We have harnessed the potential of immunocompetent brain organoids to study neurodegeneration, particularly in the context of demyelination and multiple sclerosis. By developing a novel protocol, these organoids now intrinsically generate various neuronal types, myelinating oligodendrocytes, microglia, and astrocytes (MMBOs), effectively representing a complete model of the human brain. By treating the organoids with lysolecithin to induce demyelination, we gain valuable insights into the relationship between this process, inflammatory responses of microglia and alterations in neuronal activity, which ultimately leads to neuronal degeneration. Our groundbreaking approach allows us to examine the intricate dynamics between demyelination, inflammation, and neuronal activity within the brain organoids. With microglia serving as key players in neurodegenerative processes, we can now assess their role in real time and the impact on neuronal function. This comprehensive brain organoid model opens new avenues for understanding neurodegenerative diseases and identifying potential therapeutic targets. Adopting this advanced model, we plan to uncover critical mechanisms underlying neurodegeneration and facilitate the development of innovative treatments to combat these debilitating conditions and promote remyelination.