Dually targeting human soluble epoxide hydrolase and P38 kinase to prevent neuroinflammation for the treatment of Alzheimer’s disease

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 roles in Alzheimer’s disease and their potential as biomarkers are poorly understood. Here we describe the analysis of plasma and cerebrospinal fluid lipid mediators in a case-control comparison of individuals with Alzheimer’s disease and healthy controls to investigate these knowledge gaps. Methods Lipid mediators were measured using targeted quantitative mass spectrometry. Data were analyzed using 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, yielding potential biomarkers of the disorder. The results further suggest that combined pharmacological intervention targeting both metabolic pathways may have therapeutic benefits for Alzheimer’s disease.

Download Full-text

Genetic deletion of soluble epoxide hydrolase delays the progression of Alzheimer’s disease

Journal of Neuroinflammation ◽

10.1186/s12974-019-1635-9 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 10

Author(s):

Hsueh-Te Lee ◽

Kuan-I Lee ◽

Chia-Hui Chen ◽

Tzong-Shyuan Lee

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Translational Regulation ◽

Epoxide Hydrolase ◽

Cell Types ◽

Soluble Epoxide Hydrolase ◽

Small Gtpase ◽

Activated T Cells ◽

Genetic Ablation ◽

The Brain

Abstract Background Soluble epoxide hydrolase (sEH) is a bifunctional enzyme with COOH-terminal hydrolase and NH2-terminal lipid phosphatase activities. It is expressed in various cell types in the brain and is involved in the pathogenesis of inflammatory and neurodegenerative diseases. Alzheimer’s disease (AD) is a progressive neuroinflammatory and neurodegenerative disease. However, the pathological significance of sEH and underlying molecular mechanism in AD remain unclear. Methods To examine the role of sEH in pathogenesis of AD, we used wild-type (WT) mice, soluble epoxide hydrolase deficient (sEH−/−) and two mouse models of AD, including amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (APP/PS1 Tg) and APP/PS1 Tg/sEH−/− mice. Western blotting analysis and immunohistochemistry assay were performed to evaluate the protein expression. Locomotion, nesting building ability, Y-maze, and Morris water maze tests were conducted to study mouse behavior. The levels of interleukin (IL)-1β, IL-4, IL-6, and IL-10 and the activities of NF-κB and nuclear factor of activated T cells (NFAT) were measured by commercial assay kits. The quantitative protein level profiling in the brain lysate was analyzed using LC-MS/MS approaches. Results We demonstrated that the level of sEH was increased in the brain and predominantly appeared in hippocampal astrocytes of APP/PS1 Tg mice. Genetic ablation of sEH in APP/PS1 Tg mice delayed the progression of AD as evidenced by the alleviation in behavior outcomes and Aβ plaque deposition. In addition, loss of the function of sEH in APP/PS1 Tg mice increased astrogliosis and the production of astrocyte-derived anti-inflammatory cytokines including IL-1β, IL-4, and IL-10, as well as the activity of NF-kB and NFAT. Moreover, analysis of gene ontology in the AD brain revealed that important signaling pathways and processes related to AD pathogenesis such as translational regulation, oxidative stress, cytoskeleton reorganization, and small GTPase signal transduction were altered in APP/PS1 Tg/sEH−/− mice compared with APP/PS1 Tg mice. Conclusion Our results suggest that sEH is a crucial regulator in the progression of AD and might be a potential therapeutic target for the treatment of AD.

Download Full-text

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

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00893-6 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Kamil Borkowski ◽

Theresa L. Pedersen ◽

Nicholas T. Seyfried ◽

James J. Lah ◽

Allan I. Levey ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Cytochrome P450 ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Lipid Mediators ◽

Partial Least Square ◽

Pharmacological Intervention ◽

Healthy Controls

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.

