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.
Highlights
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
First (D0), we seeded in the brain channel human iPSCderived dopaminergic (DA) neurons derived from a healthy donor, as well as human primary brain astrocytes, microglia, and pericytes at respective seeding densities, as described in the Materials section
To the best of our knowledge these donors do not carry any of the mutations in genes and SNPs associated with Parkinson’s disease (PD) susceptibility
Summary
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. 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. Experimental models of PD, such as animal models[14,15] or conventional cell culture systems[16–18], 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 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. Organs-on-Chips enable the recreation of a more physiological mircroenvironement, including co-culture of relevant cells on tissue-specific extracellular matrices (ECM), exposure to continuous flow, and in vivo-relevant mechanical forces such as the fluidic sheer stress
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