Protective effects of Peroxiredoxin 6 overexpression on amyloid β-induced apoptosis in PC12 cells
Free Radical Research (Impact Factor: 2.98). 08/2013; 47(10). DOI: 10.3109/10715762.2013.833330
Abstract Oxidative stress triggered by amyloid β (Aβ) accumulation contributes substantially to the pathogenesis of Alzheimer's disease (AD). In the present study, we examined the involvement of the antioxidant activity of peroxiredoxin 6 (Prdx 6) in protecting against Aβ25-35-induced neurotoxicity in rat PC12 cells. Treatment of PC12 cells with Aβ25-35 resulted in a dose- and time-dependent cytotoxicity that was associated with increased accumulation of intracellular reactive oxygen species (ROS) and mitochondria-mediated apoptotic cell death, including activation of caspase 3/9, inactivation of poly ADP-ribosyl polymerse (PARP), and dysregulation of Bcl-2 and Bax. This apoptotic signaling machinery was markedly attenuated in PC12 cells that overexpress wild-type Prdx 6, but not in cells that overexpress the C47S catalytic mutant of Prdx 6. This indicates that the peroxidase activity of Prdx 6 protects PC12 cells from Aβ25-35-induced neurotoxicity. The neuroprotective role of the antioxidant Prdx 6 suggests its therapeutic and/or prophylactic potential to slow the progression of AD and limit the extent of neuronal cell death caused by AD.
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- "In addition to antibodybased treatment approaches, which modulate and/or remove abnormally misfolded protein aggregates (Pankiewicz et al., 2010; Sadowski et al., 2009), other strategies to protect cells at the mitochondrial level by stabilizing or restoring mitochondrial and redox function or by interfering with energy metabolism warrant attention. Our study supports the potential utility of targeted Prdx6 augmentation as a novel adjunct treatment for neurodegenerative diseases (Pak et al., 2011; Tulsawani et al., 2010), and encouragingly results in the AD field also supports this notion (Kim et al., 2013). 2. Experimental procedures Ethics Statement: All procedures involving animals were approved by the Institutional Animal Care and Use Committee of the New York University and were performed in accordance with the U "
ABSTRACT: Protein misfolding, mitochondrial dysfunction and oxidative stress are common pathomechanisms that underlie neurodegenerative diseases. In prion disease, central to these processes is the post-translational transformation of cellular prion protein (PrP(c)) to the aberrant conformationally altered isoform; PrP(Sc). This can trigger oxidative reactions and impair mitochondrial function by increasing levels of peroxynitrite, causing damage through formation of hydroxyl radicals or via nitration of tyrosine residues on proteins. The 6 member Peroxiredoxin (Prdx) family of redox proteins are thought to be critical protectors against oxidative stress via reduction of H2O2, hydroperoxides and peroxynitrite. In our in vitro studies cellular metabolism of SK-N-SH human neuroblastoma cells was significantly decreased in the presence of H2O2 (oxidative stressor) or CoCl2 (cellular hypoxia), but was rescued by treatment with exogenous Prdx6, suggesting that its protective action is in part mediated through a direct action. We also show that CoCl2-induced apoptosis was significantly decreased by treatment with exogenous Prdx6. We proposed a redox regulator role for Prdx6 in regulating and maintaining cellular homeostasis via its ability to control ROS levels that could otherwise accelerate the emergence of prion-related neuropathology. To confirm this, we established prion disease in mice with and without astrocyte-specific antioxidant protein Prdx6, and demonstrated that expression of Prdx6 protein in Prdx6 Tg ME7-animals reduced severity of the behavioural deficit, decreased neuropathology and increased survival time compared to Prdx6 KO ME7-animals. We conclude that antioxidant Prdx6 attenuates prion-related neuropathology, and propose that augmentation of endogenous Prdx6 protein represents an attractive adjunct therapeutic approach for neurodegenerative diseases.Neurochemistry International 08/2015; DOI:10.1016/j.neuint.2015.08.006 · 3.09 Impact Factor
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- "The role of Prx6 is less clear; on the one hand, apoptosis was inhibited after amyloid beta treatment in PC12 cells overexpressing wild-type Prx6, but not in cells that overexpressed the C47S catalytic mutant. This indicates that the peroxidase activity of Prx6 protects PC12 cells from amyloid-induced neurotoxicity . However, in a mouse model after amyloid beta infusion, memory impairment in Prx6 transgenic mice was worse than C57BL/6 mice. "
ABSTRACT: This review provides an overview of the biochemistry of thiol redox couples and the significance of thiol redox homeostasis in neurodegenerative disease. The discussion is centred on cysteine/cystine redox balance, the significance of the xc(-) cystine-glutamate exchanger and the association between protein thiol redox balance and neurodegeneration, with particular reference to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and glaucoma. The role of thiol disulphide oxidoreductases in providing neuroprotection is also discussed. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.04/2015; 5:186-194. DOI:10.1016/j.redox.2015.04.004
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ABSTRACT: On a global basis, at least 15 million individuals suffer some form of a stroke every year. Of these individuals, approximately 800,000 of these cerebrovascular events occur in the United States (US) alone. The incidence of stroke in the US has declined from the third leading cause of death to the fourth, a result that can be attributed to multiple factors that include improved vascular disease management, reduced tobacco use, and more rapid time to treatment in patients that are clinically appropriate to receive recombinant tissue plasminogen activator. However, treatment strategies for the majority of stroke patients are extremely limited and represent a critical void for care. A number of new therapeutic considerations for stroke are under consideration, but it is the mammalian target of rapamycin (mTOR) that is receiving intense focus as a potential new target for cerebrovascular disease. As part of the phosphoinositide 3-kinase (PI 3-K) and protein kinase B (Akt) cascade, mTOR is an essential component of mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) to govern cell death involving apoptosis, autophagy, and necroptosis, cellular metabolism, and gene transcription. Vital for the consideration of new therapeutic strategies for stroke is the ability to understand how the intricate and complex pathways of mTOR signaling sometimes lead to disparate clinical outcomes.Current neurovascular research 04/2014; 11(2). DOI:10.2174/1567202611666140408104831 · 2.25 Impact Factor
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