Development of Metabolic Stress in Vascular Organoids under Normal Conditions and with AD/PD-Associated Genetic Backgrounds.

Vascular organoids derived from human induced pluripotent stem cells (iPSCs) are promising models for studying vascular pathology, including neurodegenerative diseases. In this study, we investigated signs of mitochondrial dysfunction in the vascular organoids derived from the iPSCs of a healthy donor, as well as patients with Alzheimer's disease (AD) and Parkinson's disease (PD). In the conditioned medium of vascular organoids from the PD patient-derived cells, but not from the AD patient-derived cells, a trend toward a disrupted NAD+/NADH balance was observed, accompanied by the reduced expression of the connexin 43 (Cx43) protein. A sign of metabolic vulnerability of endothelial cells in the vascular organoids from the PD patient-derived cells, but not from normal or AD patient-derived organoids, manifested as reduced expression of c-Myc was observed. Changes in the membrane potential were detected in the vascular organoids from the AD and PD patient-derived, as well as increase in the mitochondrial superoxide anion production were observed, which may indicate development of oxidative stress in the microvessel cells during neurodegeneration.