Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption

Iosif Pediaditakis (), Konstantia R. Kodella, Dimitris V. Manatakis, Christopher Y. Le, Chris D. Hinojosa, William Tien-Street, Elias S. Manolakos, Kostas Vekrellis, Geraldine A. Hamilton, Lorna Ewart, Lee L. Rubin and Katia Karalis ()
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Iosif Pediaditakis: Emulate Inc., 27 Drydock Avenue
Konstantia R. Kodella: Emulate Inc., 27 Drydock Avenue
Dimitris V. Manatakis: Emulate Inc., 27 Drydock Avenue
Christopher Y. Le: Emulate Inc., 27 Drydock Avenue
Chris D. Hinojosa: Emulate Inc., 27 Drydock Avenue
William Tien-Street: Emulate Inc., 27 Drydock Avenue
Elias S. Manolakos: National and Kapodistrian University of Athens
Kostas Vekrellis: Biomedical Research Foundation of Academy of Athens
Geraldine A. Hamilton: Emulate Inc., 27 Drydock Avenue
Lorna Ewart: Emulate Inc., 27 Drydock Avenue
Lee L. Rubin: Harvard University
Katia Karalis: Emulate Inc., 27 Drydock Avenue

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Parkinson’s disease and related synucleinopathies are characterized by the abnormal accumulation of alpha-synuclein aggregates, loss of dopaminergic neurons, and gliosis of the substantia nigra. Although clinical evidence and in vitro studies indicate disruption of the Blood-Brain Barrier in Parkinson’s disease, the mechanisms mediating the endothelial dysfunction is not well understood. Here we leveraged the Organs-on-Chips technology to develop a human Brain-Chip representative of the substantia nigra area of the brain containing dopaminergic neurons, astrocytes, microglia, pericytes, and microvascular brain endothelial cells, cultured under fluid flow. Our αSyn fibril-induced model was capable of reproducing several key aspects of Parkinson’s disease, including accumulation of phosphorylated αSyn (pSer129-αSyn), mitochondrial impairment, neuroinflammation, and compromised barrier function. This model may enable research into the dynamics of cell-cell interactions in human synucleinopathies and serve as a testing platform for target identification and validation of novel therapeutics.

Date: 2021
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DOI: 10.1038/s41467-021-26066-5

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