Association of plasma and CSF cytochrome P450, soluble epoxide hydrolase, and ethanolamide metabolism with Alzheimer's disease

• Type of Material: Article
• Authors: Kamil Borkowski, University of California Davis; Theresa L Pedersen, University of California Davis; Nicholas Seyfried, Emory University; James Lah, Emory University; Allan Levey, Emory University; Chadwick Hales, Emory University; Eric Dammer, Emory University; Colette Blach, Duke University; Gregory Louie, Duke University; Rima Kaddurah-Daouk, Duke University; John W Newman, University of California Davis
• Language: English
• Date: 2021-09-06
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13195-021-00893-6
• Title of Journal or Parent Work: ALZHEIMERS RESEARCH & THERAPY
• Volume: 13
• Issue: 1
• Start Page: 149
• End Page: 149
• Grant/Funding Information: The Alzheimer’s Disease Metabolomics Consortium (ADMC) is funded wholly or in part by the following National Institute on Aging grants and supplements, components of the Accelerating Medicines Partnership for AD (AMP-AD) and/or Molecular Mechanisms of the Vascular Etiology of AD (M2OVE-AD): NIA R01AG046171, RF1AG051550, RF1AG057452, R01AG059093, RF1AG058942, U01AG061359, U19AG063744, and FNIH: #DAOU16AMPA awarded to Dr. Kaddurah-Daouk at Duke University in partnership with a large number of academic institutions. Additional support was provided by Emory ADRC P30 AG066511 awarded to Allan I. Levey, Emory EHBS R01 AG070937 awarded to James J. Lah, and USDA Intramural Projects 2032-51530-022-00D and 2032-51530-025-00D awarded to John W. Newman. The USDA is an equal opportunity employer and provider.
• Keywords: Endocannabinoids; THERAPEUTIC TARGET; BILE-ACID; Life Sciences & Biomedicine; ENDOCANNABINOID SYSTEM; Science & Technology; BIOACTIVATION; POLYMORPHISMS; Neurosciences; Lipid mediators; Alzheimer's disease; FATTY-ACIDS; Oxylipins; BRAIN; EPHX2; RESOLVING LIPID MEDIATORS; Neurosciences & Neurology; Cognition; RISK; Clinical Neurology
• Research Categories: Chemistry, Biochemistry; Health Sciences, Nutrition

Abstract

Background: Alzheimer’s disease, cardiovascular disease, and other cardiometabolic disorders may share inflammatory origins. Lipid mediators, including oxylipins, endocannabinoids, bile acids, and steroids, regulate inflammation, energy metabolism, and cell proliferation with well-established involvement in cardiometabolic diseases. However, their role in Alzheimer’s disease is poorly understood. Here, we describe the analysis of plasma and cerebrospinal fluid lipid mediators in a case–control comparison of ~150 individuals with Alzheimer’s disease and ~135 healthy controls, to investigate this knowledge gap. Methods: Lipid mediators were measured using targeted quantitative mass spectrometry. Data were analyzed using the analysis of covariates, adjusting for sex, age, and ethnicity. Partial least square discriminant analysis identified plasma and cerebrospinal fluid lipid mediator discriminates of Alzheimer’s disease. Alzheimer’s disease predictive models were constructed using machine learning combined with stepwise logistic regression. Results: In both plasma and cerebrospinal fluid, individuals with Alzheimer’s disease had elevated cytochrome P450/soluble epoxide hydrolase pathway components and decreased fatty acid ethanolamides compared to healthy controls. Circulating metabolites of soluble epoxide hydrolase and ethanolamides provide Alzheimer’s disease predictors with areas under receiver operator characteristic curves ranging from 0.82 to 0.92 for cerebrospinal fluid and plasma metabolites, respectively. Conclusions: Previous studies report Alzheimer’s disease-associated soluble epoxide hydrolase upregulation in the brain and that endocannabinoid metabolism provides an adaptive response to neuroinflammation. This study supports the involvement of P450-dependent and endocannabinoid metabolism in Alzheimer’s disease. The results further suggest that combined pharmacological intervention targeting both metabolic pathways may have therapeutic benefits for Alzheimer’s disease.