Research ArticleAlzheimer’s Disease

An epoxide hydrolase inhibitor reduces neuroinflammation in a mouse model of Alzheimer’s disease

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Science Translational Medicine  09 Dec 2020:
Vol. 12, Issue 573, eabb1206
DOI: 10.1126/scitranslmed.abb1206

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Dialing up epoxy fatty acids in the brain

Neuroinflammation is strongly implicated in Alzheimer’s disease (AD). The epoxy lipids produced from arachidonic acid have anti-inflammatory properties, but they are rapidly turned over by the soluble epoxide hydrolase (sEH). Ghosh et al. now report that sEH is elevated in the brains of patients with AD and in an amyloid mouse model of AD, suggesting that blocking sEH may replenish the epoxy lipids and combat neuroinflammation. Treating AD mice with a small-molecule inhibitor of sEH restored the epoxy lipids, reduced neuroinflammation and amyloid pathology, and improved cognition. This study identifies a lipid metabolic pathway regulating neuroinflammation and provides support for further development of sEH inhibitors as a potential treatment for AD.

Abstract

Neuroinflammation has been increasingly recognized to play a critical role in Alzheimer’s disease (AD). The epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid metabolism pathway and have anti-inflammatory activities. However, their efficacy is limited because of their rapid hydrolysis by the soluble epoxide hydrolase (sEH). We report that sEH is predominantly expressed in astrocytes and is elevated in postmortem brain tissue from patients with AD and in the 5xFAD β amyloid mouse model of AD. The amount of sEH expressed in AD mouse brains correlated with a reduction in brain EpFA concentrations. Using a specific small-molecule sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we report that TPPU treatment protected wild-type mice against LPS-induced inflammation in vivo. Long-term administration of TPPU to the 5xFAD mouse model via drinking water reversed microglia and astrocyte reactivity and immune pathway dysregulation. This was associated with reduced β amyloid pathology and improved synaptic integrity and cognitive function on two behavioral tests. TPPU treatment correlated with an increase in EpFA concentrations in the brains of 5xFAD mice, demonstrating brain penetration and target engagement of this small molecule. These findings support further investigation of TPPU as a potential therapeutic agent for the treatment of AD.

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