Oxidative Stress Induces Increase in Intracellular Amyloid β-Protein Production and Selective Activation of βI and βII PKCs in NT2 Cells

Paola, Dimitri; Domenicotti, Cinzia; Nitti, Mariapaola; Vitali, Antonella; Borghi, Roberta; Cottalasso, Damiano; Zaccheo, D; Odetti, Patrizio; Strocchi, Paola; Marinari, Umberto M.; Tabaton, Massimo; Pronzato, Maria Adelaide

doi:10.1006/bbrc.2000.2756

Cited by 126 publications

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“…Since apoD provides lipid antioxidant protection in the brain (Ganfornina et al, 2008), one plausible mechanistic explanation could be due to the secondary regulation of A production by brain lipid oxidation products. Previous studies have shown that oxidative stress and the products of lipid peroxidation, HNE in particular, up-regulate the expression of BACE1 leading to increased neuronal A production (Paola et al, 2000;Tamagno et al, 2005). This would be consistent with the increase in BACE1 protein levels we observed in the APP-PS1/DKO mice as compared to their APP-PS1 littermates (Fig.…”

Section: Discussionsupporting

confidence: 90%

Apolipoprotein D modulates amyloid pathology in APP/PS1 Alzheimer's disease mice

Liu

Ruberu

Muñoz

et al. 2015

Neurobiology of Aging

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Apolipoprotein D (apoD) is expressed in the brain and levels are increased in affected brain regions in Alzheimer's disease (AD). The role that apoD may play in regulating AD pathology has not been addressed. Here, we crossed both apoD-null mice and Thy-1 human apoD transgenic mice with APP-PS1 amyloidogenic AD mice. Loss of apoD resulted in a nearly 2-fold increase in hippocampal amyloid plaque load, as assessed by immunohistochemical staining. Conversely, transgenic expression of neuronal apoD reduced hippocampal plaque load by approximately 35%. This latter finding was associated with a 60% decrease in amyloid β 1-40 peptide levels, and a 34% decrease in insoluble amyloid β 1-42 peptide. Assessment of β-site amyloid precursor protein cleaving enzyme-1 (BACE1) levels and proteolytic products of amyloid precursor protein and neuregulin-1 point toward a possible association of altered BACE1 activity in association with altered apoD levels. In conclusion, the current studies provide clear evidence that apoD regulates amyloid plaque pathology in a mouse model of AD. Disciplines Medicine and Health Sciences Publication DetailsLi, H., Ruberu, K., Sanz Munoz, S., Jenner, A. M., Spiro, A., Zhao, H., Rassart, E., Sanchez, D., Ganfornina, M. peptide levels, and a 34% decrease in insoluble amyloid-beta 1-42 peptide. Assessment of beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) levels and proteolytic products of amyloid precursor protein and neuregulin-1 point towards a possible association of altered BACE1 activity in association with altered apoD levels. In conclusion, the current studies provide clear evidence that apoD regulates amyloid plaque pathology in a mouse model of AD.

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Section: Discussionsupporting

confidence: 90%

Apolipoprotein D modulates amyloid pathology in APP/PS1 Alzheimer's disease mice

Liu

Ruberu

Muñoz

et al. 2015

Neurobiology of Aging

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“…To eliminate these free radicals, neurons may initiate mechanisms for the prevention of oxidative damage. Interestingly, some studies suggest that Aβ is initially a compensation for overwhelming concentrations of ROS [97,98] . Aβ has antioxidant activity and protects lipoproteins from oxidation in the CSF and plasma; and patients with Down syndrome with the most severe Aβ deposition show the lowest levels of 8-OHG, while neurons lacking Aβ pathology have significantly higher levels of 8-OHG [99] .…”

