Evidence of oxidative damage in Alzeimer’s disease brain: Central role for amyloid β-peptide

Dept of Chemistry, Center of Membrane Sciences and Sanders-Brown Center on Aging, University of Kentucky, Lexington 40506-0055, USA.
Trends in Molecular Medicine (Impact Factor: 9.45). 01/2002; 7(12):548-54. DOI: 10.1016/S1471-4914(01)02173-6
Source: PubMed


Amyloid beta-peptide (Abeta) is heavily deposited in the brains of Alzheimer's disease (AD) patients. Free-radical oxidative stress, particularly of neuronal lipids, proteins and DNA, is extensive in those AD brain areas in which Abeta is abundant. Recent research suggests that these observations might be linked, and it is postulated that Abeta-induced oxidative stress leads to neurodegeneration in AD brain. Consonant with this postulate, Abeta leads to neuronal lipid peroxidation, protein oxidation and DNA oxidation by means that are inhibited by free-radical antioxidants. Here, we summarize current research on phospholipid peroxidation, as well as protein and DNA oxidation, in AD brain, and discuss the potential role of Abeta in this oxidative stress.

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Available from: Alessandra Castegna, May 26, 2015
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    • "ONOO − is responsible for a wide spread biological damage in the brains of AD [6] [35]. A, the principal component of the senile plaques, is the main cause of increased ONOO − in the brain of AD [5] [41]. "
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    • "Most reactive oxygen species (ROS) are generated during respiration in mitochondria as by-products of electron transport and oxidative phosphorylation (Kirkinezos and Moraes, 2001). Excessive production and accumulation of ROS by Ab can cause functional and structural damage to various biomolecules leading to DNA cleavage, protein oxidation, and lipid peroxidation, as well as altered signal transduction , ultimately resulting in cellular dysfunction and apoptosis (Butterfield et al., 2001). Controlling ROS production and/or scavenging may be therapeutically beneficial in the treatment of neurodegenerative diseases such as AD. "
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    ABSTRACT: Sulfuretin, one of the major flavonoid glycosides found in the stem bark of Albizzia julibrissin and heartwood of Rhus verniciflua, is a known anti-oxidant. We previously demonstrated that sulfuretin inhibits neuronal death via reactive oxygen species (ROS)-dependent mechanisms in cultured cells, although other relevant mechanisms of action of this compound remain largely uncharacterized. As part of our ongoing exploration of the pharmacological actions of sulfuretin, we studied the neuroprotective effects of sulfuretin against amyloid beta (Aβ)-induced neurotoxicity in neuronal cells and investigated the possible mechanisms involved. Specifically, we found in the present study that sulfuretin significantly attenuates the decrease in cell viability, release of lactate dehydrogenase (LDH), and accumulation of ROS associated with Aβ25-35-induced neurotoxicity in neuronal cells. Furthermore, sulfuretin stimulated the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a downstream target of phosphatidylinositol 3-kinases (PI3K)/Akt. We demonstrated that sulfuretin induces the expression of heme oxygenase-1 (HO-1), an anti-oxidant response gene. Notably, we found that the neuroprotective effects of sulfuretin were diminished by an Nrf2 small interfering RNA (siRNA), the HO-1 inhibitor zinc protoporphyrin IX (ZnPP), as well as the PI3K/Akt inhibitor LY294002. Taken together, these results indicated that sulfuretin protects neuronal cells from Aβ25-35-induced neurotoxicity through activation of Nrf/HO-1 and PI3K/Akt signaling pathways. Our results also indicate that sulfuretin-induced induction of Nrf2-dependent HO-1 expression via the PI3K/Akt signaling pathway has preventive and/or therapeutic potential for the management of Alzheimer's disease (AD). Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 07/2015; 304. DOI:10.1016/j.neuroscience.2015.07.030 · 3.36 Impact Factor
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    • "Reactive oxygen species (ROS) production and Platelet-Activating Factor (PAF) play a central role in the events mediating the toxic action of amyloid aggregates, but the precise molecular mechanism is not still completely understood [Mattson, 1999; Butterfield et al., 2001; Kadowaki et al., 2005; Glabe and Kayed, 2006; Demuro et al., 2010; Jomova et al., 2010]. In hippocampal neuronal cultures, both H 2 O 2 and PAF were able to reproduce each of the events induced by oligomeric Ab1–42, including triggered sustained Ca 2þ influx via N-methyl-D-aspartic acid receptors, enhanced extracellular accumulation of glutamate, and increase in cytosolic free Ca 2þ [Shi et al., 2010]. "
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    Journal of Cellular Biochemistry 12/2014; 15(12). DOI:10.1002/jcb.24888 · 3.26 Impact Factor
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