Blood-Brain Barrier: From Physiology to Disease and Back

Abstract

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.

Panax notoginseng saponins suppress lipopolysaccharide‐induced barrier disruption and monocyte adhesion on bEnd.3 cells via the opposite modulation of Nrf2 antioxidant and NF‐κB inflammatory pathways

“…The blood‐brain barrier (BBB) is a highly evolved microvasculature system that regulates molecular flux between blood and brain and acts as a dynamic “physical barrier” to maintain the homeostasis of the central nervous system (Sweeney, Zhao, Montagne, Nelson, & Zlokovic, ). The barrier is mainly formed with endothelial cells that line cerebral microvessels and connected by tight junction proteins (TJs; Rhea & Banks, ).…”

“…As a result, the paracellular and transcellular traffic of hydrophilic substances across the BBB are greatly restricted (Rhea & Banks, ). The degeneration of TJs, especially zonula occludens‐1 (ZO‐1), claudin‐5, and occludin, are concomitant with BBB disruption and disclosed to exacerbate the progression of many cerebral diseases, such as Alzheimer's disease, Parkinson's disease, traumatic brain injury, cerebral ischemia, and intracerebral hemorrhage (Sweeney et al, ). Therefore, drugs protecting BBB integrity may facilitate the alleviation of cerebral diseases.…”

Nicotinamide riboside rescues angiotensin II–induced cerebral small vessel disease in mice

“…41 Previous studies of BBB permeability in CSVD have focused on tight junction proteins, such as zonula occludens-1 (ZO-1), occludin, and claudin-5. 42,43 The decreased expression of claudin-5, the key tight junction protein of the BBB, has been reported in a CSVD model. 38 In addition, growing evidence has indicated that limited caveolae-mediated transcytosis maintains BBB integrity in the CNS, 44 and BBB disruption due to increased vesicle transport has been confirmed in many models.…”

“…The impairment of the BBB predicts cognitive impairment at one year . Previous studies of BBB permeability in CSVD have focused on tight junction proteins, such as zonula occludens‐1 (ZO‐1), occludin, and claudin‐5 . The decreased expression of claudin‐5, the key tight junction protein of the BBB, has been reported in a CSVD model .…”

Engineering tissue‐specific blood vessels

“…The BBB creates crucial obstacles to drug delivery due to its high regulation and low rates of transcytosis and has been studied in depth for characterization and drug delivery purposes. A comprehensive recent review on BBB can be found elsewhere …”