In diseases such as AD that are characterized by protein aggregation, the presence of a true interstitial compartment is important for modeling pathology. Previous three-dimensional (3D) tissue engineering approaches have embedded neural progenitors or cell types of interest in a matrix or a scaffold [40,58]. While these ingenious approaches can model AD phenotypes, they do not recapitulate spontaneous pathology resulting from endogenous cellular characteristics, but rather necessitate the overexpression of fAD genes. In the current work, we took advantage of scaffold-free 3D tissue culture protocols to create neural organoids using iPSCs from fAD patients and healthy controls. The dense nature of these cultures likely facilitates protein aggregation, while remaining amenable to experimental manipulation such as compound treatment.
