Oxidized Docosahexaenoic Acid Species and Lipid Peroxidation Products Increase Amyloidogenic Amyloid Precursor Protein Processing

One of the main characteristics of Alzheimer's disease (AD) is the beta-amyloid peptide (A beta) generated by beta- and gamma-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 A beta 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 omega-3 and omega-6 PUFAs, HNE and 4-hydroxy-hexenal, in human neuroblastoma cells and mouse mixed cortical neurons. In the presence of oxidized lipids A(3 and soluble beta-secreted APP levels were elevated, whereas soluble alpha-secreted APP was decreased, suggesting a shift from the nonamyloidogenic to the amyloidogenic pathway of APP processing. Furthermore, beta- and gamma-secretase activity was increased by oxidized lipids via increased gene expression and additionally by a direct effect on beta-secretase activity. Importantly, only 1% oxidized DHA was sufficient to revert the protective effect of DHA and to significantly increase A beta. 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. (C) 2015 S. Karger AG, Basel