The lipid peroxidation product 4-hydroxy-2-nonenal (HNE) is proposed to be a toxic factor in the pathogenesis of Alzheimer disease. The primary products of lipid peroxidation are phospholipid hydroperoxides, and degraded reactive aldehydes, such as HNE, are considered secondary peroxidation products. In this study, we investigated the role of amyloid-beta peptide (A beta) in the formation of phospholipid hydroperoxides and HNE by copper ion bound to A beta. The A beta1-42-Cu2+ (1:1 molar ratio) complex showed an activity to form phospholipid hydroperoxides from a phospholipid, 1-palmitoyl-2-linoleoyl phosphatidylcholine, through Cu2+ reduction in the presence of ascorbic acid. The phospholipid hydroperoxides were considered to be a racemic mixture of 9-hydroperoxide and 13-hydroperoxide of the linoleoyl residue. When Cu2+ was bound to 2 molar equivalents of A beta(1-42) (2 A beta1-42-Cu2+), lipid peroxidation was inhibited. HNE was generated from one of the phospholipid hydroperoxides, 1-palmitoyl-2-(13-hydroperoxy-cis-9, trans-11-octadecadienoyl) phosphatidylcholine (PLPC-OOH), by free Cu2+ in the presence of ascorbic acid through Cu2+ reduction and degradation of PLPC-OOH. HNE generation was markedly inhibited by equimolar concentrations of A beta(1-40) (92%) and A beta(1-42) (92%). However, A beta(1-42) binding 2 or 3 molar equivalents of Cu2+ (A beta1-42-2Cu2+, A beta1-42-3Cu2+) acted as a pro-oxidant to form HNE from PLPC-OOH. These findings suggest that, at moderate concentrations of copper, A beta acts primarily as an antioxidant to prevent Cu2+-catalyzed oxidation of biomolecules, but that, in the presence of excess copper, pro-oxidant complexes of A beta with Cu2+ are formed.
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"First, since iron and copper are suggested to play an important role in the self-assembly and neurotoxicity of Ab (Atwood et al., 2004; Bush et al., 1994; Exley, 2006; Hayashi et al., 2007; Jobling et al., 2001; Nakamura et al., 2007), Ab toxicity is expectedly attenuated by such chelators (Huang et al., 1999; Opazo et al., 2002; Rottkamp et al., 2001; Schubert & Chevion, 1995). In fact, the ability of Ab to sequestrate redox metals likely explains conflicting in vivo and in vitro reports demonstrating Ab as both oxidant (Behl, Davis, Cole, & Schubert, 1992) and antioxidant (Hayashi et al., 2007; Nakamura et al., 2007; Nunomura et al., 2001; Smith, Casadesus, Joseph, & Perry, 2002). Second, redox metals, as redoxactive centers, lead to free radical generation (Bishop et al., 2002; Castellani et al., 2007; Sayre et al., 2000; Smith et al., 1997) and oxidative stress, which contribute to the initiation and promotion of neurodegeneration (Casadesus et al., 2004; Markesbery, 1997; Perry et al., 1998; Smith et al., 1995). "
", Cu 2+ binds to A and elicits similar response in terms of activation of A aggregation, H 2 O 2 generation and other oxidative stress-mediated neuronal toxicity   . Specifically, Cu 2+ has high binding affinity towards A at His13, His14, His6 and Tyr10 residues . "
[Show abstract][Hide abstract] ABSTRACT: Curcumin (diferuloylmethane), a polyphenol extracted from the plant Curcuma longa, is widely used in Southeast Asia, China and India in food preparation and for medicinal purposes. Since the second half of the last century, this traditional medicine has attracted the attention of scientists from multiple disciplines to elucidate its pharmacological properties. Of significant interest is curcumin's role to treat neurodegenerative diseases including Alzheimer's disease (AD), and Parkinson's disease (PD) and malignancy. These diseases all share an inflammatory basis, involving increased cellular reactive oxygen species (ROS) accumulation and oxidative damage to lipids, nucleic acids and proteins. The therapeutic benefits of curcumin for these neurodegenerative diseases appear multifactorial via regulation of transcription factors, cytokines and enzymes associated with (Nuclear factor kappa beta) NFκB activity. This review describes the historical use of curcumin in medicine, its chemistry, stability and biological activities, including curcumin's anti-cancer, anti-microbial, anti-oxidant, and anti-inflammatory properties. The review further discusses the pharmacology of curcumin and provides new perspectives on its therapeutic potential and limitations. Especially, the review focuses in detail on the effectiveness of curcumin and its mechanism of actions in treating neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and brain malignancies.
Current Neuropharmacology 07/2013; 11(4):338-78. DOI:10.2174/1570159X11311040002 · 3.05 Impact Factor
"An accumulation of products of free radical damage in central nervous system (CNS) in subjects with ATD has been described (Butterfield et al., 2006, 2007; Mangialasche et al., 2009) and it is believe that oxidative damage to critical molecules occurs early in the pathogenesis of ATD; perhaps is the earliest feature of an ATD brain (Nunomura et al., 2001; Zhu et al., 2001, 2004, 2007) and precedes pronounced neuropathological alterations (Baldeiras et al., 2008; Lovell and Markesbery, 2007; Nunomura et al., 2001). In fact, some evidences have suggested that the ß-amyloid deposition in ATD neurons may be considered as an effort to protect these cells against damage due to oxidative stress (Bonda et al., 2010; Hayashi et al., 2007; Nakamura et al., 2007). Enzymatic and non-enzymatic defense systems are responsible to maintain an adequate oxidative state. "
[Show abstract][Hide abstract] ABSTRACT: It is well known that oxidative stress is one of the earliest events in Alzheimer's disease pathogenesis, indicating that may play a key role in this disease. In our study, we measured the levels of oxidative stress indicators (TBARS and protein carbonyls content) and the non-enzymatic (glutathione (GSH) and oxidized glutathione (GSSG)) and enzymatic (glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD)) defense systems in the plasma of 46 patients diagnosed of ATD and 46 age-matched controls. We found decreased levels in total GSH in ATD patients, although healthy control women showed lower levels of total GSH than healthy control men. On the contrary, we found increased levels of TBARS and carbonyl groups content in ATD patients in both genders. The activity of the plasma antioxidant enzymes showed no changes for SOD activity in ATD patients, independently of the gender, although western blot analysis showed an increase in SOD-1 protein. CAT activity was also decreased in ATD patients, although this decrease is mainly due to the decrease found in men but not in women. However, western blot analysis did not show differences in CAT protein between controls and ATD patients. Finally, a decrease of GPx activity was found in ATD patients in both genders. However, as with CAT protein, western blot analysis did not show differences in GPx protein between controls and ATD patients. Our results suggest that there is a defect in the antioxidant defense system that is incapable of responding to increased free radical production, which may lead to oxidative damage and the development of the pathological alterations that characterize the neurodegenerative disorder of patients with ATD. Thus, oxidative damage could be one important aspect for the onset of ATD and oxidative stress markers could be useful to diagnose the illness in their earliest stages through both non-invasive, reliable and cost-affordable methods.