Transcellular routes of blood–brain barrier disruption

Abstract

Disruption of the blood–brain barrier (BBB) can occur through different mechanisms and pathways. As these pathways result in increased permeability to different classes of substances, it is likely that the neurological insults that occur will also differ for these pathways. The major categories of BBB disruption are paracellular (between cells) and transcellular (across cells) with a subcategory of transcellular leakage involving vesicles (transcytotic). Older literature, as well as more recent studies, highlights the importance of the transcellular pathways in BBB disruption. Of the various transcytotic mechanisms that are thought to be active at the BBB, some are linked to receptor-mediated transcytosis, whereas others are likely involved in BBB disruption. For most capillary beds, transcytotic mechanisms are less clearly linked to permeability than are membrane spanning canaliculi and fenestrations. Disruption pathways share cellular mechanisms to some degree as exemplified by transcytotic caveolar and transcellular canaliculi formations. The discovery of some of the cellular components involved in transcellular mechanisms of BBB disruption and the ability to measure them are adding greatly to our classic knowledge, which is largely based on ultrastructural studies. Future work will likely address the conditions and diseases under which the various pathways of disruption are active, the different impacts that they have, and the cellular biology that underlies the different pathways to disruption.

Preserved blood-brain barrier and neurovascular coupling in female 5xFAD model of Alzheimer’s disease

“…In a healthy brain, AMT is suppressed by homeostatic mechanisms ( Andreone et al, 2017 ; Ayloo and Gu, 2019 ; Mathiesen Janiurek et al, 2019 ). However, in aging, neuroinflammation, and after stroke, AMT is disinhibited, allowing a surge of macromolecules into the brain which, in turn, can cause and facilitate neurodegeneration ( Knowland et al, 2014 ; Sadeghian et al, 2018 ; Yang et al, 2020 ; Erickson and Banks, 2022 ; Zhu et al, 2022 ). Whether AMT is increased in AD-like pathology remained hitherto unaddressed.…”

Brain Cancer Chemotherapy through a Delivery System across the Blood-Brain Barrier into the Brain Based on Receptor-Mediated Transcytosis Using Monoclonal Antibody Conjugates

“…Regional BBB disruption is often invoked by brain cancers but it is a biologically transient and inconstant environment, depending on the pathology, physical condition, and individual variability. VEGFs secreted from brain cancer cells induced angiogenesis, lost the astrocyte endfeet, and destroyed the tight junctions to form fenestration (up to 15 nm in diameter between common endothelial cells, potentially including the BBB [ 36 , 37 ]). Even such a BBB scenario, called the brain–tumor barrier, restricted material permeation to some extent, which permeation was conducted through the paracellular fenestration pathway and transcellular pinocytosis [ 38 , 39 ].…”

Vascular Effects on Cerebrovascular Permeability and Neurodegeneration

“…Depending on the size of a substance, one or the other pathway can be used in extravasation. For example, a moderately large virus may not fit the gaps formed for a paracellular transport and would likely use a transcellular pathway involving vesicular transport [ 53 ]. In normal conditions, brain vessels are characterized with higher transendothelial electrical resistance than in peripheral circulation, indicating tighter junctions and therefore suggesting lesser paracellular transport than in skeletal muscle [ 54 ].…”