Exp Neurobiol 2018; 27(5): 350-364
Published online October 31, 2018
© The Korean Society for Brain and Neural Sciences
Ling Li1,†, Jee Hoon Roh2,†, Eun Hyuk Chang3,4, Yoonkyung Lee1, Suji Lee1, Minchul Kim1, Wonyoung Koh1, Jong Wook Chang3,4, Hee Jin Kim3,5, Mahito Nakanishi6, Roger A. Barker7, Duk L. Na3,5*, and Jihwan Song1*
1CHA Stem Cell Institute, Department of Biomedical Science, CHA University, Seongnam 13488, Korea.
2Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
3Neuroscience Center, Samsung Medical Center, Seoul 06351, Korea.
4Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul 06351, Korea.
5Department of Neurology, Samsung Medical Center, Seoul 06351, Korea.
6Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki 305-8561, Japan.
7John van Geest Cambridge Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge CB2 0PY, UK.
Correspondence to: *To whom correspondence should be addressed.
Jihwan Song, TEL: 82-31-881-7140, FAX: 82-31-881-7249
Duk L. Na, TEL: 82-2-3410-3591, FAX: 82-2-3410-0052
†These authors contributed equally to the work.
Disease modeling of Alzheimer's disease (AD) has been hampered by the lack of suitable cellular models while animal models are mainly based on the overexpression of AD-related genes which often results in an overemphasis of certain pathways and is also confounded by aging. In this study, we therefore developed and used induced pluripotent stem cell (iPSC) lines from a middle-aged AD patient with a known presenilin 1 (PSEN1) mutation (Glu120Lys; PS1-E120K) and as a control, an elderly normal subject. Using this approach, we demonstrated that the extracellular accumulation of Aβ was dramatically increased in PS1-E120K iPSC-derived neurons compared with the control iPSC line. PS1-E120K iPSC-derived neurons also exhibited high levels of phosphorylated tau, as well as mitochondrial abnormalities and defective autophagy. Given that the effect of aging is lost with iPSC generation, these abnormal cellular features are therefore indicative of PSEN1-associated AD pathogenesis rather than primary changes associated with aging. Taken together, this iPSC-based approach of AD modeling can now be used to better understand AD pathogenesis as well as a tool for drug discovery.