Section: Oxidative Stress Is An Important Contributor To the Pathologmentioning

confidence: 99%

Oxidative stress in Alzheimer’s disease

2014

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Oxidative stress plays a significant role in the pathogenesis of Alzheimer's disease (AD), a devastating disease of the elderly. The brain is more vulnerable than other organs to oxidative stress, and most of the components of neurons (lipids, proteins, and nucleic acids) can be oxidized in AD due to mitochondrial dysfunction, increased metal levels, infl ammation, and β-amyloid (Aβ) peptides. Oxidative stress participates in the development of AD by promoting Aβ deposition, tau hyperphosphorylation, and the subsequent loss of synapses and neurons. The relationship between oxidative stress and AD suggests that oxidative stress is an essential part of the pathological process, and antioxidants may be useful for AD treatment.Keywords: Alzheimer's disease; oxidative stress; β-amyloid; tau; metals; antioxidants ·Review· IntroductionThe human brain, although it constitutes only 2% of the body weight, consumes ~20% of the oxygen supplied by the respiratory system [1] . The high energy-consumption of the brain means that it is more susceptible to oxidative stress than any other organ. As the basic functional unit of the brain, the neuron is particularly vulnerable to oxidative damage because it has a higher metabolic rate than other cells [2] . The oxidation of lipids, proteins, and nucleic acids in neurons is a common pathological feature of Alzheimer's disease (AD) [3] . Neurons contain a large amount of polyunsaturated fatty acids (PUFAs) that can interact with reactive oxygen species (ROS), leading to a selfpropagating cascade of lipid peroxidation and molecular destruction [4] . Furthermore, neurons contain low levels of glutathione, an essential antioxidant for eliminating free radicals [5] . Therefore, neurons are highly susceptible to oxidative stress.An increased oxidative burden has been reported in the brains of non-demented elderly and/or sporadic AD patients [6,7] . Increased levels of oxidative stress biomarkers in the blood reflect such stress in the brain [8,9] . Currently, many blood markers of oxidative stress have been identified in AD patients or related animal models, including protein carbonyls and 3-nitrotyrosine [10,11] , , malondialdehyde (MDA) [12] , 4-hydroxynonenal (4-HNE), and F2-isoprostanes (F2-IsoPs) [13][14][15][16] . Apart from the intracellular accumulation of free radicals, changes in the activities or expressions of antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, have also been described in both the central nervous system and peripheral tissues of AD patients [14,17] . Thus, oxidative stress is an important pathological feature in AD.However, how and where the oxidative stress originates in AD are open questions. Research has suggested that mitochondrial dysfunction [12,18,19] , metal accumulation [12,20,21] , hyperphosphorylated tau [22,23] , inflammation [24,25] , and β-amyloid (Aβ) accumulation [12,19] are the basic mechanisms underlying the induction of oxidative stress. Deficiency or destruction of components of the antioxidant system such as SOD in the mi...

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“…There are additional links between intracellular production of Aβ and oxidant stress. In studies with NT2 cells, incubation with 4-hydroxy-2,3-nonenal resulted in elevated levels of intracellular Aβ [48]. These data, though fragmentary and principally in cell culture, suggest linkage between generation of intracellular Aβ and oxidant stress.…”

Section: Oxidant Stress In Admentioning

confidence: 89%

Mitochondrial amyloid-beta peptide: Pathogenesis or late-phase development?

Yan

Xiong

Stern

2006

JAD

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Abstract. Mitochondrial and metabolic dysfunction have been linked to Alzheimer's disease for some time. Key questions regarding this association concern the nature and mechanisms of mitochondrial dysfunction, and whether such changes in metabolic properties are pathogenic or secondary, with respect to neuronal degeneration. In terms of mitochondria and Alzheimer's, altered function could reflect intrinsic properties of this organelle, potentially due to mutations in mitochondrial DNA, or extrinsic changes secondary to signal transduction mechanisms activated in the cytosol. This review presents data relevant to these questions, and considers the implication of recent findings demonstrating the presence of amyloid-β peptide in mitochondria, as well as intra-mitochondrial molecular targets with which it can interact. Regardless of the underlying mechanism(s), it is likely that mitochondrial dysfunction contributes to oxidant stress which is commonly observed in brains of patients with Alzheimer's and transgenic models of Alzheimer's-like pathology.

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Oxidative Stress Induces Increase in Intracellular Amyloid β-Protein Production and Selective Activation of βI and βII PKCs in NT2 Cells

Cited by 126 publications

References 0 publications

Apolipoprotein D modulates amyloid pathology in APP/PS1 Alzheimer's disease mice

Apolipoprotein D modulates amyloid pathology in APP/PS1 Alzheimer's disease mice

Oxidative stress in Alzheimer’s disease

Mitochondrial amyloid-beta peptide: Pathogenesis or late-phase development?

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