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Larkey","award":["23PRE1018124"],"award-info":[{"award-number":["23PRE1018124"]}]},{"name":"Jeff and Diane Larkey","award":["P20GM144041"],"award-info":[{"award-number":["P20GM144041"]}]},{"name":"Jeff and Diane Larkey","award":["P20GM103476"],"award-info":[{"award-number":["P20GM103476"]}]},{"name":"Jeff and Diane Larkey","award":["P30GM149404"],"award-info":[{"award-number":["P30GM149404"]}]},{"name":"Jeff and Diane Larkey","award":["1P20GM121334"],"award-info":[{"award-number":["1P20GM121334"]}]},{"name":"Jeff and Diane Larkey","award":["R35 ES0304431"],"award-info":[{"award-number":["R35 ES0304431"]}]},{"name":"Jeff and Diane Larkey","award":["P42 ES004699"],"award-info":[{"award-number":["P42 ES004699"]}]},{"name":"Jeff and Diane Larkey","award":["U54 NS127758"],"award-info":[{"award-number":["U54 NS127758"]}]},{"name":"Jeff and Diane Larkey","award":["A25-1690"],"award-info":[{"award-number":["A25-1690"]}]},{"name":"Jeff and Diane Larkey","award":["2-SRA-2022-1210-S-B"],"award-info":[{"award-number":["2-SRA-2022-1210-S-B"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is an increasing global healthcare crisis with few effective treatments. The accumulation of amyloid plaques and hyper-phosphorylated tau are thought to underlie the pathogenesis of AD. However, current studies have recognized a prominent role of cerebrovascular dysfunction in AD. We recently reported that SNPs in soluble epoxide hydrolase (sEH) are linked to AD in human genetic studies and that long-term administration of an sEH inhibitor attenuated cerebral vascular and cognitive dysfunction in a rat model of AD. However, the mechanisms linking changes in cerebral vascular function and neuroprotective actions of sEH inhibitors in AD remain to be determined. This study investigated the effects of administration of an sEH inhibitor, 1-(1-Propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU), on neurovascular coupling, blood\u2013brain barrier (BBB) function, neuroinflammation, and cognitive dysfunction in an hAPP\/PS1 TgF344-AD rat model of AD. We observed predominant \u03b2-amyloid accumulation in the brains of 9\u201310-month-old AD rats and that TPPU treatment for three months reduced amyloid burden. The functional hyperemic response to whisker stimulation was attenuated in AD rats, and TPPU normalized the response. The sEH inhibitor, TPPU, mitigated capillary rarefaction, BBB leakage, and activation of astrocytes and microglia in AD rats. TPPU increased the expression of pre- and post-synaptic proteins and reduced loss of hippocampal neurons and cognitive impairments in the AD rats, which was confirmed in a transcriptome and GO analysis. These results suggest that sEH inhibitors could be a novel therapeutic strategy for AD.<\/jats:p>","DOI":"10.3390\/ijms26062433","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T06:59:59Z","timestamp":1741589999000},"page":"2433","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["A Soluble Epoxide Hydrolase Inhibitor Improves Cerebrovascular Dysfunction, Neuroinflammation, Amyloid Burden, and Cognitive Impairments in the hAPP\/PS1 TgF344-AD Rat Model of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"given":"Xing","family":"Fang","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane J.","family":"Border","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huawei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lavanya","family":"Challagundla","sequence":"additional","affiliation":[{"name":"Molecular and Genomics Facility, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasleen","family":"Kaur","sequence":"additional","affiliation":[{"name":"Molecular and Genomics Facility, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Hee","family":"Hwang","sequence":"additional","affiliation":[{"name":"Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1408-8317","authenticated-orcid":false,"given":"Bruce D.","family":"Hammock","sequence":"additional","affiliation":[{"name":"Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1463-3610","authenticated-orcid":false,"given":"Fan","family":"Fan","sequence":"additional","affiliation":[{"name":"Physiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5581-0217","authenticated-orcid":false,"given":"Richard J.","family":"Roman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,8]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2024, June 27). 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