Amyloid-beta Oligomers-induced Mitochondrial DNA Repair Impairment Contributes to Altered Human Neural Stem Cell Differentiation

Jing Lu, Yi Li, Cristiana Mollinari, Enrico Garaci, Daniela Merlo, Gang Pei

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Amyloid-beta(42) oligomers (A beta O-42), the proximate effectors of neurotoxicity observed in Alzheimer's disease (AD), can induce mitochondrial oxidative stress and impair mitochondrial function besides causing mitochondrial DNA (mtDNA) damage. A beta O-42 also regulate the proliferative and differentiative properties of stem cells. Objective: We aimed to study whether A beta O-42-induced mtDNA damage is involved in the regulation of stem cell differentiation. Method: Human iPSCs-derived neural stem cell (NSC) was applied to investigate the effect of A beta O-42 on reactive oxygen species (ROS) production and DNA damage using mitoSOX staining and long-range PCR lesion assay, respectively. mtDNA repair activity was measured by non-homologous end joining (NHEJ) in vitro assay using mitochondria isolates and the expression and localization of NHEJ components were determined by Western blot and immunofluorescence assay. The expressions of Tuj-1 and GFAP, detected by immunofluorescence and qPCR, respectively, were examined as an index of neurons and astrocytes production. Results: We show that in NSC A beta O-42 treatment induces ROS production and mtDNA damage and impairs DNA end joining activity. NHEJ components, such as Ku70/80, DNA-PKcs, and XRCC4, are localized in mitochondria and silencing of XRCC4 significantly exacerbates the effect of A beta O-42 on mtDNA integrity. On the contrary, pre-treatment with Phytic Acid (IP6), which specifically stimulates DNA-PK-dependent end-joining, inhibits A beta O-42-induced mtDNA damage and neuronal differentiation alteration. Conclusion: A beta O-42-induced mtDNA repair impairment may change cell fate thus shifting human NSC differentiation toward an astrocytic lineage. Repair stimulation counteracts A beta O-42 neurotoxicity, suggesting mtDNA repair pathway as a potential target for the treatment of neurodegenerative disorders like AD.
Original languageEnglish
Pages (from-to)934-949
Number of pages16
JournalCurrent Alzheimer Research
Volume16
Issue number10
DOIs
Publication statusPublished - 2019

Keywords

  • Amyloid-beta
  • mitochondria
  • DNA damage
  • DNA repair
  • human neural stem cell
  • differentiation

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