A neuronal model of Alzheimer's disease: An insight into the mechanisms of oxidative stress-mediated mitochondrial injury

P. Sompol, W. Ittarat, J. Tangpong, Y. Chen, I. Doubinskaia, I. Batinic-Haberle, H. M. Abdul, D. A. Butterfield, D. K. St. Clair

Research output: Contribution to journalArticlepeer-review

118 Scopus citations


Alzheimer's disease (AD) is associated with β-amyloid accumulation, oxidative stress and mitochondrial dysfunction. However, the effects of genetic mutation of AD on oxidative status and mitochondrial manganese superoxide dismutase (MnSOD) production during neuronal development are unclear. To investigate the consequences of genetic mutation of AD on oxidative damages and production of MnSOD during neuronal development, we used primary neurons from new born wild-type (WT/WT) and amyloid precursor protein (APP) (NLh/NLh) and presenilin 1 (PS1) (P264L) knock-in mice (APP/PS1) which incorporated humanized mutations in the genome. Increasing levels of oxidative damages, including protein carbonyl, 4-hydroxynonenal (4-HNE) and 3-nitrotyrosine (3-NT), were accompanied by a reduction in mitochondrial membrane potential in both developing and mature APP/PS1 neurons compared with WT/WT neurons suggesting mitochondrial dysfunction under oxidative stress. Interestingly, developing APP/PS1 neurons were significantly more resistant to β-amyloid 1-42 treatment, whereas mature APP/PS1 neurons were more vulnerable than WT/WT neurons of the same age. Consistent with the protective function of MnSOD, developing APP/PS1 neurons have increased MnSOD protein and activity, indicating an adaptive response to oxidative stress in developing neurons. In contrast, mature APP/PS1 neurons exhibited lower MnSOD levels compared with mature WT/WT neurons indicating that mature APP/PS1 neurons lost the adaptive response. Moreover, mature APP/PS1 neurons had more co-localization of MnSOD with nitrotyrosine indicating a greater inhibition of MnSOD by nitrotyrosine. Overexpression of MnSOD or addition of MnTE-2-PyP5+ (SOD mimetic) protected against β-amyloid-induced neuronal death and improved mitochondrial respiratory function. Together, the results demonstrate that compensatory induction of MnSOD in response to an early increase in oxidative stress protects developing neurons against β-amyloid toxicity. However, continuing development of neurons under oxidative damage conditions may suppress the expression of MnSOD and enhance cell death in mature neurons.

Original languageEnglish
Pages (from-to)120-130
Number of pages11
Issue number1
StatePublished - Apr 22 2008

Bibliographical note

Funding Information:
This work was supported by NIH grants PO1AG 05119 and RO1 CA 49797 to Dr. Daret K. St. Clair and by the Royal Golden Jubilee Research Fellowship (The Thailand Research Fund) to Pradoldej Sompol. We are particularly grateful to Dr. Dorothy Flood, Cephalon Inc., for the critical review and valuable suggestions that improved the quality of this manuscript.


  • APP/PS1
  • Alzheimer's disease
  • MnSOD
  • SOD mimetic
  • oxidative stress
  • β-amyloid

ASJC Scopus subject areas

  • General Neuroscience


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