Sander markx lab
More specifically, the ESG limits the interaction of the circulating blood cells with the ECs forming the vessel wall, and partially restricts the passage of large molecules, e.g., plasma proteins and cytokines, across the BBB, while the junction proteins mainly restrict the transport of ions and small molecules. Together, these structural components confer an immune privilege to the CNS by restricting interactions with the periphery. Another is a matrix-like surface glycocalyx layer (endothelial surface glycocalyx, ESG) of a mucopolysaccharide structure consisting of glycoproteins, acidic oligosaccharides, terminal sialic acids, proteoglycan, and glycosaminoglycan aggregates. One is an elaborated paracellular junction composed of tight junctions (TJs) and adherens junctions (AJs) in the narrow cleft between adjacent ECs. The barrier function of the BBB is mainly determined by two anatomic features of BMECs. The brain-specific microvascular endothelial cell (BMEC) is an essential structural component of the BBB.
To protect the brain from blood-borne neural toxins, the BBB between the central nervous system (CNS) and the cerebral circulation maintains very low permeability due to its unique structure. Therefore, we speculated that BBB integrity is compromised in 22q11.2DS-associated schizophrenia (22q11.2DS-SCZ), which could contribute to psychiatric-disease-related pathophysiology in patients with 22q11.2DS-SCZ. Alterations in the expression of claudin-5 have been observed in the prefrontal cortex of patients with schizophrenia. Several genes within the deletion domain, such as claudin-5 and TBX1, are critical for the integrity of the BBB and vascular development. Of a particular note, endothelial tight junction signaling has been shown to be altered in patients with schizophrenia, in which 12 out of 21 tight-junction-related genes are reduced. For example, abnormalities in neurovascular unit (NVU) components have been reported in the frontal cortex of the postmortem brains of schizophrenia and autism patients. Across the major psychiatric disorders, blood–brain barrier (BBB) dysregulation is one of the widely observed phenotypes. However, the large number of genes that reside within the 22q11.2 microdeletion add significant complexity to studying the molecular mechanisms associated with the observed neuropsychiatric phenotypes. An important entry point for such investigations is 22q11.2DS. To deal with this challenge, it is important to understand the pathophysiology underlying these psychiatric conditions. It is well known that schizophrenia patients require long-term medical care and impose a major economic burden on the healthcare system. About one-third of 22q11.2 deletion carriers develop schizophrenia or schizoaffective disorder, which is roughly 30 times higher than the general population. Patients who carry a 22q11.2 microdeletion can present with highly variable phenotypes that involve multiple organ systems, which historically have been categorized and referred to as DiGeorge syndrome, velo-cardio-facial (VCF) syndrome, or 22q11.2 deletion syndrome (22q11.2DS). Microdeletions at band q11.2 of human chromosome 22 are the most common interstitial deletion in humans, with an incidence of approximately 1 in every 4000 live births. Our findings suggest that neurovascular coupling can be targeted in developing novel therapeutical strategies for the treatment of 22q11.2 deletion syndrome.
An enrichment analysis further suggests that the genes within the altered gene expression network also contribute to neurodevelopmental disorders.
A transcriptome study also suggests that the transcriptional network related to the cell–cell junctions in the compromised BBB is substantially altered. Correspondingly, tight junction proteins and the endothelial glycocalyx that determine the integrity of the BBB are significantly disrupted. We found that the solute permeability of the BBB formed from patient HBMECs increases by ~1.3–1.4-fold, while the trans-endothelial electrical resistance decreases to ~62% of the control values.
We utilized a set of human brain microvascular endothelial cells (HBMECs) derived from the induced pluripotent stem cell (iPSC) lines of patients with 22q11.2-deletion-syndrome-associated schizophrenia. Here, we investigate if BBB integrity is compromised in 22q11.2 deletion syndrome (also called DiGeorge syndrome), which is one of the validated genetic risk factors for schizophrenia. However, the cellular and molecular mechanisms of such alterations remain unclear. An altered BBB has been described in various neuropsychiatric disorders, including schizophrenia. The blood–brain barrier (BBB) is important in the normal functioning of the central nervous system.