Oxylipin Profiling of Alzheimer’s Disease in Nondiabetic and Type 2 Diabetic Elderly

Abstract

Oxygenated lipids, called “oxylipins,” serve a variety of important signaling roles within the cell. Oxylipins have been linked to inflammation and vascular function, and blood patterns have been shown to differ in type 2 diabetes (T2D). Because these factors (inflammation, vascular function, diabetes) are also associated with Alzheimer’s disease (AD) risk, we set out to characterize the serum oxylipin profile in elderly and AD subjects to understand if there are shared patterns between AD and T2D. We obtained serum from 126 well-characterized, overnight-fasted elderly individuals who underwent a stringent cognitive evaluation and were determined to be cognitively healthy or AD. Because the oxylipin profile may also be influenced by T2D, we assessed nondiabetic and T2D subjects separately. Within nondiabetic individuals, cognitively healthy subjects had higher levels of the nitrolipid 10-nitrooleate (16.8% higher) compared to AD subjects. AD subjects had higher levels of all four dihydroxyeicosatrienoic acid (DiHETrE) species: 14,15-DiHETrE (18% higher), 11,12 DiHETrE (18% higher), 8,9-DiHETrE (23% higher), and 5,6-DiHETrE (15% higher). Within T2D participants, we observed elevations in 14,15-dihydroxyeicosa-5,8,11-trienoic acid (14,15-DiHETE; 66% higher), 17,18-dihydroxyeicosa-5,8,11,14-tetraenoic acid (17,18-DiHETE; 29% higher) and 17-hydroxy-4,7,10,13,15,19-docosahexaenoic acid (17-HDoHE; 105% higher) and summed fatty acid diols (85% higher) in subjects with AD compared to cognitively healthy elderly, with no differences in the DiHETrE species between groups. Although these effects were no longer significant following stringent adjustment for multiple comparisons, the consistent effects on groups of molecules with similar physiological roles, as well as clear differences in the AD-related profiles within nondiabetic and T2D individuals, warrant further research into these molecules in the context of AD.

Oxylipin Profiles in Plasma of Patients with Wilson’s Disease

“…An interesting finding of our work is an increase of OEA and EPA, substances that are known preventers of oxidative stress [33,34]. Although oxidative stress can be viewed as a common disruption in various pathologies, which may suggest similarities in the oxidized forms of lipids, the variations in the oxylipin profiles obtained in various diseases do not support this point of view [24][25][26]28,29]. Our data sheds light onto some appropriate compensatory mechanisms that may be involved in WD.…”

“…Oxylipin profiles were investigated for the study of mechanisms, and as diagnostic markers for diseases, such as Alzheimer's disease [24], female breast cancer [26], alcohol-related liver disease [25], atherosclerotic diseases [28], and coronary artery disease [29]. Importantly, every disease was characterized by a special set of oxylipins: 9-HODE [26], 20-HETE [25], 8-HETE, LTB4, 9-HODE and 13-HODE [28], 9-HETE, and F(2)-isoprostanes [29].…”

“…The roles of oxidative stress in the pathogenesis of WD, and dietary omega-3 PUFAs' usefulness in an animal model of WD suggest that oxylipins may be involved in the clinical manifestation of WD. Moreover, the number of some lipid-related nuclear receptors, such as retinoid X receptor (RXR), peroxisome proliferator-activated receptor α (PPARα), and hepatocyte nuclear factor 4 alpha (HNF4A), is generally decreased in WD animal models and humans [9,[21][22][23][24][25]. It is important to note that although oxylipins exhibit multiple effects, they somehow change the state of the innate immunity system [13][14][15].…”

“…The development of mass spectrometric methods for oxylipin detection made it possible to obtain oxylipin profiles from the plasma of patients with diseases, such as Alzheimer's disease [24], alcohol-related liver disease [25], or cancer [26]. However, no such studies have been conducted to characterize WD.…”

Cytochrome P450 Metabolism of Polyunsaturated Fatty Acids and Neurodegeneration

“…Even though there is a controversy, in randomized clinical trials studying the effects of ω-3 PUFAs in AD, most observational studies have shown the beneficial effects of ω-3 intake on reducing the incidence of AD [ 9 , 13 , 18 ]. Additionally, the oxylipin profiles of blood serum in AD subjects show around 20% higher levels of dihydroxyeicosatrienoic acid (which is the product of the sEH metabolism of the epoxy-metabolite of AA) as compared to the elderly individuals that were cognitively healthy [ 20 ]. Therefore, sEH is an important enzyme in PUFA metabolism and a lucrative drug target for NDs [ 21 ].…”