Anti-Aβ Drug Screening Platform Using Human iPS Cell-Derived Neurons for the Treatment of Alzheimer's Disease

Background: Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive decline during middle to late adult life. The AD brain is characterized by deposition of amyloid beta peptide (A beta), which is produced from amyloid precursor protein by beta- and gamma-secretase (presenilin complex)-mediated sequential cleavage. Induced pluripotent stem (iPS) cells potentially provide an opportunity to generate a human cell-based model of AD that would be crucial for drug discovery as well as for investigating mechanisms of the disease. Methodology/Principal Findings: We differentiated human iPS (hiPS) cells into neuronal cells expressing the forebrain marker, Foxg1, and the neocortical markers, Cux1, Satb2, Ctip2, and Tbr1. The iPS cell-derived neuronal cells also expressed amyloid precursor protein, beta-secretase, and gamma-secretase components, and were capable of secreting A beta into the conditioned media. A beta production was inhibited by beta-secretase inhibitor, gamma-secretase inhibitor (GSI), and an NSAID; however, there were different susceptibilities to all three drugs between early and late differentiation stages. At the early differentiation stage, GSI treatment caused a fast increase at lower dose (A beta surge) and drastic decline of A beta production. Conclusions/Significance: These results indicate that the hiPS cell-derived neuronal cells express functional beta- and gamma-secretases involved in A beta production; however, anti-A beta drug screening using these hiPS cell-derived neuronal cells requires sufficient neuronal differentiation.