論文

査読有り 国際誌
2020年4月

Pathological manifestation of the induced pluripotent stem cell-derived cortical neurons from an early-onset Alzheimer's disease patient carrying a presenilin-1 mutation (S170F).

Cell proliferation
  • Ling Li
  • ,
  • Hee Jin Kim
  • ,
  • Jee Hoon Roh
  • ,
  • Minchul Kim
  • ,
  • Wonyoung Koh
  • ,
  • Younghoon Kim
  • ,
  • Hyohoon Heo
  • ,
  • Jaehoon Chung
  • ,
  • Mahito Nakanishi
  • ,
  • Taeyoung Yoon
  • ,
  • Chang Pyo Hong
  • ,
  • Sang Won Seo
  • ,
  • Duk L Na
  • ,
  • Jihwan Song

53
4
開始ページ
e12798
終了ページ
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1111/cpr.12798

OBJECTIVES: Alzheimer's disease (AD) is the most common neurodegenerative disease which is characterized by the formation of amyloid beta (Aβ) plaques and neurofibrillary tangles. These abnormal proteins induce disturbance in mitochondrial dynamics and defect in autophagy system. Since presenilin-1 (PS1) is a core component in γ-secretase complex, the mutations of PS1 gene cause the interference of γ-secretase activity and lead to the increased Aβ42 secretion. We aimed to characterize the patient-specific induced pluripotent stem cell (iPSC) line carrying PS1-S170F mutation. Furthermore, we tested whether disease-modifying drug can reduce AD pathology in the AD iPSC-derived neurons. MATERIALS AND METHODS: Mononuclear cells (MNCs) were isolated freshly from the peripheral blood of an autosomal dominant AD (ADAD) patient carrying presenilin-1 (PS1) mutation (Ser170Phe; PS1-S170F) and a cognitively normal control. We generated induced pluripotent stem cell (iPSC) lines, which were differentiated into functional cortical neurons. Then, we measured the markers indicative of AD pathogenesis using immunocytochemistry and Western blot. We also investigated the mitochondrial dynamics in the AD iPSC-derived neurons using Mito-tracker. RESULTS: We observed that both extracellular and intracellular Aβ levels were dramatically increased in the PS1-S170F iPSC-derived neurons, compared with the control iPSC-derived neurons. Furthermore, PS1-S170F iPSC-derived neurons showed high expression levels of p-Tau, which were detected both in the soma and neurites. The mitochondrial velocity in the PS1-S170F iPSC-derived neurons was much reduced, compared with that of the control. We also found a significant decrease of fusion-related protein Mfn1 (membrane proteins mitofusin 1) and an increase of fission-related protein DRP1 (dynamin-related protein 1) in the PS1-S170F iPSC-derived neurons. We further observed the defects of autophagy-related clearance in the PS1-S170F iPSC-derived neurons. Finally, we demonstrated the levels of Aβ and p-Tau can be dramatically reduced by the treatment of LY-2886721, a BACE1 inhibitor. CONCLUSIONS: Taken together, we have established and characterized the pathological features of an AD patient carrying PS1-S170F mutation using iPSC technology, which will be the first case on this mutation and this iPSC line will serve as a useful resource for studying AD pathogenesis and drug screening in the future.

リンク情報
DOI
https://doi.org/10.1111/cpr.12798
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32216003
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162796

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