title: Oxidized Docosahexaenoic Acid Species and Lipid  Peroxidation Products Increase Amyloidogenic  Amyloid Precursor Protein Processing.
abstract: One of the main characteristics of Alzheimer's disease (AD) is the β-amyloid peptide (Aβ) generated by β- and γ-secretase processing of the amyloid precursor protein (APP). Previously it has been demonstrated that polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA), are associated with a reduced risk of AD caused by decreased Aβ production. However, in epidemiological studies and nutritional approaches, the outcomes of DHA-dependent treatment were partially controversial. PUFAs are very susceptible to reactive oxygen species and lipid peroxidation, which are increased during disease pathology. In line with published results, lipid peroxidation was elevated in human postmortem AD brains; especially 4-hydroxy-nonenal (HNE) was increased. To investigate whether lipid peroxidation is only a consequence or might also influence the processes leading to AD, we analyzed 7 different oxidized lipid species including 5 oxidized DHA derivatives and the lipid peroxidation products of ω-3 and ω-6 PUFAs, HNE and 4-hydroxy-hexenal, in human neuroblastoma cells and mouse mixed cortical neurons. In the presence of oxidized lipids Aβ and soluble β-secreted APP levels were elevated, whereas soluble α-secreted APP was decreased, suggesting a shift from the nonamyloidogenic to the amyloidogenic pathway of APP processing. Furthermore, β- and γ-secretase activity was increased by oxidized lipids via increased gene expression and additionally by a direct effect on β-secretase activity. Importantly, only 1% oxidized DHA was sufficient to revert the protective effect of DHA and to significantly increase Aβ production. Therefore, our results emphasize the need to prevent DHA from oxidation in nutritional approaches and might help explain the divergent results of clinical DHA studies.
authors.forename: Marcus O W
authors.initials: MO
authors.lastname: Grimm
authors.forename: Viola J
authors.initials: VJ
authors.lastname: Haupenthal
authors.forename: Janine
authors.initials: J
authors.lastname: Mett
authors.forename: Christoph P
authors.initials: CP
authors.lastname: Stahlmann
authors.forename: Tamara
authors.initials: T
authors.lastname: Blümel
authors.forename: Nadine T
authors.initials: NT
authors.lastname: Mylonas
authors.forename: Kristina
authors.initials: K
authors.lastname: Endres
authors.forename: Heike S
authors.initials: HS
authors.lastname: Grimm
authors.forename: Tobias
authors.initials: T
authors.lastname: Hartmann
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000031:analogs & derivatives* / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D015227:Lipid Peroxidation; D008297:Male; D013058:Mass Spectrometry; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D010084:Oxidation-Reduction; D060888:Real-Time Polymerase Chain Reaction; D014015:Tissue Banks
chemical_list: D016229:Amyloid beta-Peptides; D004281:Docosahexaenoic Acids; D053829:Amyloid Precursor Protein Secretases