Early pathogenic event of Alzheimer's disease documented in iPSCs from patients with PSEN1 mutations

Juan Yang, Hanzhi Zhao, Yu Ma, Guilai Shi, Jian Song, Yu Tang, Song Li, Ting Li, Nan Liu, Fan Tang, Junjie Gu, Lingling Zhang, Zhuohua Zhang, Xiaohui Zhang, Ying Jin, Weidong Le

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Alzheimer's disease (AD) is the most common age-related dementia characterized by progressive neuronal loss. However, the molecular mechanisms for the neuronal loss is still debated. Here, we used induced pluripotent stem cells (iPSCs) derived from somatic cells of familial AD patients carrying PSEN1 mutations to study the early pathogenic event of AD. We found that premature neuronal differentiation with decreased proliferation and increased apoptosis occured in AD-iPSC-derived neural progenitor cells (AD-NPCs) once neuronal differentiation was initiated, together with higher levels of Aβ42 and phosphorylated tau. Premature neuronal differentiation in AD-NPCs was caused by PSEN1 mutations and might be correlated to multiple dysregulated processes including but not limited to Wnt-Notch pathway. Our study documented previously unappreciated early NPC dysfunction in AD-NPCs, providing valuable new insights into the early mechanisms underlying AD pathogenesis.

Original languageEnglish (US)
Pages (from-to)7900-7913
Number of pages14
JournalOncotarget
Volume8
Issue number5
DOIs
StatePublished - 2017

Keywords

  • Alzheimer's disease
  • Apoptosis
  • Induced pluripotent stem cells
  • Neural progenitor cells
  • Premature neuronal differentiation

ASJC Scopus subject areas

  • Oncology

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