Dysfunctional neurovascular interactions and neuroprogression in early-course psychosis: ex vivo investigation with patient-derived stem cells

Massachusetts General Hospital, Boston MA

Investigators

Abstract

Biomarker studies in early course psychosis (ECP) have repeatedly observed four independent phenomena. First, the presence of decline in symptoms, cognition and functioning that begins in ECP with a neuroprogressive course in ~40% of individuals. Second, the evidence of blood brain barrier (BBB) dysfunction in neuroimaging, postmortem, blood and CSF studies in ~40% of individuals with psychotic disorders. Third postmortem, neuroimaging, genetic and cellular studies show differences in synaptic biology that contribute to neurocircuit dysfunction in psychotic disorders. Fourth, our studies using induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (BMECs) show that individuals with psychotic disorders have intrinsic deficits in BMEC barrier properties and that the BMEC secretome modulates dendrite morphology in human iPSC-derived cortical neurons. These findings suggest that BBB deficits may play a role in neuroprogression in ECP. While many of these findings have been replicated, they have not been mechanistically linked with each other. Developing assays using iPSC-derived BMECs and neurons to measure ex vivo BBB function and neuronal biology respectively, hold unprecedented opportunities to identify molecular, cellular, and circuit-level changes related to neuroprogression in ECP. Yet, clinical and iPSC-derived cellular studies to date have been performed separately without demonstrating a mechanistic relationship between neuroprogression and cellular/molecular factors of ECP. Therefore, there is a critical need to unite clinical trajectories and iPSC-derived BMEC/neuron studies in the same individuals to mechanistically link neuroprogression to ex vivo BBB dysfunction in ECP. The overall objectives for this project are to identify cellular-molecular substrates underlying neuroprogression in ECP and develop reliable biomarkers that can be leveraged for novel therapeutics. Our central hypothesis is that intrinsic deficits in iPSC-derived BMECs will correlate with the presence of neuroprogression in ECP and systematic interrogation of these BMECs will identify mechanisms contributing to this neuroprogression. We aim to develop a integrated translational neuroscience experimental framework by leveraging complementary clinical and ex vivo studies of BBB function in the same cohort of ECP individuals to delineate mechanistic links between neuroprogression and BBB function in ECP. Here, we aim to test the following hypotheses: 1) ex vivo BBB dysfunction is linked to neuroprogression in ECP, 2) there is a dual cellular hit with intrinsic neuronal deficits in ECP that are exacerbated by BMEC dysfunction, and 3) that TNF-MMP1 signaling and Rho-associated kinase regulation of CLDN5 phosphorylation and localization in BMECs underlie BBB dysfunction in ECP. The proposed research is innovative in combining longitudinal clinical (i.e., psychosis symptoms, cognition, and functioning) assessments and ex vivo BBB function studies in the same patients to better understand the cellular/molecular deficits associated with neuroprogression in ECP. The proposed research is significant because it will contribute meaningfully to the biological mechanisms underlying neuroprogression in ECP.