In the current work, we focused our efforts on determining whether or not these organoid systems could model age-related AD-like pathology. The pioneering works that we drew our techniques from used the organoid system as a means to study neurodevelopment [53,64,66,67]. Since work by several groups has suggested that iPSC reprogramming “re-sets” the epigenome, and that other phenotypes associated with cellular aging, such as mitochondrial function and telomere length, are returned to a “juvenile-like” state [86,87], the obvious question is: to what extent can we model phenotypes associated with aging in human neural cells? While we observe robust AD-like phenotypes that increase with “age” in the organoids, the extent to which the organoid tissue represents the aged human brain has not been examined. We believe that the scaffold-free three dimensional model has good potential for studying neurological diseases. This will be important for future works to use this model system to examine other AD related phenotypes, such as neuroinflammation, gliosis, DNA damage, U1 tangles [88] and synaptic dysfunction. Also, without a means of tissue perfusion, the organoid suffers from the
