Advancements in brain organoid models for neurodegenerative disease research

Neurodegenerative diseases (NDs) such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) are progressive disorders characterized by complex, human-specific pathology that poses challenges to drug discovery efforts. Traditional models, including two-dimensional cell cultures and animal models, often fall short in replicating the intricate cellular interactions observed in human neurodegeneration. This review explores the potential of brain organoid technology to address these limitations and offer a model more relevant to humans. Recent advancements in induced pluripotent stem cell (iPSC) technology have enabled the generation of patient-derived brain organoids that differentiate into various neural cell types within 3-dimensional structures. These iPSC-derived brain organoids establish a physiologically relevant microenvironment that mimics human brain architecture and cellular diversity. This review synthesizes studies on the application of brain organoids in modeling PD and AD pathology, including approaches to improve model fidelity. Brain organoids replicate disease-specific features, including dopaminergic neuron degeneration in PD and amyloid plaque formation in AD, offering valuable insights into disease mechanisms and potential therapeutic targets. However, challenges remain, including incomplete maturation, batch variability, and the absence of vascularization and complete cortical layering. Bioengineering approaches, including CRISPR-based gene editing and organ-on-a-chip technologies, are being investigated to overcome these obstacles. Brain organoid technology presents a transformative platform for the study of NDs, facilitating detailed research into disease mechanisms and testing of therapeutics. Overcoming existing challenges is crucial for maximizing the translational value of brain organoids, advancing personalized medicine, and supporting the development of effective therapies for NDs.