Year: 2021
Type: article
Abstract: Neuroimmune dysregulation is implicated in neuropsychiatric disorders including schizophrenia. As the blood-brain barrier is the immunological interface between the brain and the periphery, we investigated whether this vascular phenotype is intrinsically compromised in the most common genetic risk factor for schizophrenia, the 22q11.2 deletion syndrome (22qDS). Blood-brain barrier like endothelium differentiated from human 22qDS+schizophrenia-induced pluripotent stem cells exhibited impaired barrier integrity, a phenotype substantiated in a mouse model of 22qDS. The proinflammatory intercellular adhesion molecule-1 was upregulated in 22qDS+schizophrenia-induced blood-brain barrier and in 22qDS mice, indicating compromise of the blood-brain barrier immune privilege. This immune imbalance resulted in increased migration/activation of leucocytes crossing the 22qDS+schizophrenia blood-brain barrier. We also found heightened astrocyte activation in murine 22qDS, suggesting that the blood-brain barrier promotes astrocyte-mediated neuroinflammation. Finally, we substantiated these findings in post-mortem 22qDS brain tissue. Overall, the barrier-promoting and immune privilege properties of the 22qDS blood-brain barrier are compromised, and this might increase the risk for neuropsychiatric disease.
Source: Brain
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
Funders: Fulbright Program, University of Pennsylvania, Fondation pour l'Aide à la Recherche sur la Sclérose en Plaques, National Institutes of Health, University of Texas Health Science Center at San Antonio, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G160977755, G1976284351, G2141602806, G2547135128, Generating and accelerating the maturation of Pvalb-fast spiking interneurons from human stem cells, G3498118121, G3692776336, G3696318295, IPSC phenotype, mitochondrial haplotype and psychosis in 22q11 deletion syndrome, Evolution of Psychosis in Youth: Multimodal Risk and Resilience Markers, 2/2 Brain, Behavior and Genetic Studies of the 22q11 Deletion Studies, G5047885607, G6067885870, Multidisciplinary Training in Cardiovascular Biology, G66900451, G741339269, G7697879484, The Intellectual and Developmental Disabilities Research Center (IDDRC) at CHOP/Penn
OpenAlex ID: W3155614547