Into rather unexplored terrain—transcellular transport across the blood–brain barrier

Abstract

Efficient neuronal signaling in the central nervous system strictly depends on a well-balanced microenvironment around glial cells, synapses, and axons. Unique features of the blood-brain barrier (BBB) endothelium largely determine the composition of this micro-milieu and are dependent on the tight interplay with surrounding astrocytes and pericytes. BBB endothelial cells are endowed with a highly restrictive junctional complex that occludes the intercellular cleft, thereby preventing paracellular diffusion. The paracellular pathway is subject to extensive research as integrity loss of the junctional complex is associated with many neuropathologies, inflammation, and edema. Another important feature of the BBB endothelium is the low prevalence of nonspecific, transcytotic events, including (macro)pinocytosis, clathrin-dependent and caveolin-dependent endocytosis and the subsequent trafficking of vesicles to the opposite membrane. Although less studied, evidence is accruing that this pathway importantly contributes to increased BBB permeability, often when the junctional complex remains intact. Here, we review current knowledge on the contribution of the transcellular pathway to the BBB leak observed in different pathologic conditions. In addition, we hypothesize that nonselective, large pore connexin and pannexin channels may contribute to transcellular transport, either by providing a direct diffusion pathway across the endothelial monolayer, or indirectly, by exerting control over intracellular levels of the signaling ion Ca(2+) that is involved in many steps of the vesicular pathway. We conclude that transcytotic events at the BBB, despite being less acknowledged, cannot be simply dismissed as done in the past, but actively contribute to BBB leakage in many different pathologies. GLIA 2016;64:1097-1123.

Endosomal trafficking regulates receptor-mediated transcytosis of antibodies across the blood brain barrier

“…47 Some specific pathways favoring transcytosis have started to emerge from this study; in particular, it appears that a subset of MVBs bearing markers of exocytosing MVBs may be an important pathway leading to abluminal exocytosis of the BBB-crossing FC5 antibody. MVBs were initially regarded as purely prelysosomal structures along the degradative endosomal pathway of internalized proteins.…”

Immunoglobulin G transport increases in an in vitro blood–brain barrier model with amyloid‐β and with neuroinflammatory cytokines

“…Evidence for increased caveolar endocytosis at the BBB in disease is particularly strong in stroke models (De Bock et al, 2016), which have a strong inflammatory response. Increases in caveolar endocytosis are present after stroke (Haley & Lawrence, 2016;Reeson et al, 2015) and appear to be responsible for the acute increase in molecular transport as tight junction remodeling does not occur until 48-58 hr after stroke induction (Knowland et al, 2014).…”

“…In neurodegenerative disease and brain injury, there is evidence for increased vesicular transport across the BBB before any breakdown in the paracellular barrier (De Bock et al, 2016), therefore IgG transport and uptake experiments were performed in two disease states to quantify these changes. To mimic AD, BMECs were incubated with 5 μM Aβ₁₋₄₀, the primary component of vascular plaques in cerebral amyloid angiopathy that often accompanies AD, or Aβ₁₋₄₂, the primary component of neuritic plaques associated with neurodegeneration in AD.…”

The “Frail” Brain Blood Barrier in Neurodegenerative Diseases: Role of Early Disruption of Endothelial Cell to Cell Connections

“…The BBB endothelial cells are also involved in the transport and sorting of the nutrients by the blood to the central nervous system. The passage of metabolites is controlled by an elaborate highly restrictive junction complex acting between endothelial cells [79], able to grants the continuity of the tissues, thus reducing the random outflow of the compounds.…”

“…Apparently, there is no connection between a lower transcytosis rate and the alteration of the endothelial junctions [122], but rather it is likely linked to an altered formation of the vesicle coating. The lack of this coating is observed especially in Alzheimer's disease and multiple sclerosis [79]. Clathrin-coated vesicles are mainly involved in the transport of ligand-receptor complexes, including those which carry LDLs and iron-transferrin towards the brain [123]; compared to clathrins, caveolae are even more engaged in the impairment of transcytosis in case of diseases affecting the BBB, such as severe strokes and ischemia [84].…”