Association between frontal cortex oxidative damage and beta-amyloid as a function of age in Down syndrome

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1822

Article

Cenini, Giovanna^1,2  Dowling, Amy L. S.^2,3  Beckett, Tina L.^2,4  Barone, Eugenio^1,2,5  Mancuso, Cesare⁵  Murphy, Michael Paul^2,4  LeVine, Harry, III^2,4  Lott, Ira T.^6,7  Schmitt, Frederick A.^2,8  Butterfield, D. Allan¹  Head, Elizabeth^2,3 

[1] Univ Kentucky, Dept Chem, Ctr Membrane Sci, Lexington, KY 40536 USA

[2] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA

[3] Univ Kentucky, Dept Mol & Biomed Pharmacol, Lexington, KY 40536 USA

[4] Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA

[5] Catholic Univ, Sch Med, Inst Pharmacol, I-00168 Rome, Italy

[6] Univ Calif Irvine, Dept Neurol, MIND, Irvine, CA 92697 USA

[7] Univ Calif Irvine, Dept Pediat, MIND, Irvine, CA 92697 USA

[8] Univ Kentucky, Dept Neurol, Lexington, KY 40536 USA

关键词: Alzheimer disease;    4-Hydroxy-2-nonenal;    3-Nitrotyrosine;    Oligomer;    Protein carbonyl;    Trisomy 21;   

DOI  :  10.1016/j.bbadis.2011.10.001

来源: Elsevier

【 摘 要 】

Down syndrome (DS) is the most common genetic cause of intellectual disability in children, and the number of adults with DS reaching old age is increasing. By the age of 40 years, virtually all people with DS have sufficient neuropathology for a postmortem diagnosis of Alzheimer disease (AD). Trisomy 21 in DS leads to an overexpression of many proteins, of which at least two are involved in oxidative stress and AD: superoxide dismutase 1 (SOD1) and amyloid precursor protein (APP). In this study, we tested the hypothesis that DS brains with neuropathological hallmarks of AD have more oxidative and nitrosative stress than those with DS but without significant AD pathology, as compared with similarly aged-matched non-DS controls. The frontal cortex was examined in 70 autopsy cases (n = 29 control and n = 41 DS). By ELISA, we quantified soluble and insoluble A beta 40 and A beta 42, as well as oligomers. Oxidative and nitrosative stress levels (protein carbonyls, 4-hydroxy-2-trans-nonenal (HNE)-bound proteins, and 3-nitrotyrosine) were measured by slot-blot. We found that soluble and insoluble amyloid beta peptide (A beta) and oligomers increase as a function of age in DS frontal cortex. Of the oxidative stress markers, HNE-bound proteins were increased overall in DS. Protein carbonyls were correlated with A beta 40 levels. These results suggest that oxidative damage, but not nitrosative stress, may contribute to the onset and progression of AD pathogenesis in DS. Conceivably, treatment with antioxidants may provide a point of intervention to slow pathological alterations in DS. (C) 2011 Elsevier B.V. All rights reserved.

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