In AD research, drug development has been slowed by the variable pharmacology of drugs in stable cell lines, primary cultures, and animal models. In general, primary neuronal culture is a preferred cellular model for testing drugs. In our study, all 2D neuronal cultures exhibited significant reduction of Aβ40 and Aβ42 when cells were exposed to BACE1 or γ-secretase inhibitor (Figs 7 and 8). However, inhibition of Aβ production was quite variable amongst our iPSC-derived neuronal lines, with some neuronal cultures exhibiting minimal response to standard BACE1 inhibitor and most exhibiting saturation of inhibition (Figs 7 and 8). The former phenomenon may be related to individual genotypes, and suggests that Aβ generation and turnover may be affected by individual genetic background, an observation with significant implications for development of Aβ-directed AD therapeutics. Our research subjects have not been genetically evaluated, and future research will focus on identification of genotypes associated with this variation. One specific study is underway to understand the apoE genotypes that might be different among these five subjects.
