[Application of neural organoids containing microglia to neurodegenerative disease research]

In recent years, the "translational gap" has become problematic in drug development, wherein promising results from animal experiments and in vitro tests fail to demonstrate the expected efficacy and safety in clinical trials. This translational gap has also impacted on the development of therapeutic agents for brain diseases, including Alzheimer's disease (AD). While microglia, which are immune cells in the brain, have gained attention as therapeutic targets of AD, the inter-species difference in microglia between humans and experimental model animals may cause this gap. To reveal the pathogenic mechanisms of AD and develop a therapeutic strategy, experimental models that appropriately reproduce pathological conditions using human-derived materials are required. Pluripotent stem cells can differentiate into various cells such as neurons and microglia. Therefore, it is expected that the creation of neural organoids from human pluripotent stem cells will enable the construction of a human-based analysis system that can reproduce three-dimensional brain structures and intercellular interactions, thereby overcoming the translational gap. Furthermore, combining patient-derived induced pluripotent stem cells and gene editing technology with neural organoid technology is leading to cutting-edge research. In this review, we introduce global research trends aimed at developing neural organoids containing microglia derived from human pluripotent stem cells and applying them to elucidate the pathogenesis and to develop therapeutic drugs for AD.