2-nonenal--(trans)-isomer and Alzheimer-Disease

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 Aβ40 and Aβ42, 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 (Aβ) 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 Aβ40 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.

Topics: Adolescent; Adult; Age Factors; Aldehydes; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Down Syndrome; Female; Frontal Lobe; Humans; Male; Middle Aged; Nitrosation; Oxidation-Reduction; Oxidative Stress; Superoxide Dismutase; Superoxide Dismutase-1; Tyrosine

Oxidative damage and amyloid-β (Aβ) protein misfolding are prominent features of Alzheimer's disease (AD). In vitro studies indicated a direct linkage between these two features, where lipid oxidation products augmented Aβ misfolding. We tested this linkage further, mimicking specific conditions present in amyloid plaques. In vitro lipid oxidation and lipid modification of Aβ were thus performed with elevated levels of copper or physiological levels of calcium. These in vitro experiments were then confirmed by in vivo immunohistochemical and chemical tagging of oxidative damage in brains from the PSAPP mouse model of AD. Our in vitro findings indicate that: 1) high levels of copper prevent lipid oxidation; 2) physiological concentrations of calcium reduce 4 hydroxy-2-nonenal (HNE) modification of Aβ; and 3) anti-Aβ and HNE antibody epitopes are differentially masked. In vivo we demonstrated increased lipid oxidation around plaques but 4) a lack of immunological colocalization of HNE-adducts with Aβ. Thus, the lack of colocalization of Aβ and HNE-adduct immunostaining is most likely due to a combination of metals inhibiting HNE modification of Aβ, quenching lipid oxidation and a masking of HNE-Aβ histopathology. However, other forms of oxidative damage colocalize with Aβ in plaques, as demonstrated using a chemical method for identifying oxidative damage. Additionally, these findings suggest that HNE modification of Aβ may affect therapeutic antibodies targeting the amino terminal of Aβ and that metals effect on lipid oxidation and lipid modification of Aβ could raise concerns on emerging anti-AD treatments with metal chelators.

Topics: Aldehydes; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Calcium; Copper Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Lipid Bilayers; Lipid Metabolism; Lipid Peroxidation; Male; Mice; Mice, Transgenic; Mutation; Oxidation-Reduction; Peptide Fragments; Plaque, Amyloid; Presenilin-1; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization