The contribution of inflammatory astrocytes to BBB impairments in a brain-chip model of Parkinson's disease.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 06 2023
20 06 2023
Historique:
received:
23
10
2021
accepted:
26
05
2023
medline:
22
6
2023
pubmed:
21
6
2023
entrez:
20
6
2023
Statut:
epublish
Résumé
Astrocyte dysfunction has previously been linked to multiple neurodegenerative disorders including Parkinson's disease (PD). Among their many roles, astrocytes are mediators of the brain immune response, and astrocyte reactivity is a pathological feature of PD. They are also involved in the formation and maintenance of the blood-brain barrier (BBB), but barrier integrity is compromised in people with PD. This study focuses on an unexplored area of PD pathogenesis by characterizing the interplay between astrocytes, inflammation and BBB integrity, and by combining patient-derived induced pluripotent stem cells with microfluidic technologies to generate a 3D human BBB chip. Here we report that astrocytes derived from female donors harboring the PD-related LRRK2 G2019S mutation are pro-inflammatory and fail to support the formation of a functional capillary in vitro. We show that inhibition of MEK1/2 signaling attenuates the inflammatory profile of mutant astrocytes and rescues BBB formation, providing insights into mechanisms regulating barrier integrity in PD. Lastly, we confirm that vascular changes are also observed in the human postmortem substantia nigra of both males and females with PD.
Identifiants
pubmed: 37339976
doi: 10.1038/s41467-023-39038-8
pii: 10.1038/s41467-023-39038-8
pmc: PMC10282096
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3651Subventions
Organisme : Howard Hughes Medical Institute
Pays : United States
Informations de copyright
© 2023. The Author(s).
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