Sortilin regulates blood–brain barrier integrity

Abstract

Brain homeostasis depends on the existence of the blood-brain barrier (BBB). Despite decades of research, the factors and signalling pathways for modulating and maintaining BBB integrity are not fully elucidated. Here, we characterise the expression and function of the multifunctional receptor, sortilin, in the cells of the BBB, in vivo and in vitro. We show that sortilin acts as an important regulatory protein of the BBB's tightness. In rats lacking sortilin, the BBB was leaky, which correlated well with relocated distribution of the localisation of zonula occludens-1, VE-cadherin and βcatenin junctional proteins. Furthermore, the absence of sortilin in brain endothelial cells resulted in decreased phosphorylation of Akt signalling protein and increased the level of phospho-ERK1/2. As a putative result of MAPK/ERK pathway activity, the junctions between the brain endothelial cells were disintegrated and the integrity of the BBB became compromised. The identified barrier differences between wild-type and Sort1−/− brain endothelial cells can pave the way for a better understanding of sortilin's role in the healthy and diseased BBB.

Secreted Amyloid Precursor Protein Alpha (sAPPα) Regulates the Cellular Proteome and Secretome of Mouse Primary Astrocytes

“…It is known that sAPPα influences learning and memory by modulating the expression of the proteins involved with neurite outgrowth, synaptogenesis and neurotransmission [ 34 , 54 , 55 , 56 , 57 , 69 ]. Given the close proximity of astrocytes to neurons and their expression of several putative sAPPα receptors [ 39 , 48 , 49 , 50 , 51 , 52 , 53 ], sAPPα produced in vivo by neurons or generated extracellularly from the astrocyte itself could influence the molecular biology of astrocytes.…”

“…Multiple receptors for sAPPα have been identified in neurons that are also expressed in astrocytes, including gamma-aminobutyric acid type B receptor subunit 1a (GABABR1a) [ 46 , 47 ], nicotinic a7-nACh receptors (a7-nAChRs) [ 39 , 48 ], sortilin [ 49 , 50 ], sorting-protein-related receptor A (SORLA) [ 51 , 52 ] and APP itself [ 53 ]. Nevertheless, no information concerning how sAPPα affects astrocytes is currently available.…”

Subcellular trafficking and transcytosis efficacy of different receptor types for therapeutic antibody delivery at the blood‒brain barrier

“…Within this receptor family, the sortilin receptor is a particularly dynamic receptor that traffics between the cell surface, endosomes and the trans-Golgi network [ 25 ]. The receptor is expressed in the BBB [ 36 ] and readily internalizes antibodies without the capacity to recycle [ 25 ]. This feature might serve well for delivering therapeutic constructs for the endothelial cell layer itself.…”

A year in review: brain barriers and brain fluids research in 2022

“…Occludin was discovered as a new substrate of BACE1 and leads to cerebral small vessel disease pathogenesis ([ 11 ]). Toth et al [ 12 ] have described sortilin as another novel junction regulator. Rats lacking this receptor in brain endothelial cells exhibited a leaky BBB that was associated with a relocalization of the junction proteins ZO-1, VE-cadherin and β-catenin.…”