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.

APP Function and Lipids: A Bidirectional Link

“…It should be mentioned, that oxidized DHA species and the lipid-peroxidation products of PUFAs are able to increase amyloidogenic APP-processing and hence Aβ-generation. In a recent study we demonstrated, that only 1% oxidized DHA reverts the positives effects of DHA on Aβ-production indicating that PUFAs have to be prevented from oxidation in nutritional approaches (Grimm et al, 2016a). In such approaches DHA often is combined with E-vitamins due to their high antioxidative properties acting as scavengers of radicals and peroxides (Kamal-Eldin and Appelqvist, 1996).…”

“…Because of its six double-bonds DHA is very susceptible to lipid-peroxidation resulting in oxidative stress known to be involved in AD pathogenesis (Smith et al, 1994; Yatin et al, 1998; Fam et al, 2002; Cai et al, 2011). Indeed, the levels of PUFA oxidation products are elevated in AD-affected brains, indicating the reduced DHA content in these tissues to be caused by increased oxidative damage (Sayre et al, 1997; Markesbery and Lovell, 1998; Montine and Morrow, 2005; Grimm et al, 2016a). …”

Regulation of Alpha-Secretase ADAM10 In vitro and In vivo: Genetic, Epigenetic, and Protein-Based Mechanisms

“…PPARalpha is known to be involved in fatty acid metabolism. In this regard, it is of interest that lowering the cholesterol amount of cells increased ADAM10's catalytic but not transcriptional activity (Kojro et al, 2010) and that various fatty acids and lipids such as Docosahexaenoic acid (DHA) interfere with the balance of APP processing (e.g., Eckert et al, 2011; Grimm et al, 2016). Additionally, Sex-determining region Y-box 2 (Sox2), a major factor of adult tissue homeostasis and regeneration control, was recently identified to upregulate ADAM10 expression in HEK293 cells using overexpression experiments (Sarlak et al, 2016).…”

The Impact of Vitamin E and Other Fat-Soluble Vitamins on Alzheimer´s Disease

“…α-tocopherol and α-tocopherol quinine have also been found to negatively affect Aβ aggregation, Aβ-induced toxicity, inflammatory processes, the generation of ROS, and the oxidation of lipids in cultured cells [103,104,105,106,107]. The fact that only 1% of DHA-lipid peroxidation products is sufficient to reverse the Aβ-lowering effect of unoxidized DHA emphasizes the relevance of preventing lipids from oxidation [32]. In addition, chronic α-tocopherol depletion, by knocking out the α-tocopherol transfer protein, enhances Aβ deposition in the brain of APP-transgenic mice with amelioration of the effects after α-tocopherol reception [108].…”

“…Lipids, especially PUFAs, are very susceptible to reactive oxygen species (ROS) and lipid peroxidation, resulting in oxidative stress, known to be involved in AD pathogenesis [31]. Notably, recently it has been shown that different oxidation products of DHA increase amyloidogenic processing of APP, whereas unoxidized DHA is known to decrease Aβ levels [24,32], emphasizing the need to prevent DHA and other lipids from oxidation in nutritional approaches. Due to its anti-oxidative activity vitamin E is especially believed to be beneficial for AD.…”