Τίτλος:
Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2021, The Author(s).
Συγγραφείς:
Pediaditakis, I.
Kodella, K.R.
Manatakis, D.V.
Le, C.Y.
Hinojosa, C.D.
Tien-Street, W.
Manolakos, E.S.
Vekrellis, K.
Hamilton, G.A.
Ewart, L.
Rubin, L.L.
Karalis, K.
Περιοδικό:
Nature Communications
Εκδότης:
Institute of Geographic Sciences and Natural Resources Research
Λέξεις-κλειδιά:
alpha synuclein; microtubule associated protein 2; reactive oxygen metabolite; trehalose; alpha synuclein; transcriptome, blood; brain; nervous system disorder; neurology; pathology, adult; Article; astrocyte; blood brain barrier; brain; cell interaction; dopaminergic nerve cell; endothelium cell; fluid flow; gene ontology; human; human cell; human tissue; microglia; mitochondrion; nervous system inflammation; Parkinson disease; pericyte; RNA sequencing; substantia nigra; synucleinopathy; transcriptomics; blood brain barrier; diagnostic imaging; gliosis; metabolism; pathology; phosphorylation; substantia nigra, alpha-Synuclein; Astrocytes; Blood-Brain Barrier; Brain; Dopaminergic Neurons; Endothelial Cells; Gliosis; Humans; Microglia; Mitochondria; Parkinson Disease; Pericytes; Phosphorylation; Substantia Nigra; Synucleinopathies; Transcriptome
DOI:
10.1038/s41467-021-26066-5
