{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:55:03Z","timestamp":1792068903712,"version":"4.4.0"},"reference-count":49,"publisher":"Society for Neuroscience","issue":"42","license":[{"start":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T00:00:00Z","timestamp":1618358400000},"content-version":"vor","delay-in-days":202,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81930034"],"award-info":[{"award-number":["81930034"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Guandong Natural Science Foundation","doi-asserted-by":"publisher","award":["2016A030308005"],"award-info":[{"award-number":["2016A030308005"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Guangzhou Science and Technology Project","award":["201804020061"],"award-info":[{"award-number":["201804020061"]}]},{"name":"Key-Area Research and Development Program of Guangdong Provience","award":["2018B030334001"],"award-info":[{"award-number":["2018B030334001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2020,10,14]]},"abstract":"<jats:p>Alzheimer's disease (AD) is the leading cause of late-onset dementia, and there exists an unmet medical need for effective treatments for AD. The accumulation of neurotoxic amyloid-\u03b2 (A\u03b2) plaques contributes to the pathophysiology of AD.<jats:italic>EPHX2<\/jats:italic>encoding soluble epoxide hydrolase (sEH)\u2014a key enzyme for epoxyeicosatrienoic acid (EET) signaling that is mainly expressed in lysosomes of astrocytes in the adult brain\u2014is cosited at a locus associated with AD, but it is unclear whether and how it contributes to the pathophysiology of AD. In this report, we show that the pharmacologic inhibition of sEH with 1-trifluoromethoxyphenyl- 3-(1-propionylpiperidin-4-yl) urea (TPPU) or the genetic deletion of<jats:italic>Ephx2<\/jats:italic>reduces A\u03b2 deposition in the brains of both male and female familial Alzheimer's disease (5\u00d7FAD) model mice. The inhibition of sEH with TPPU or the genetic deletion of<jats:italic>Ephx2<\/jats:italic>alleviated cognitive deficits and prevented astrocyte reactivation in the brains of 6-month-old male 5\u00d7FAD mice. 14,15-EET levels in the brains of these mice were also increased by sEH inhibition. In cultured adult astrocytes treated with TPPU or 14,15-EET, astrocyte A\u03b2 clearance was increased through enhanced lysosomal biogenesis. Infusion of 14,15-EET into the hippocampus of 5\u00d7FAD mice prevented the aggregation of A\u03b2. Notably, a higher concentration of 14,15-EET (200 ng\/ml) infusion into the hippocampus reversed A\u03b2 deposition in the brains of 6-month-old male 5\u00d7FAD mice. These results indicate that EET signaling, especially 14,15-EET, plays a key role in the pathophysiology of AD, and that targeting this pathway is a potential therapeutic strategy for the treatment of AD.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>There are limited treatment options for Alzheimer's disease (AD).<jats:italic>EPHX2<\/jats:italic>encoding soluble epoxide hydrolase (sEH) is located at a locus that is linked to late-onset AD, but its contribution to the pathophysiology of AD is unclear. Here, we demonstrate that sEH inhibition or<jats:italic>Ephx2<\/jats:italic>deletion alleviates pathology in familial Alzheimer's disease (5\u00d7FAD) mice. Inhibiting sEH or increasing 14,15-epoxyeicosatrienoic acid (EET) enhanced lysosomal biogenesis and amyloid-\u03b2 (A\u03b2) clearance in cultured adult astrocytes. Moreover, the infusion of 14,15-EET into the hippocampus of 5\u00d7FAD mice not only prevented the aggregation of A\u03b2, but also reversed the deposition of A\u03b2. Thus, 14,15-EET plays a key role in the pathophysiology of AD and therapeutic strategies that target this pathway may be an effective treatment.<\/jats:p>","DOI":"10.1523\/jneurosci.1246-20.2020","type":"journal-article","created":{"date-parts":[[2020,9,24]],"date-time":"2020-09-24T21:50:19Z","timestamp":1600984219000},"page":"8188-8203","source":"Crossref","is-referenced-by-count":51,"title":["14,15-Epoxyeicosatrienoic Acid Alleviates Pathology in a Mouse Model of Alzheimer's 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