These data indicate that organoids created from multiple fAD patient iPSC lines demonstrate robust and relevant AD-like phenotypes. To determine whether these phenotypes are indeed a result of altered Aβ production, we treated the fAD organoids with two compounds well known to reduce amyloid aggregation: the γ-secretase inhibitor Compound E (Comp-E; γ2) and a BACE-1 β-secretase inhibitor (β-Secretase Inhibitor IV, EMD Millipore) [40,74]. These experiments also allow us to determine the feasibility of pharmacologic manipulation in the organoid cultures. Comp-E and β-Secretase Inhibitor IV, or DMSO vehicle, were added to the culture media of 30-day-old fAD organoids and replenished with every media change (Fig 3A). At day 60 (30 days of treatment) we assessed Aβ and pTau pathology (Fig 3A) and showed that compound treatment significantly reduced the number of amyloid aggregates in the fAD organoids in dose dependent manner, compared to vehicle treated fAD tissue (Fig 3B). This reduction was particularly evident in the in 90-day-old fAD organoids treated for 60-days (Fig 3C). In contrast to the dramatic reduction of Aβ aggregation with compound treatment, immunoreactivity for pTau was
