Prevention of β-amyloid induced toxicity in human iPS cell-derived neurons by inhibition

Abstract Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive decline dueto 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 forebrainmarker 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. Weobserved in neurons differentiated from both hiPS cell lines that Aβ induced toxicity correlated with cell cycle re-entry andwas inhibited by pharmacological inhibitors or shRNAs against Cyclin-dependent kinase 2 (Cdk2). As one of the hiPS cell lineshas been developed commercially to supply large quantities of differentiated neurons (iCell® Neurons), we screened achemical library containing several hundred compounds and discovered several small molecules as effective blockers againstAβ1–42 toxicity, including a Cdk2 inhibitor. To our knowledge, this is the first demonstration of an Aβ toxicity screen usinghiPS cell-derived neurons. This study provided an excellent example of how hiPS cells can be used for disease modeling andhigh-throughput compound screening for neurodegenerative diseases.© 2012 Elsevier B.V. All rights reserved.Abbreviations: iPS cells, induced pluripotent stem cells; hiPS-C4, hiPS cell line UC C0406 iPS-C4; ES cells, embryonic stem cells; NPCs,neural progenitor cells; CCEs, cell cycle events; Aβ, β-amyloid; NFTs, neurofibrillary tangles; APP, amyloid precursor protein; AD,Alzheimer's disease; PD, Parkinson disease; Cdk, Cyclin-dependent kinase; shRNA, small hairpin RNA; Rb, retinoblastoma protein; TUNEL,terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling; FACS, fluorescence-activated cell sorting; CBPs,calcium-binding proteins.⁎ Correspondence to: L. Lei, No. 194 Xuefu Road, Nangang District, Harbin 150081, China. Fax: +86 451 87503326 or Z. Zhong, Building 3,898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai 201203, China. Fax: +86 21 61590844.E-mail addresses: leil086@yahoo.com.cn (L. Lei), zhong.z.zhong@gsk.com (Z. Zhong).1873-5061/$ - see front matter © 2012 Elsevier B.V. All rights reserved.http://dx.doi.org/10.1016/j.scr.2012.11.005Available online atwww.sciencedirect.comwww.elsevier.com/locate/scrStem Cell Research (2013) 10, 213–227