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Exp Neurobiol. 2018 Oct;27(5):350-364. doi: 10.5607/en.2018.27.5.350. Epub 2018 Oct 31.

iPSC Modeling of Presenilin1 Mutation in Alzheimer's Disease with Cerebellar Ataxia.

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CHA Stem Cell Institute, Department of Biomedical Science, CHA University, Seongnam 13488, Korea.
Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
Neuroscience Center, Samsung Medical Center, Seoul 06351, Korea.
Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul 06351, Korea.
Department of Neurology, Samsung Medical Center, Seoul 06351, Korea.
Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki 305-8561, Japan.
John van Geest Cambridge Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge CB2 0PY, UK.


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.


Alzheimer disease; Amyloid beta; Autophagy; Presenilin1; Tau; stem cell

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