Department of Chemistry and Faculty Associate, Sanders-Brown Center on Aging
Free radical oxidative stress is a hallmark of aging and age-related neurodegenerative disorders such as Alzheimer's disease (AD). Such oxidative stress is manifested in neurons by protein oxidation, lipid peroxidation, reactive oxygen species (ROS) production, mitochondrial dysfunction, and functional impairment of key transmembrane transport proteins, among many others. Our laboratory studies these and other aspects of oxidative stress in brain membranes using a variety of techniques, including magnetic resonance (both EPR and NMR), fluorescence, chemiluminescence, Western blotting, HPLC analysis, enzyme kinetics, etc. Our group has described how oxidative stress associated with amyloid b-peptide, a 42-amino acid peptide deposited in AD brains, leads to neurotoxicity and how various antioxidants can modulate or prevent this oxidative stress and neuronal death. For example, the figure, illustrating results from confocal laser fluorescence microscopy, shows how Ab leads to ROS formation in neurons, but the free radical antioxidant vitamin E markedly inhibits this oxidation. Insight into the molecular basis for and potential therapeutic interventions in aging and age-related neurodegenerative disorders is envisaged from our research.
Our laboratory is the first to use proteomics to identify oxidatively modified brain proteins in subjects with AD and, arguably, its earliest form, mild cognitive impairment (MCI). Proteins identified have provided new insights into molecular processes involved in mechanisms of neuronal death in and progression of AD.
Αb(1-42) Added to Neurons Induces ROS that are Blocked by Vitamin E
Processes involved in redox proteomics, which is used to identify oxidatively modified brain proteins in Alzheimer's disease and other neurodegenerative disorders.
W.O. Opii, E. Head, D.M. Turner, W.M. Pierce and D.A. Butterfield, "Proteomic Expression Analysis of Brain Proteins Form Dementia Free Nonagenarians: Relevance to Successful Aging and Alzheimer's Disease," manuscript in preparation (2010).
R. Sultana, G. Cenini, and D.A. Butterfield, "SAMP8: A Model to Understand the Role of Oxidative Stress in Age-Related Diseases Including Alzheimer's Disease," in The Senescence Accelerated Mouse (SAM): Achievements and Future Directions, (T. Takeda, Ed.), SAM Foundation Press, Tokyo, in press (2010).
S.S. Hardas, D.A. Butterfield, R. Sultana, M. Dan, R.L. Florence, J.M. Unrine, U.M. Graham, P. Wu, E.A. Grulke, M.T. Tseng, and R.A. Yokel, "Brain Distribution and Toxicological Evaluation of a Systemically Delivered Engineered Nanoscale Ceria," Toxicological Sciences, in press (2010).
F. Di Domenico, R. Sultana, G.F. Tiu, N.N. Scheff, M. Perluigi, C. Cini, D.A. Butterfield, "Protein Levels of Heat Shock Proteins 27, 32, 60, 70, 90 and Thioredoxin-1 in Amnestic Mild Cognitive Impairment: An Investigation on the Role of Cellular Stress Response in the Progression of Alzheimer's Disease," Brain Research, in press (2010).
Q. Huang, C, Aluise, G. Joshi, R. Sultana, D. St. Clair, W. Markesbery, D.A. Butterfield, "Potential in vivo amelioration by N-acetyl-L-cysteine of oxidative stress in brain in human double mutant APP/PS-1 knock-in mice: Towards therapeutic modulation of mild cognitive impairment (MCI)," Journal of Neuroscience Research, in press (2010).
M. Perluigi, F. Di Domenico, C. Blarzino, C. Foppoli, C. Cini, A. Giorgi, C. Grillo, F. De Marco, D.A. Butterfield, M.E. Schininna, and R. Coccia, "Effects of EVB-Induced Oxidative Stress on Protein Expression and Specific Protein Oxidation in Normal Human Epithelial Keratinocytes: A Proteomics Approach," Proteome Science, in press (2010).
D.A. Butterfield, S.S. Hardas and M.L. Bader Lange, "Oxidatively Modified Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) and Alzheimer Disease: Many Pathways to Neurodegeneration," Journal of Alzheimer's Disease, in press (2010).
C.D. Aluise, R. Sultana, J. Tangpong, M. Vore, D. St. Clair, J.A. Moscow and D.A. Butterfield, "Chemobrain (Chemofog) as a Potential Side Effect of Doxrubicin Administration: Role of Cytokine-induced, Oxidative/Nitrosative Stress in Cognitive Dysfunction," in Chemo-Fog (ed by R.B. Faffa and R.J. Tallarida), Landes Bioscience, Austin, TX, in press (2010).
