Mitochondria-targeted antioxidants protect against amyloid-β toxicity in Alzheimer's disease neurons

Maria Manczak, Peizhong Mao, Markus J. Calkins, Anda Cornea, Arubala Reddy, Michael P. Murphy, Hazel H. Szeto, Byung Park, P (Hemachandra) Reddy

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282 Scopus citations

Abstract

The purpose of our study was to investigate the effects of the mitochondria-targeted antioxidants, MitoQ and SS31, and the anti-aging agent resveratrol on neurons from a mouse model (Tg2576 line) of Alzheimer's disease (AD) and on mouse neuroblastoma (N2a) cells incubated with the amyloid-β (Aβ) peptide. Using electron and confocal microscopy, gene expression analysis, and biochemical methods, we studied mitochondrial structure and function and neurite outgrowth in N2a cells treated with MitoQ, SS31, and resveratrol, and then incubated with Aβ. In N2a cells only incubated with the Aβ, we found increased expressions of mitochondrial fission genes and decreased expression of fusion genes and also decreased expression of peroxiredoxins. Electron microscopy of the N2a cells incubated with Aβ revealed a significantly increased number of mitochondria, indicating that Aβ fragments mitochondria. Biochemical analysis revealed that function is defective in mitochondria. Neurite outgrowth was significantly decreased in Aβ-incubated N2a cells, indicating that Aβ affects neurite outgrowth. However, in N2a cells treated with MitoQ, SS31, and resveratrol, and then incubated with Aβ, abnormal expression of peroxiredoxins and mitochondrial structural genes were prevented and mitochondrial function was normal; intact mitochondria were present and neurite outgrowth was significantly increased. In primary neurons from amyloid-β precursor protein transgenic mice that were treated with MitoQ and SS31, neurite outgrowth was significantly increased and cyclophilin D expression was significantly decreased. These findings suggest that MitoQ and SS31 prevent Aβ toxicity, which would warrant the study of MitoQ and SS31 as potential drugs to treat patients with AD.

Original languageEnglish (US)
JournalJournal of Alzheimer's Disease
Volume20
Issue numberSUPPL.2
DOIs
Publication statusPublished - 2010

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Keywords

  • Amyloid-β
  • amyloid-β protein precursor
  • cyclophilin D
  • mitochondria-targeted antioxidants
  • peroxiredoxins

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

Cite this

Manczak, M., Mao, P., Calkins, M. J., Cornea, A., Reddy, A., Murphy, M. P., ... Reddy, P. H. (2010). Mitochondria-targeted antioxidants protect against amyloid-β toxicity in Alzheimer's disease neurons. Journal of Alzheimer's Disease, 20(SUPPL.2). https://doi.org/10.3233/JAD-2010-100564