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

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.

Cysteamine as a novel disease-modifying compound for Parkinson's disease: Over a decade of research supporting a clinical trial.

To date, medical and surgical interventions offered to patients with Parkinson's disease (PD) serve only to manage clinical symptoms; they have not shown the capacity to halt nor reverse degenerative processes. There is therefore an urgent need to identify and/or develop therapeutic strategies that will demonstrate 'disease modifying' capacities. The molecule cystamine, and its reduced form cysteamine, act via a number of pathways determined to be critical to the pathogenesis of PD. In particular, cystamine is capable of crossing the blood-brain barrier, and both agents (cystamine and cysteamine) can promote the secretion of neurotrophic factors, inhibit oxidative stress, reduce inflammatory responses and importantly, have already been trialed in humans for a number of other clinical indications. In the last decade, our laboratory has accumulated compelling evidence that both cystamine and cysteamine can halt, and even reverse, ongoing neurodegenerative processes in a number of different models of PD, and as such, should now be taken forward to clinical trials in PD.