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

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.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Ghosh A,Comerota MM,Wan D,Chen F,Propson NE,Hwang SH,Hammock BD,Zheng H

doi

10.1126/scitranslmed.abb1206

subject

Has Abstract

pub_date

2020-12-09 00:00:00

issue

573

eissn

1946-6234

issn

1946-6242

pii

12/573/eabb1206

journal_volume

12

pub_type

杂志文章

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