Review Oxidative stress in Alzheimer's disease brain: New insights from redox proteomics D. Allan Butterfield a,b,c, ⁎ , Marzia Perluigi a,d , Rukhsana Sultana a,b a Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA b Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA c Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA d Department of Biochemical Sciences, University of Rome “La Sapienza”, 00185 Rome, Italy Accepted 13 June 2006 Available online 15 June 2006 Abstract Alzheimer's disease, an age-related neurodegenerative disorder, is characterized clinically by a progressive loss of memory and cognitive functions. Neuropathologically, Alzheimer's disease is defined by the accumulation of extracellular amyloid protein deposited senile plaques and intracellular neurofibrillary tangles made of abnormal and hyperphosphorylated tau protein, regionalized neuronal death, and loss of synaptic connections within selective brain regions. Evidence has suggested a critical role for amyloid-β peptide metabolism and oxidative stress in Alzheimer's disease pathogenesis and progression. Among the other indices of oxidative stress in Alzheimer's disease brain are protein carbonyls and 3-nitrotyrosine, which are the markers of protein oxidation. Thus, in this review, we discuss the application of redox proteomics for the identification of oxidatively modified proteins in Alzheimer's disease brain and also discuss the functions associated with the identified oxidized proteins in relation to Alzheimer's disease pathology. The information obtained from proteomics may be helpful in understanding the molecular mechanisms involved in the development and progression of Alzheimer's disease as well as of other neurodegenerative disorders. Further, redox proteomics may provide potential targets for drug therapy in Alzheimer's disease. © 2006 Elsevier B.V. All rights reserved. Keywords: Redox proteomics; Alzheimer's disease; Oxidative stress; Protein oxidation; Hippocampus; Inferior parietal lobule Contents 1. Introduction ............................................................... 40 2. Proteomics ............................................................... 41 2.1. Two-dimensional electrophoresis (2-DE) ............................................ 41 2.2. Mass spectrometry and data base searching ........................................... 42 3. Redox proteomics in Alzheimer's disease ............................................... 42 3.1. Alzheimer's disease brain tissues ................................................ 43 3.2. Oxidative modifications of proteins in Alzheimer's disease ................................... 43 3.2.1. Energy dysfunction ................................................... 44 3.2.2. Excitotoxicity...................................................... 44 3.2.3. Proteosomal dysfunction ................................................ 45 3.2.4. Cholinergic alterations and lipid asymmetry changes ................................. 45 3.2.5. Neuritic abnormalities ................................................. 45 European Journal of Pharmacology 545 (2006) 39 – 50 www.elsevier.com/locate/ejphar ⁎ Corresponding author. Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA. Tel.: +1 859 257 3184; fax: +1 859 257 5876. E-mail address: dabcns@uky.edu (D.A. Butterfield). 0014-2999/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2006.06.026