Disruption of the Blood-Brain Barrier in 22q11.2 Deletion Syndrome

Abstract

Neuroimmune dysregulation is implicated in neuropsychiatric disorders including schizophrenia (SZ).As the blood brain barrier (BBB) is the immunological interface between the brain and the periphery, we investigated whether the BBB is intrinsically compromised in the most common genetic risk factor for SZ, the hemizygous deletion of chromosome 22q11.2 (22qDS). BBB-like endothelium (iBBB) differentiated from human 22qDS+SZ-induced pluripotent stem cells exhibited impaired barrier integrity, a phenotype substantiated in a mouse model of 22qDS. The proinflammatory intercellular adhesion molecule-1 (ICAM-1) was upregulated in 22qDS+SZ iBBB and 22qDS mice, indicating compromise of the BBB immune privilege. This immune imbalance resulted in increased migration/activation of leukocytes crossing the 22qDS+SZ iBBB. Finally, we found heightened astrocyte activation in murine and human 22qDS, suggesting that the BBB promotes astrocyte-mediated neuroinflammation. Overall, the barrier-promoting and immune privilege properties of the 22qDS BBB are compromised, and this might increase the risk for neuropsychiatric disease. 4

Continuous monitoring reveals protective effects ofN-acetylcysteine amide on an isogenic microphysiological model of the neurovascular unit

“…However, cell spreading likely contributes to our early signal plateaus. Importantly, our observations match some [70,71] (though not all) [72] prior studies of CSER with hiBMEC (using monoculture in on commercial, non-permeable substrates). The inconsistencies in literature are likely due to a strong dependence of CSER on the precise electrode geometry.…”

Continuous Monitoring Reveals Protective Effects of N‐Acetylcysteine Amide on an Isogenic Microphysiological Model of the Neurovascular Unit

“…Although we seek to minimize those parameters by analyzing resistance at a frequency of 6 kHz (in line with similar experiments), [ 18 ] cell spreading does likely contribute to our early signal plateaus. Importantly, our observations of an early plateau match some [ 79,80 ] (though not all; inconsistencies likely due to different electrode geometries) [ 18,81 ] prior studies of ECIS with hiBMEC (using monoculture on commercial, non‐permeable substrates). Interestingly, the daily measurements presented by Motallebnejad et al.…”

The Role of Brain Microvascular Endothelial Cell and Blood-Brain Barrier Dysfunction in Schizophrenia

“…BBB disruption in one or more of the following components: paracellular, transcellular or extracellular matrix may be a final common pathological pathway in schizophrenia that results from genetic alterations that increase the vulnerability to psychosis. For example, CLDN5 knockdown in a mouse model leads to an increase in the extravasation of gadolinium into the brain [38], while a study using human iPSC-BMECs from schizophrenia patients with 22q deletion syndrome identified an increase in leukocyte transmigration into the brain that was meditated by the increased expression of ICAM1 [67]. GWAS studies have identified common risk variants for schizophrenia in ESAM and LRP1.…”

“…However, it is unclear if these differences were specific to BMEC [66]. Interestingly, a recent study using stem cell-derived BMEC from schizophrenia patients with 22q11 deletion syndrome identified impaired barrier integrity and upregulation of endothelial ICAM1 that was associated with increased leukocyte transmigration [67]. However, further studies are required to determine which of the multiple genes deleted in this syndrome are associated with this BBB phenotype.…”

“…Coculturing BMEC with neural progenitor cells, pericytes, or astrocytes further enhances BBB function, with the combination of BMEC, pericytes, and astrocytes providing the greatest TEER values (∼5,000 Ω × cm 2 ) [116]. These protocols have been used to generate BMEC from patients with Huntington disease and schizophrenia with 22q11 deletion syndrome [67, 71] and to test the effects of various infectious agents on BBB function [112, 117].…”