Prevention of β-amyloid induced toxicity in human iPS cell-derived neurons by inhibition of Cyclin-dependent kinases and associated cell cycle events

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive decline due to the selective neuronal loss in the cortex and hippocampus of the brains. Generation of human induced pluoripotent stem (hiPS) cells holds great promise for disease modeling and drug discovery in AD. In this study, we used neurons with forebrain marker expression from two unrelated hiPS cell lines. As both populations of neurons were vulnerable to β-amyloid 1-42 (Aβ1-42) aggregates, a hallmark of AD pathology, we used them to investigate cellular mediators of Aβ1-42 toxicity. We observed in neurons differentiated from both hiPS cell lines that Aβ induced toxicity correlated with cell cycle re-entry and was inhibited by pharmacological inhibitors or shRNAs against Cyclin-dependent kinase 2 (Cdk2). As one of the hiPS cell lines has been developed commercially to supply large quantities of differentiated neurons (iCell® Neurons), we screened a chemical library containing several hundred compounds and discovered several small molecules as effective blockers against Aβ1-42 toxicity, including a Cdk2 inhibitor. To our knowledge, this is the first demonstration of an Aβ toxicity screen using hiPS cell-derived neurons. This study provided an excellent example of how hiPS cells can be used for disease modeling and high-throughput compound screening for neurodegenerative diseases.