J.B. Owen and D.A. Butterfield, "Measurement of Oxidized/Reduced Glutathione Ratio," in Methods of Molecular Biology: Protein Misfolding in Cellular Stress in Disease and Ageing--Concepts and Protocols, (Ed. by P. Bross), Humana Press, Totawa, NJ, in press (2010).
D.A. Butterfield and H. Mohmmad Abdul, "Lipids in Alzheimer's Disease Brain," in Handbook of Neurochemistry and Molecular Neurobiology (A.Lajtha, Ed.), Springer Publishing, New York, pp. 563-582 (2009).
T.T. Reed, W.M. Pierce Jr., D.M. Turner, W.R. Markesbery, D.A. Butterfield, "Proteomic identification of nitrated brain proteins in early Alzheimer's disease inferior parietal lobule," Journal of Cellular and Molecular Medicine 8B, 2019-2029 (2009).
R. Sultana and D.A. Butterfield, "Oxidatively Modified, Mitochondria-Relevant Brain Proteins in Subjects with Alzheimer Disease and Mild Cognitive Impairment," J. Bioenergetics Biomembranes 41, 441-446 (2009).
V. Calabrese, C. Cornelius, E. Rizzarelli, J.B. Owen, A.T. Dinkova-Kostova and D.A. Butterfield, "Nitric Oxide in Cell Survival: A Janus Molecule," Antioxidants and Redox Signaling 11, 2717-2739 (2009).
D.A. Butterfield and M.L. Bader Lange, "Multifunctional Roles of Enolase in Alzheimer Disease Brain: Beyond Altered Glucose Metabolism," Journal of Neurochemistry 111, 915-933 (2009).
R.A. Sowell, C.D. Aluise and D.A. Butterfield, "Acetyl-L-Carnitine and Ferulic Acid Action in Aging and Neurodegenerative Diseases," in Micronutrients and Brain Health, L.A. Packer, Ed., Taylor and Francis Publisher, Boca Raton, FL, pp. 341-353 (2009).
R. Sultana and D.A. Butterfield, "Proteomics Identification of Carbonylated and HNE-Bound Brain Proteins in Alzheimer's Disease," Neuroproteomics Methods in Molecular Biology 566, 123-135 (2009).
455. R.A. Yokel, R.L. Florence, J.M. Unrine, M.T. Tseng, U.M. Graham, P. Wu, E.A. Grulke, R. Sultana, S.S. Hardas and D.A. Butterfield, "Biodistribution and Oxidative Stress Effects of a Systemically-Introduced Commercial Ceria Engineered Nanomaterial," Nanotoxicology, 3, 234-248 (2009).
R. Sultana, R.A. Sowell, and D.A. Butterfield, "Nitrated Proteins in the Progression of Alzheimer's Disease: A Proteomics Comparison of Mild Cognitive Impairment and Alzheimer's Disease Brain," in Oxidative Neural Injury (S.C. Veasey, Ed.), Humana Press, New York, NY, pp. 137-157 (2009).
R. Sultana, M. Perluigi, and D.A. Butterfield, Proteomics Identification of Oxidatively Modified Proteins in Brain," in Proteomics: Methods and Protocols (J. Reinders and A. Sickmann, Eds.), Humana Press, New York, NY pp. 291-301 (2009).
C.D. Aluise, D. St. Clair, M. Vore and D.A. Butterfield, "In Vivo Amelioration of Doxorubicin Induced Oxidative Stress in Plasma by Gamma-Glutamylcysteine Ethyl Ester (GCEE)," Cancer Letters 282, 25-29 (2009).
R. Sultana, T. Reed and D.A. Butterfield, "Detection of 4-Hydroxy-2-Nonenal- and 3-Nitrotyrosine-Modified Proteins Using a Proteomics Approach," Methods Molec. Biol. 519, 351-361 (2009).
R. Sultana, M. Perluigi and D.A. Butterfield, "Oxidatively Modified Proteins in Alzheimer's Disease, Mild Cognitive Impairment and Animal Models of AD: Role of Abeta in Pathogenesis," Acta Neuropathologica 118, 131-150 (2009).
T.T. Reed, R. Sultana and D.A. Butterfield, "Redox Proteomics of Oxidatively Modified Brain Proteins in Mild Cognitive Impairment," in Neuroproteomics (O. Alzate, Editor), Taylor and Francis Publishers, Boca Raton, FL, pp. 163-195 (2009).
M. Perluigi, R. Sultana, G. Cenini, F. Di Domenico, M. Memo, W.M. Pierce, R. Coccia and D.A. Butterfield, "Redox Proteomics Identification of HNE-Modified Brain Proteins in Alzheimer's Disease: Role of Lipid Peroxidation in Alzheimer's Disease Pathogenesis,"Proteomics--Clinical Applications 3, 682-693 (2009).