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J Alzheimers Dis. 2010;22(2):593-607. doi: 10.3233/JAD-2010-100960.

Lipid oxidation and modification of amyloid-β (Aβ) in vitro and in vivo.

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1
Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, College Station, TX 77843-1114, USA.

Abstract

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.

PMID:
20847409
DOI:
10.3233/JAD-2010-100960
[Indexed for MEDLINE]

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