The contribution of inflammatory astrocytes to BBB impairments in a brain-chip model of Parkinson’s disease

A. de Rus Jacquet (), M. Alpaugh, H. L. Denis, J. L. Tancredi, M. Boutin, J. Decaestecker, C. Beauparlant, L. Herrmann, M. Saint-Pierre, M. Parent, A. Droit, S. Breton and F. Cicchetti ()
Additional contact information
A. de Rus Jacquet: Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences
M. Alpaugh: Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences
H. L. Denis: Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences
J. L. Tancredi: Janelia Research Campus, Howard Hughes Medical Institute
M. Boutin: Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences
J. Decaestecker: Centre de Recherche du CHU de Québec - Université Laval, Axe Endocrinologie et Néphrologie
C. Beauparlant: Centre de Recherche du CHU de Québec - Université Laval, Axe Endocrinologie et Néphrologie
L. Herrmann: Centre de Recherche du CHU de Québec - Université Laval, Axe Endocrinologie et Néphrologie
M. Saint-Pierre: Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences
M. Parent: Université Laval
A. Droit: Centre de Recherche du CHU de Québec - Université Laval, Axe Endocrinologie et Néphrologie
S. Breton: Centre de Recherche du CHU de Québec - Université Laval, Axe Reproduction, santé de la mère et de l’enfant
F. Cicchetti: Centre de Recherche du CHU de Québec - Université Laval, Axe Neurosciences

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39038-8

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