Download Full-text

Pharmacological inhibition of soluble epoxide hydrolase as a new therapy for Alzheimer’s Disease

10.1101/605055 ◽

2019 ◽

Cited By ~ 2

Author(s):

Christian Griñán-Ferré ◽

Sandra Codony ◽

Eugènia Pujol ◽

Jun Yang ◽

Rosana Leiva ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Therapeutic Effects ◽

Beneficial Effects ◽

Age Related ◽

Novel Target ◽

Age Related Cognitive Decline

AbstractThe inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with two compounds that have entered clinical trials. However, the role of this enzyme in the neuroinflammation process has been largely neglected. Herein, we disclose the pharmacological validation of sEH as a novel target for the treatment of Alzheimer’s Disease (AD). Of interest, we have found that sEH is upregulated in brains from AD patients. We have evaluated the cognitive impairment and the pathological hallmarks in two models of age-related cognitive decline and AD using three structurally different and potent sEH inhibitors as chemical probes. Our findings supported our expectations on the beneficial effects of central sEH inhibition, regarding of reducing cognitive impairment, tau hyperphosphorylation pathology and the number of amyloid plaques. Interestingly, our results suggest that reduction of inflammation in the brain is a relevant therapeutic strategy for all stages of AD.

Download Full-text

Pharmacological Inhibition of Soluble Epoxide Hydrolase as a New Therapy for Alzheimer’s Disease

Neurotherapeutics ◽

10.1007/s13311-020-00854-1 ◽

2020 ◽

Cited By ~ 4

Author(s):

Christian Griñán-Ferré ◽

Sandra Codony ◽

Eugènia Pujol ◽

Jun Yang ◽

Rosana Leiva ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Pharmacological Inhibition ◽

New Therapy

Download Full-text

Docosahexaenoic Acid Increases the Potency of Soluble Epoxide Hydrolase Inhibitor in Alleviating Streptozotocin-Induced Alzheimer’s Disease-Like Complications of Diabetes

Frontiers in Pharmacology ◽

10.3389/fphar.2019.00288 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 9

Author(s):

Rohit Pardeshi ◽

Nityanand Bolshette ◽

Kundlik Gadhave ◽

Mohammad Arfeen ◽

Sahabuddin Ahmed ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Docosahexaenoic Acid ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Complications Of Diabetes ◽

Soluble Epoxide Hydrolase Inhibitor

Download Full-text

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

10.1101/2021.03.09.21252423 ◽

2021 ◽

Author(s):

Kamil Borkowski ◽

Theresa L. Pedersen ◽

Nicholas T. Seyfried ◽

James J. Lah ◽

Allan I. Levey ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cytochrome P450 ◽

Metabolic Pathways ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Lipid Mediators ◽

Pharmacological Intervention ◽

Therapeutic Benefits ◽

Cardiometabolic Disorders

AbstractAlzheimer’s disease shares inflammatory origin with cardiometabolic disorders. Lipid mediators, including oxylipins, endocannabinoids, bile acids and steroids are potent regulators of inflammation, energy metabolism and cell proliferation with well-established involvement in cardiometabolic diseases. However, their role in Alzheimer’s disease is poorly understood. In the current study we provide comprehensive analysis of plasma and CSF lipid mediators in a case-control comparison of patients with Alzheimer’s disease, utilizing a targeted quantitative mass spectrometry approach. In both plasma and CSF, we observed Alzheimer’s disease patients to have elevated components of cytochrome P450/soluble epoxide hydrolase pathway and lower levels of fatty acids ethanolamides, when compared to the healthy controls. Multivariate analysis revealed that circulating metabolites of soluble epoxide hydrolase together with ethanolamides are strong and independent predictors for Alzheimer’s disease. Both metabolic pathways are potent regulators of inflammation with soluble epoxide hydrolase being reported to be upregulated in the brains of Alzheimer’s disease patients. This study provides further evidence for the involvement of inflammation in Alzheimer’s disease and argues for further research into the role of the cytochrome P450/soluble epoxide hydrolase pathway and fatty acid ethanolamides in this disorder. Further, these findings suggest that a combined pharmacological intervention targeting both metabolic pathways may have therapeutic benefits for Alzheimer’s disease.

Download Full-text