Elucidating the Role of Soluble Epoxide Hydrolase and Arachidonic Acid Metabolism in Neuroinflammation and Alzheimer’s Disease

2021

The development of amyloid beta plaque and neurofibrillary tangle pathologies in Alzheimer’s disease (AD) is accompanied by prominent neuroinflammation. Prolonged activation of microglia and astrocytes in the brain and the release of proinflammatory cytokines and reactive oxygen species create a toxic environment to neurons, leading to memory impairment and neurodegeneration. In support of this idea, epidemiological studies indicated protective effects of nonsteroidal anti-inflammatory drugs (NSAIDs) against AD. However, randomized clinical trials failed to demonstrate efficacy, underscoring the need to identify a more effective therapy targeting neuroinflammation.

The most common NSAIDs are cyclooxygenase (COX) inhibitors that act on the arachidonic acid (ARA) metabolism to block the release of proinflammatory lipids, the prostaglandins. Contrary to prostaglandins, ARA metabolism also produces epoxy lipids, and these specialized lipids have been shown to display anti-inflammatory and vascular-protecting activities. However, their effects are limited because they are rapidly broken down by the soluble epoxide hydrolase (sEH). We found that sEH levels are elevated and, correspondingly, the epoxy lipids are diminished, in the brain of AD patients and mouse models. We thus reasoned that blocking sEH may restore the epoxy lipids and promote brain health in AD conditions. We tested this hypothesis by removing sEH in AD mice and by treating the AD mice with a small molecule sEH inhibitor with blood-brain barrier (BBB) penetration. We found that both the sEH removal and the inhibitor treatment restored the epoxy lipids, reduced neuroinflammation, attenuated amyloid pathology and improved cognition. These findings support sEH blockade as a potential therapy for AD treatment.

Neuroinflammation is a complex process that involves changes of multiple cell types and the cross-talk among them. Besides astrocytes and microglia, the vascular endothelial cells play an essential role in BBB integrity, and their impairment also has been implicated in AD. The ARA signaling pathway is active in all these cell types and produces both pro- and anti-inflammatory lipids. We suspect that the beneficial effect of sEH inhibition is conferred through a combination of the multiple cell types. However, how the sEH pathway and the ARA metabolism are regulated in these cells, and how they coordinate to impact AD progression, are not known. Building on our compelling work on sEH, we aim to gain a deeper and broader understanding of the sEH pathway and ARA metabolism in AD. We propose to isolate microglia, astrocytes and vascular endothelial cells from the brain of AD mouse models and perform gene expression and lipid profiling to decipher how the ARA pathway and their lipid metabolites are changed in response to amyloid beta and neurofibrillary tangle pathologies. In addition, we will determine whether sEH inhibition affords therapeutic benefit against both amyloid and neurofibrillary tangle pathologies, and what are the key cell types and lipid species that mediate these effects. Overall, these studies will achieve a new mechanistic and therapeutic understanding of sEH inhibition, and also identify new targets in the ARA pathway for AD therapy.


Funding to Date

$167,920

Focus

Studies of Innate Immune Pathology, Translational

Researchers

Hui Zheng, Ph.D.