Increased Expression but Reduced Activity of Antioxidant Enzymes in Alzheimer's Disease.

A growing body of data suggests that free radicals are involved in the pathogenesis of Alzheimer's disease (AD). Increased expression of antioxidant enzymes, such as superoxide dismutase (SOD), and their co-localization to senile plaques and dystrophic neurites have established a firm association between free-radical mediated injury and the disease neuropathology. While several studies have confirmed these findings, there is conflicting information regarding the activity of some of the enzymes. In the current report, we assayed the activity of superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px) from the same areas of the tissue showing increased expression of SOD1 and SOD2 (parallel sequential slices). Nine brains with neuropathologically confirmed AD and six neuropathologically normal, age-matched, controls were examined. Despite marked increased expression of SOD1 and SOD2 within senile plaques in all the cases studied, the activities of SOD, GSH-Px and catalase were significantly lower in AD than in control brains. The difference was most profound in the case of catalase followed by GSH-Px and SOD. These data are in qualitative agreement with that of several laboratories, and support a decrease rather than an increase, in antioxidant enzyme activity. The findings suggest two main possibilities. On one hand, the observed reduced activity along with antigenically increased expression may be consistent with inactivation of excess protein that has been synthesized under conditions of high oxidative stress. Increased protein oxidation coupled with enzyme inactivation is a documented, aging-associated phenomenon. Alternatively, the increased immuno-reactivity may reflect a redistribution phenomenon as the enzymes become more concentrated at the sites of increased oxidative stress, despite an over all reduction in their activity.

[1]  R. Mohs,et al.  Consortium to establish a registry for Alzheimer's disease (CERAD) clinical and neuropsychological assessment of Alzheimer's disease. , 2002, Psychopharmacology bulletin.

[2]  M. Tabaton,et al.  Amyloid‐β Deposition in Alzheimer Transgenic Mice Is Associated with Oxidative Stress , 1998, Journal of neurochemistry.

[3]  R. D'Hooge,et al.  Superoxide Dismutase Activity in Cerebrospinal Fluid of Patients with Dementia and Some Other Neurological Disorders , 1998, Alzheimer disease and associated disorders.

[4]  M. Freedman,et al.  Increased Peroxidation and Reduced Antioxidant Enzyme Activity in Alzheimer's Disease , 1998, Experimental Neurology.

[5]  N. Robakis,et al.  Alzheimer's disease: a re-examination of the amyloid hypothesis , 1998, Trends in Neurosciences.

[6]  G. Perry,et al.  Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[7]  R. Vos,et al.  Cerebrovascular Hypoperfusion: A Risk Factor for Alzheimer's Disease? , 1997, Annals of the New York Academy of Sciences.

[8]  T. Montine,et al.  4‐Hydroxy‐2‐Nonenal Pyrrole Adducts in Human Neurodegenerative Disease , 1997, Journal of neuropathology and experimental neurology.

[9]  D. Yew,et al.  Processing of Alzheimer's amyloid precursor protein during H2O2-induced apoptosis in human neuronal cells. , 1997, Biochemical and biophysical research communications.

[10]  Joseph S. Beckman,et al.  Widespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease , 1997, The Journal of Neuroscience.

[11]  D. Patterson,et al.  Structure of human chromosome 21--for an understanding of genetic diseases including Down's syndrome. , 1997, Bioscience, biotechnology, and biochemistry.

[12]  D. Perl,et al.  Evidence of neuronal oxidative damage in Alzheimer's disease. , 1996, The American journal of pathology.

[13]  J. Zweier,et al.  Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid β-peptide , 1995, Nature Medicine.

[14]  N. Robakis,et al.  Heat-shock induces abnormalities in the cellular distribution of amyloid precursor protein (APP) and APP fusion proteins , 1995, Neuroscience Letters.

[15]  Mark A. Smith,et al.  Carbonyl‐Related Posttranslational Modification of Neurofilament Protein in the Neurofibrillary Pathology of Alzheimer's Disease , 1995, Journal of neurochemistry.

[16]  C. Behl,et al.  Amyloid peptides are toxic via a common oxidative mechanism. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Margaglione,et al.  Cu/Zn superoxide dismutase in patients with non-familial Alzheimer’s disease , 1995, Aging.

[18]  D. Price,et al.  Localization of superoxide dismutases in Alzheimer's disease and Down's syndrome neocortex and hippocampus. , 1995, The American journal of pathology.

[19]  G. Perry,et al.  Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer's disease. , 1994, The American journal of pathology.

[20]  C. Behl,et al.  Hydrogen peroxide mediates amyloid β protein toxicity , 1994, Cell.

[21]  M. Mattson,et al.  β-Amyloid Peptide Free Radical Fragments Initiate Synaptosomal Lipoperoxidation in a Sequence-Specific Fashion: Implications to Alzheimer′s Disease , 1994 .

[22]  N. Robakis,et al.  Immunohistochemical evidence of antioxidant stress in Alzheimer's disease , 1992 .

[23]  M. Mattson,et al.  beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[24]  A. Dalton,et al.  Red cell superoxide dismutase, glutathione peroxidase and catalase in Down syndrome patients with and without manifestations of Alzheimer disease. , 1990, American journal of medical genetics.

[25]  Andreas Weidemann,et al.  Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein , 1989, Cell.

[26]  R. A. Omar,et al.  Antioxidant enzymes and survival of normal and simian virus 40-transformed mouse embryo cells after hyperthermia. , 1987, Cancer research.

[27]  H. Wiśniewski,et al.  Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[28]  E. Stadtman,et al.  Age-related changes in oxidized proteins. , 1987, The Journal of biological chemistry.

[29]  N. Robakis,et al.  CHROMOSOME 21q21 SUBLOCALISATION OF GENE ENCODING BETA-AMYLOID PEPTIDE IN CEREBRAL VESSELS AND NEURITIC (SENILE) PLAQUES OF PEOPLE WITH ALZHEIMER DISEASE AND DOWN SYNDROME , 1987, The Lancet.

[30]  B. Winblad,et al.  Superoxide dismutase isoenzymes in normal brains and in brains from patients with dementia of Alzheimer type , 1985, Journal of the Neurological Sciences.

[31]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[32]  G. Glenner,et al.  Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein , 1984 .

[33]  Oliver H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[34]  B. Lucchesi Free radicals and tissue injury , 1998 .

[35]  H. Kaneto,et al.  Oxidative stress caused by glycation of Cu,Zn-superoxide dismutase and its effects on intracellular components. , 1996, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[36]  Lin Chen,et al.  Regional brain activity of free radical defense enzymes in autopsy samples from patients with Alzheimer's disease and from nondemented controls. , 1994, The International journal of neuroscience.

[37]  F. Tagliavini,et al.  Down syndrome as a key to the time sequence of brain changes in Alzheimer disease. , 1992, Progress in clinical and biological research.

[38]  L. Flohé,et al.  Superoxide dismutase assays. , 1984, Methods in enzymology.

[39]  H. Aebi,et al.  Catalase in vitro. , 1984, Methods in enzymology.

[40]  L. Flohé,et al.  Assays of glutathione peroxidase. , 1984, Methods in enzymology.