapeutics) penetrate poorly. P-glycoprotein actively excludes a long list including loperamide, digoxin, vincristine, paclitaxel, and many opioids and antidepressants. Strategies to bypass include intrathecal administration (chemotherapy for CNS leukemia), inhibition of efflux pumps, prodrug design, receptor-mediated transport conjugates, and focused ultrasound.

Cerebrospinal fluid is produced by the choroid plexus (~500 mL/day) and circulates through ventricles and the subarachnoid space. The choroid plexus has its own barrier — the blood-CSF barrier — formed by tight junctions between epithelial cells. CSF composition differs sharply from plasma: lower protein, lower glucose (about two-thirds of plasma), lower potassium, higher chloride. Lumbar puncture analyzes CSF for cell count, protein, glucose, and culture; the gradient and patterns help diagnose meningitis, hemorrhage, and demyelinating disease.

BBB properties emerge during embryonic development and mature through early childhood. Wnt7a and Wnt7b signaling from neural progenitors induces barrier gene expression in nascent endothelium. Pericytes are essential for barrier function — pericyte-deficient mice have leaky vessels. Astrocyte recruitment further matures the barrier. The neonatal BBB is more permeable than adult, which has implications for kernicterus (bilirubin entry into basal ganglia) and certain drug effects in infants.

Until 2015, the brain was considered an immune-privileged site without lymphatic drainage. Recent work has identified meningeal lymphatic vessels along dural sinuses that drain into deep cervical lymph nodes. The glymphatic system — a perivascular pathway driven by aquaporin-4 on astrocyte end-feet — clears metabolic waste during sleep, including beta-amyloid. Disruption of glymphatic function is implicated in Alzheimer's pathogenesis. This rewriting of brain immunology is among the most important neuroscience findings of the past decade.