Brain Endothelial Cell-Cell Junctions: How to “Open” the Blood Brain Barrier

Abstract

The blood-brain barrier (BBB) is a highly specialized structural and biochemical barrier that regulates the entry of blood-borne molecules into brain, and preserves ionic homeostasis within the brain microenvironment. BBB properties are primarily determined by junctional complexes between the cerebral endothelial cells. These complexes are comprised of tight and adherens junctions. Such restrictive angioarchitecture at the BBB reduces paracellular diffusion, while minimal vesicle transport activity in brain endothelial cells limits transcellular transport. Under normal conditions, this largely prevents the extravasation of large and small solutes (unless specific transporters are present) and prevents migration of any type of blood-borne cell. However, this is changed in many pathological conditions. There, BBB disruption (“opening”) can lead to increased paracellular permeability, allowing entry of leukocytes into brain tissue, but also contributing to edema formation. In parallel, there are changes in the endothelial pinocytotic vesicular system resulting in the uptake and transfer of fluid and macromolecules into brain parenchyma. This review highlights the route and possible factors involved in BBB disruption in a variety of neuropathological disorders (e.g. CNS inflammation, Alzheimer’s disease, Parkinson’s disease, epilepsy). It also summarizes proposed signal transduction pathways that may be involved in BBB “opening”.

The age-related deficit in LTP is associated with changes in perfusion and blood-brain barrier permeability

“…Despite this, infiltration of circulating cells has been shown to occur when BBB permeability is increased. Thus T cell infiltration has been found in CNS tissues of patients with Parkinson's disease (Stone et al, 2009) and Alzheimer's disease (Schindowski et al, 2007;Togo et al, 2002) and infiltration of cells has also been reported following ischemic insult and with age (Popescu et al, 2009) and bacterial and viral infections (Stamatovic et al, 2008). In this study, increased BBB permeability was associated with increased expression of IP-10 and MCP-1.…”

Microglia and Monocyte-Derived Macrophages in Stroke

“…These events are followed by relatively small increases of T and B lymphocytes. Strokeinduced disruption of the blood-brain barrier (BBB) facilitates the migration of immune cells into the brain [29][30][31]. Circulating monocytes gain access to brain parenchyma via endothelial migration and differentiate into tissue macrophages.…”

The Blood-Brain Barrier and Epilepsy

“…VVO on the other hand are large collection of interconnected vesicles and vacuoles. The fusion of vesicles, vacuole with luminal and abluminal plasma membranes creates transcellular pathways confirmed in the several ultrastructural studies (Stamatovic et al, 2008).…”

“…The impediment to ion movement results in the high in vivo electrical resistance of the BBB, of 1800 Ω cm 2 . This high electrical resistance or low conductance of the potential paracellular pathway emphasises the extreme effectiveness of the TJs in occluding this pathway by effectively reducing the movement of ions (Abbott et al, 2010;Paolinelli et al, 2011;Stamatovic et al, 2008). However, the BBB is a dynamic structure capable of rapid modulation in response to physiological or pathological signals.…”

“…These include the general paucity of vesicular transport at the BBB, the presence of enzymes that by degradation prevent the entry of a variety of compunds, and the presence of a wide range of transport systems. Because nonlipid soluble compounds only diffuse slowly across the BBB, the latter are necessary for both the entrance of nutrients into brain and the clearance of waste products from brain (Stamatovic et al, 2008).…”