Article

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

Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
Neuroscience (Impact Factor: 3.33). 05/2008; 153(1):120-30. DOI: 10.1016/j.neuroscience.2008.01.044
Source: PubMed

ABSTRACT Alzheimer's disease (AD) is associated with beta-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 beta-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-PyP(5+) (SOD mimetic) protected against beta-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 beta-amyloid toxicity. However, continuing development of neurons under oxidative damage conditions may suppress the expression of MnSOD and enhance cell death in mature neurons.

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    • "These studies indicate that, in contrast to non-neuronal cells, constitutive p53 expression is pro-oxidant in neurons and in the nervous system, suggesting its implication in aging and neurodegenerative conditions [162]. Under conditions associated with neurodegeneration, reduced expression of MnSOD is observed in association with p53 upregulation in models of Alzheimer's disease [163] while p53-dependent sestrin 2 upregulation occurs under conditions of Parkinson's disease [164]. p66Shc deficiency reduces axonal injury in a mouse model of multiple sclerosis [165] and protects hippocampal neurons against cell death induced by H 2 O 2 or NO donor treatment [166]. "
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    • "4-HNE readily reacts with lysine, cysteine, and histidine to form protein adducts [53]. These 4-HNE adducts have been implicated in the etiology of Alzheimer’s disease and Parkinson’s disease [54], [55]. Nrf2 activation robustly protects astrocytes from 4-HNE toxicity (Figure 3) and regulates genes responsible for detoxifying 4-HNE, including both glutathione S-transferase A4 (GSTA4) and prostaglandin reductase-1 (PTGR1) (Figure 5) [5], [7], [56], [57], [58]. "
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