Arch Neurosci. 2014 July; 2(3): e20078. DOI: 10.5812/archneurosci.20078 Published online 2014 July 30. Review Article Oxidative Stress Gated by Fenton and Haber Weiss Reactions and Its Association With Alzheimer’s Disease Tushar Kanti Das 1 ; Mas Rina Wati 1 ; Kaneez Fatima-Shad 2,* 1 Institute of Health Sciences, University Brunei Darussalam, Brunei Darussalam, Brunei 2 School of Medical and Molecular Biosciences, Faculty of Science, University Technology Sydney, Sydney, Australia *Corresponding author: Kaneez Fatima-Shad, School of Medical and Molecular Biosciences, Faculty of Science, University Technology Sydney, Sydney, Australia. Tel: +61-4320644886, E-mail: KaneezFatima-Shad@uts.edu.au Received: May 29, 2014; Revised: Jun 15, 2014; Accepted:Jun 17, 2014 Context: Involvement of reactive oxygen species (ROS) in a variety of physiological and pathological processes has attracted a growing interest. In fact, identification of this global signaling system has provided new insights into underlying pathophysiological mechanisms of various diseases such as Alzheimer’s disease (AD). Understanding this information may lead to the development of novel therapeutic strategies. Evidence Acquisitions: Limited efficacy of current medications for neurological disorders and dementias such as AD has led to considerable research interests in new drug development. Based on the modulatory effects of the Fenton reactions with transition metals such as iron, copper, zinc and aluminum on ROS and the effect of free radicals on neuroinflammatory and neurodegenerative processes, we hypothesized that pharmacological manipulation of the transition metals gated hydroxyl ion might be beneficial in treating neurological disorders such as AD. Results: Catalytic activities of transition metals gated by the Fenton reactions are involved in the survival and pathological signaling pathways, neural plasticity, and neuroprotection. Furthermore, ROS and RNS have proved to exhibit overwhelming pathological effects leading to a variety of neurological disorders. Conclusions: In the present investigation, an overview was made on regulatory role of the Fenton reaction gated catalytic activities of transition metals and some evidence regarding their mechanisms leading to Alzheimer’s disease. Based on the neuroinflammatory and neurodegenerative effects of transition metals, drugs with antagonizing effects could be a promising therapeutic alternative for Alzheimer’s disease. Keywords:Fenton Haber Weiss Reactions; Reactive Oxygen Species; Metals; Alzheimer’s disease Copyright © 2014, Tehran University of Medical Sciences; Published by Kowsar. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited. 1. Context The Fenton and Haber Weiss reaction plays a significant role in oxidative stress causing numerous degenerative diseases such as Alzheimer’s disease (AD). Reactive oxy- gen species (ROS) and reactive nitrogen species (RNS) are produced by the reaction causing oxidative stress in AD. Iron, copper and aluminum promote the formation of free radicals such as Hydroxyl radicals causing dam- age to DNA, proteins, lipids and carbohydrates. Hydrox- yl radicals produced by Fenton reaction, causes the Aβ42 toxicity (1, 2) in AD. Hydroxyl radicals can be produced in the presence of Ferric ions and converts soluble hu- man fibrinogen into an insoluble fibrin- like aggregate observed in neurodegenerative diseases such as AD (3). DNA bases can be modified by the Fenton gated oxida- tive stress and base substitutions G→C (in the presence of Ferrous), G→T and C→T (Copper and Nickel) (4) by the reaction with ROS. Signal transduction molecules, such as extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-Jun N -terminal kinase (JNK), phosphoinosit- ide 3- kinase (PI3K), p38 and transcription factors such as activator protein-1(AP-1), and p53 are activated by ROS (4, 5). Hydroxyl radicals can damage DNA by p53 pathway and accelerate AD development. Mutation in tumor sup- pressor gene (TP53) is associated with AD pathogenesis (2, 6). Oxidative stress is mainly produced by the Fenton re- action by removal of one electron from the molecular oxygen (O 2 ) results in the formation of superoxide (O 2- ) which often produces other ROS species such as H 2 O 2 and Peroxynitrite (ONOO)-and hydroxyl radicals (OH) (7). However under normal conditions, O 2- has been emerged as an important signaling molecule, which controls specific biochemical reactions and metabolic processes (8). The link between O 2- production and H 2 O 2 can involve a reduced flavin enzyme, which transfers an electron to activate molecular oxygen into superoxide which either released or enzymatically converted into H2O2 (9, 10) or modified by drugs such as statins (11). One of the greatest challenges in the field of ROS-gated diseases is to bridge the knowledge gap between atomic