The first generation of iPSC line from a Korean Alzheimer’s disease patient carrying APP-V715M mutation exhibits a distinct mitochondrial dysfunction

Ling Li, Jee Hoon Roh, Hee Jin Kim, Hyun Jung Park, Minchul Kim, Wonyoung Koh, Hyohoon Heo, Jong Wook Chang, Mahito Nakanishi, Taeyoung Yoon, Duk L. Na, Jihwan Song

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease, which is pathologically defined by the accumulation of amyloid plaques and hyper-phosphorylated tau aggregates in the brain. Mitochondrial dysfunction is also a prominent feature in AD, and the extracellular Aβ and phosphorylated tau result in the impaired mitochondrial dynamics. In this study, we generated an induced pluripotent stem cell (iPSC) line from an AD patient with amyloid precursor protein (APP) mutation (Val715Met; APP-V715M) for the first time. We demonstrated that both extracellular and intracellular levels of Aβ were dramatically increased in the APP-V715M iPSC-derived neurons. Furthermore, the APP-V715M iPSC-derived neurons exhibited high expression levels of phosphorylated tau (AT8), which was also detected in the soma and neurites by immunocytochemistry. We next investigated mitochondrial dynamics in the iPSC-derived neurons using Mito-tracker, which showed a significant decrease of anterograde and retrograde velocity in the APP-V715M iPSC-derived neurons. We also found that as the Aβ and tau pathology accumulates, fusion-related protein Mfn1 was decreased, whereas fission-related protein DRP1 was increased in the APP-V715M iPSC-derived neurons, compared with the control group. Taken together, we established the first iPSC line derived from an AD patient carrying APP-V715M mutation and showed that this iPSC-derived neurons exhibited typical AD pathological features, including a distinct mitochondrial dysfunction.

Original languageEnglish
Pages (from-to)329-336
Number of pages8
JournalExperimental Neurobiology
Volume28
Issue number3
DOIs
Publication statusPublished - 2019 Jun 1
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C2746, HI14C3319, HI18C0335020119), the National Research Foundation of Korea (NRF-2018M3C7A1056894), the Ministry of Trade, Industry and Energy (MOTIE 10060305), and the Asan Institute for Life Sciences (2016-0670). We are also grateful to Tokiwa-Bio, Ajinomoto and Matrixome for providing the SeVdp vectors, StemFit® medium and iMatrix-511, respectively for our iPSC research, and to Drs. John C. Morris and Chang-Seok Ki for their valuable comments for the case. The authors declare no competing financial interests.

Publisher Copyright:
Copyright © Experimental Neurobiology 2019.

Keywords

  • APP
  • Alzheimer’s disease
  • Amyloid beta
  • IPSC
  • Mitochondrial dysfunction

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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