Vascularized midbrain assembloids show neuroinflammation and dopaminergic neuron vulnerability in Parkinson’s Disease

The use of micro-physiological systems has rapidly risen in the last years due to their translatability and complex cellular composition. Human midbrain-specific organoids contain neuroectoderm-derived cell types and are suitable for brain region-specific disease modeling. However, the lack of vasculature in these systems reduces oxygenation and nutrient supply. Furthermore, neurovascular interactions cannot be studied, and disease phenotypes affecting vascular and neurovascular structures cannot be assessed. To overcome these limitations, in this work, we successfully incorporated a vascular network into midbrain organoids by fusion with vascular organoids. Midbrain-vascular assembloids are enriched in vascular cells and microglia. We observed a decrease in hypoxia and cell death in these assembloids. Furthermore, microglia and endothelial cells increased their morphological complexity. Assembloids derived from a Parkinson’s disease patient carrying a LRRK2-G2019S mutation displayed a pro-inflammatory phenotype and altered electrophysiological properties. Midbrain-vascular assembloids increase the midbrain model complexity and allow for neuroinflammation studies in Parkinson’s disease.