Modeling Alzheimer’s Disease by Induced Pluripotent Stem Cells Carrying APP D678H Mutation

Kuo Hsuan Chang, Guey Jen Lee-Chen, Ching Chang Huang, Jia Li Lin, Yi Jing Chen, Pei Chi Wei, Yen Shi Lo, Chin Fa Yao, Ming Wei Kuo, Chiung Mei Chen

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Alzheimer’s disease (AD), probably caused by abnormal accumulation of β-amyloid (Aβ) and aberrant phosphorylation of tau, is the most common cause of dementia among older people. Generation of patient-specific neurons by induced pluripotent stem cell (iPSC) technology facilitates exploration of the disease features in live human neurons from AD patients. In this study, we generated iPSCs from two familial AD patients carrying a heterozygous D678H mutation in the APP gene (AD-iPSCs). The neurons derived from our AD-iPSCs demonstrated aberrant accumulation of intracellular and secreted Aβ42 and Aβ40, reduction of serine 9 phosphorylation in glycogen synthase kinase 3β (GSK3β) hyperphosphorylation of threonine 181 and serine 396 in tau protein, impaired neurite outgrowth, downregulation of synaptophysin, and increased caspase 1 activity. The comparison between neurons derived from a sibling pair of wild-type and mutated iPSCs successfully recapitulated these AD phenotypes. Treatment with indole compound NC009-1 (3-((1H-Indole-3-yl)methyl)-4-(2-nitrophenyl)but-3-en-2-one), a potential Aβ aggregation reducer, normalized the Aβ levels and GSK3β and tau phosphorylation, attenuated caspase 1 activity, and improved neurite outgrowth in AD-iPSC-derived neurons. Thus, APP D678H iPSCs-derived neurons recapitulate the cellular characteristics relevant to AD and enable exploration of the underlying pathogenesis and therapeutic strategies for AD.

Original languageEnglish
Pages (from-to)3972-3983
Number of pages12
JournalMolecular Neurobiology
Volume56
Issue number6
DOIs
Publication statusAccepted/In press - 2018 Jan 1

    Fingerprint

Keywords

  • Alzheimer’s disease
  • APP
  • Induced pluripotent stem cells
  • Neurite outgrowth
  • Tau

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Chang, K. H., Lee-Chen, G. J., Huang, C. C., Lin, J. L., Chen, Y. J., Wei, P. C., Lo, Y. S., Yao, C. F., Kuo, M. W., & Chen, C. M. (Accepted/In press). Modeling Alzheimer’s Disease by Induced Pluripotent Stem Cells Carrying APP D678H Mutation. Molecular Neurobiology, 56(6), 3972-3983. https://doi.org/10.1007/s12035-018-1336-x