Modelling Neurodegeneration with Brain Organoids and Organ-on-Chip Technologies

Neurodevelopmental and neurodegenerative disorders arise from intricate disruptions in brain architecture and function, often rooted in early development. Traditional models have limited capacity to replicate human neural complexity, prompting the emergence of advanced in vitro systems. This review discusses the evolution of brain organoids, assembloids, and organ-on-chip technologies derived from human pluripotent stem cells, highlighting their transformative impact on modeling Alzheimer’s and Parkinson’s diseases. Recent innovations—such as region-specific organoids, vascularized constructs, microfluidic systems, and integration of neuronal diversity—have enhanced the fidelity of these models in replicating human brain physiology and pathology. Organoid-based platforms have revealed novel insights into disease mechanisms, drug discovery, and therapeutic interventions, offering unprecedented windows into amyloid aggregation, neuroinflammation, dopaminergic neuron degeneration, and gut-brain axis interactions. Despite their promise, challenges persist, including limited vascularization, cellular stress, variability, and high production costs in organ-on-chip systems. Advances in standardization, vascularization, and immune system integration are critical for improving reproducibility and translational relevance. By bridging key gaps between basic neuroscience and clinical application, brain organoid technologies represent a new frontier in understanding and treating complex neurological diseases.