The blood-brain barrier (BBB) prevents neurotoxic plasma components, blood cells,
and pathogens from entering the brain. At the same time, the BBB regulates transport
of molecules into and out of the central nervous system (CNS), which maintains tightly
controlled chemical composition of the neuronal milieu that is required for proper
neuronal functioning. In this review, we first examine molecular and cellular mechanisms
underlying the establishment of the BBB. Then, we focus on BBB transport physiology,
endothelial and pericyte transporters, and perivascular and paravascular transport.
Next, we discuss rare human monogenic neurological disorders with the primary genetic
defect in BBB-associated cells demonstrating the link between BBB breakdown and neurodegeneration.
Then, we review the effects of genes underlying inheritance and/or increased susceptibility
for Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, and
amyotrophic lateral sclerosis (ALS) on BBB in relation to other pathologies and neurological
deficits. We next examine how BBB dysfunction relates to neurological deficits and
other pathologies in the majority of sporadic AD, PD, and ALS cases, multiple sclerosis,
other neurodegenerative disorders, and acute CNS disorders such as stroke, traumatic
brain injury, spinal cord injury, and epilepsy. Lastly, we discuss BBB-based therapeutic
opportunities. We conclude with lessons learned and future directions, with emphasis
on technological advances to investigate the BBB functions in the living human brain,
and at the molecular and cellular level, and address key unanswered questions.