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: 3.36). 05/2008; 153(1):120-30. DOI: 10.1016/j.neuroscience.2008.01.044
Source: PubMed


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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Available from: Daret K St Clair, Jan 13, 2014
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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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    ABSTRACT: The p53 tumor suppressor plays a central role in dictating cell survival and death as a cellular sensor for a myriad of stresses including DNA damage, oxidative and nutritional stress, ischemia and disruption of nucleolar function. Activation of p53-dependent apoptosis leads to mitochondrial apoptotic changes via the intrinsic and extrinsic pathways triggering cell death execution most notably by release of cytochrome c and activation of the caspase cascade. Although it was previously believed that p53 induces apoptotic mitochondrial changes exclusively through transcription-dependent mechanisms, recent studies suggest that p53 also regulates apoptosis via a transcription-independent action at the mitochondria. Recent evidence further suggests that p53 can regulate necrotic cell death and autophagic activity including mitophagy. An increasing number of cytosolic and mitochondrial proteins involved in mitochondrial metabolism and respiration are regulated by p53, which influences mitochondrial ROS production as well. Cellular redox homeostasis is also directly regulated by p53 through modified expression of pro- and anti-oxidant proteins. Proper regulation of mitochondrial size and shape through fission and fusion assures optimal mitochondrial bioenergetic function while enabling adequate mitochondrial transport to accommodate local energy demands unique to neuronal architecture. Abnormal regulation of mitochondrial dynamics has been increasingly implicated in neurodegeneration, where elevated levels of p53 may have a direct contribution as the expression of some fission/fusion proteins are directly regulated by p53. Thus, p53 may have a much wider influence on mitochondrial integrity and function than one would expect from its well-established ability to transcriptionally induce mitochondrial apoptosis. However, much of the evidence demonstrating that p53 can influence mitochondria through nuclear, cytosolic or intra-mitochondrial sites of action has yet to be confirmed in neurons. Nonetheless, as mitochondria are essential for supporting normal neuronal functions and in initiating/propagating cell death signaling, it appears certain that the mitochondria-related functions of p53 will have broader implications than previously thought in acute and progressive neurological conditions, providing new therapeutic targets for treatment. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction and Neurodegenerative Diseases.
    Preview · Article · Jan 2014 · Biochimica et Biophysica Acta
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    • "Schuessel et al. (2005) found that the activity of Cu/ZnSOD did not change in brains from male Thy1-APP751 SL mice as compared to WT mice. In contrast, Sompol and colleagues demonstrated that developing APP/PS1 neurons have increased MnSOD protein and activity, and mature APP/PS1 neurons exhibited lower MnSOD levels compared to mature WT neurons (Sompol et al., 2008). Here, we show that SOD activity in brain showed a trend, but not a statistically-significant reduction in APP/PS1 mice vs. WT mice. "
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    ABSTRACT: Increasing evidence demonstrates that β-amyloid (Aβ) elicits oxidative stress, which contributes to the pathogenesis and disease progression of Alzheimer's disease (AD). Thus, there is interest in developing antioxidant therapies for the prevention/treatment of cognitive decline during AD. We reported previously that puerarin has antioxidative properties in vitro. Therefore, the aim of the present study was to determine whether puerarin improves cognitive function and reduces oxidative stress in amyloid precursor protein/presenilin-1 (APP/PS1) mice, a well established AD mouse model, and explore its potential mechanism. Our results show that oral administration of puerarin significantly ameliorates cognitive impairment in APP/PS1 mice assessed by the Morris water maze (MWM) test. This was accompanied by a significant decrease in the levels of lipid peroxidation (LPO) through, at least in part, induction of nuclear factor erythroid 2-related factor 2 (Nrf2) target gene heme oxygenase 1 (HO-1) in the hippocampus of APP/PS1 transgenic mice at 9 months of age, but without altering brain Aβ burden. Furthermore, puerarin significantly activated Akt, reduced activation of glycogen synthase kinase 3β (GSK-3β), and induced nuclear translocation of Nrf2 in the hippocampus of APP/PS1 mice but did not alter ERK1/2 phosphorylation. Thus, puerarin may improve cognitive performance in APP/PS1 mice through activation of the Akt/GSK-3β signaling pathway. These findings suggest that puerarin might be an attractive agent for prevention and treatment of cognitive impairment and dementia.
    Preview · Article · Dec 2013 · The International Journal of Neuropsychopharmacology
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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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