Modeling Alpha-Synuclein Pathology in a Human Brain-Chip to Assess Blood-Brain Barrier Disruption

Published: 13 August 2021| Version 1 | DOI: 10.17632/bdnf2srwcg.1
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Description

Experimental Parkinson's disease (PD) models, such as animal models or conventional cell culture systems, have advanced our understanding of the role of αSyn and its aggregated forms in the development of the disease and the induction of neuronal toxicity. However, these models have not been able to uncover the dynamics of the specific interactions between the brain parenchymal cells and the BBB in normal or pathological states. To address this need, we exposed the human Brain-Chip to αSyn fibrils that led to a progressive accumulation of phosphorylated αSyn and the associated induction of specific aspects of αSyn toxicity, such as mitochondrial dysfunction and oxidative stress. We also found that exposure of Brain-Chip to αSyn fibrils results in microglial activation, astrogliosis, and a time-dependent neuronal loss, as described in PD patients. Finally, our results show tight junctions' derangement and progressively compromised BBB permeability in response to αSyn fibrils. This is in line with previous studies showing deregulation of claudin as a key determinant of the BBB integrity and paracellular permeability. Interestingly, control over the amount of αSyn accumulation by treatment with the autophagy inducer trehalose rescued the compromised BBB permeability and the derangement of the tight junctions, suggesting a prospective therapeutic approach for treating compromised BBB implicated in PD. The purpose of this database is to provide the microscope images that have led to the conclusions shown in this report.

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