Generation of mature human brain organoids for the study of neurodegenerative diseases

The maturation of the human brain shows species-specific differences of neoteny when compared to lower mammals. This process encompass a time window that expands from late embryonic stages to early adolescence. Major features of brain maturation are the acquisition of phenotypic complex traits such as axonal and dendritic trees and the presence of dendritic spines which correlate with higher functionality and connectivity of the neurons. Interestingly, human transcriptomic data has shown a narrow time window from the birth of the individual to the first two years of life where major transcriptomic changes occur. Here, we address human-specific species features of brain maturation using a multicellular human in vitro brain organoid model composed of neurons and glia cell types. Long-term human brain organoids are analysed functionally for the acquisition of mature neuronal phenotypes to understand the time line of maturation compared to the in vivo situation. Further, we show that long-term human brain organoids acquire features characteristic of the adult human brain and that they can recapitulate hallmarks of AD in vitro.