Melanie Alpaugh
Aurélie De Rus Jacquet
Dr. Aurélie de Rus Jacquet and Dr. Melanie Alpaugh, Université Laval
Scientific publication
de Rus Jacquet, A., Alpaugh, M., Denis, H.L. et al. The contribution of inflammatory astrocytes to BBB impairments in a brain-chip model of Parkinson’s disease. Nat Commun 14, 3651 (2023).
Development of a new brain-chip leads to important discoveries about the role of astrocytes, inflammation and the blood brain barrier in Parkinson’s Disease development
Astrocytes are star-shaped cells that are found in the brain and spinal cord along side neurons. Among their many roles, astrocytes are mediators of the brain immune response, and astrocyte reactivity is a pathological feature of Parkinson’s Disease (PD). They are also involved in the formation and maintenance of the blood-brain barrier (BBB) and barrier integrity is also compromised in people with PD. In a new study, Aurélie de Rus Jacquet and Melanie Alpaugh report that astrocytes derived from PD patient-derived cells are pro-inflammatory and dysfunctional. Furthermore, they found a cellular target whose inhibition in these astrocytes rescued blood brain barrier formation. Finally, they also looked in brain tissue from patients that had PD, and found defects in blood vessels confirming their findings in cultured human cells.
In order to make these discoveries, the researchers combined patient-derived induced pluripotent stem cells (iPSCs) with microfluidic technologies to generate a 3D human BBB chip. Using this technology, they found that astrocytes derived from female donors harboring a gene mutation called LRRK2 G2019S expressed markers of inflammation and failed to support the formation of a functional blood vessels in cell cultures. Additionally, the researchers studied gene expression in these cells, to identify potential target to restore the defects observed. After testing multiple potential targets, they identified a specific signaling pathway involved in inflammation that was affected and more importantly, were able to find a compound targeting this pathway that restored blood vessel formation.
Collectively, this study proposes a framework where BBB impairments may be, at least in part, mediated by disease-induced astrocyte alterations. The LRRK2 G2019S mutation appears to maintain astrocytes in a reactive state and dysregulate genes involved in brain vessel formation. In addition, the results suggest that a shared signaling pathway may mediate both inflammation and loss of barrier integrity in PD.
This publication is among the first to provide evidence that PD astrocytes can initiate defects in brain blood vessel formation, and that the BBB could play a role in disease progression. The findings from the article also suggest that the BBB could serve as a novel drug target. In addition, the BBB-chip model developed by Aurélie de Rus Jacquet and Melanie Alpaugh show promise as a new tool for drug discovery efforts for many brain diseases, leading to collaborations with startup and pharmaceutical industries. Lastly, the use of cells from patients to establish the model allow the inclusion of samples from groups traditionally under-represented in scientific studies, and the researchers are leading efforts to create a model with iPSCs from Indigenous donors.
About Dr. Aurélie de Rus Jacquet and Dr. Melanie Alpaugh
Drs. Aurélie de Rus Jacquet and Melanie Alpaugh performed this work as postdoctoral fellows in the laboratory of Dr. Francesca Cicchetti, at Université Laval. The conceptual basis for this study was Dr. de Rus Jacquet’s prior work on Parkinson’s disease astrocytes as a postdoctoral fellow in Erin O’Shea’s laboratory at Janelia Research Campus (Howard Hughes Medical Institute). The blood-brain barrier model was developed by Dr. Alpaugh with the support of Dr. Cicchetti. Aurélie de Rus Jacquet is now an Assistant Professor at Université Laval and she continues her research on the role of glial cells and the blood-brain barrier in Parkinson’s disease. Melanie Alpaugh is now an Assistant Professor at the University of Guelph where she is studying interactions between cardiovascular disease and neurological disorders.
Sources of funding
This work was supported by Parkinson’s Foundation, the Canadian Institutes of Health Research (CIHR) and from the Fonds de Recherche du Québec en Santé (FRQS).
