A Soluble Epoxide Hydrolase Inhibitor Improves Cerebrovascular Dysfunction, Neuroinflammation, Amyloid Burden, and Cognitive Impairments in the hAPP/PS1 TgF344-AD Rat Model of Alzheimer’s Disease
Year: 2025
Type: article
Abstract: Alzheimer's 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-brain barrier (BBB) function, neuroinflammation, and cognitive dysfunction in an hAPP/PS1 TgF344-AD rat model of AD. We observed predominant β-amyloid accumulation in the brains of 9-10-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.
DOI: 10.3390/ijms26062433
Authors: Xing Fang, Jane J. Border, Huawei Zhang, Lavanya Challagundla, Jasleen Kaur, Sung Hee Hwang, Bruce D. Hammock, Fan Fan, Richard J. Roman
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,499
Awards: G1147831117, G1872805673, Renal Therapeutic Angiogenesis Using the Novel Biologic ELP-VEGF, G2366971526, G2810375270, G2815811356, G2981186621, G302438542, G3274119350, G3319444792, Mississippi Center of Excellence in Perinatal Research, Phase 2, G376898795, G3794810640, Sex differences in hypertension, cognitive function and renal hemodynamics; a role for B cells and autoantibodies, G3966409118, G4169595814, G4336173267, G4780715803, Diversity Supplement to UC Davis CounterACT Center of Excellence: Role of IL-1β in mediating the chronic adverse neurological effects of acute organophosphate intoxication., G4920171302, G4933539558, Molecular Center of Health and Disease, G5517034332, G5671849667, G5681973034, A Preclinical Trial of Therapeutic Angiogenesis Plus Angioplasty and Stenting for Renal Vascular Disease, G6310260574, Cardiorenal and Metabolic Diseases Research Center, G7219996302, Role of Piezo1 on the Regulation of Cerebral Blood Flow in Alzheimer's Disease, G7478541850, G7585204016, G7667852719, G773047840, Biomarkers of Exposure to Hazardous Substances, G7931899898, G8273040561, G8543181674, G8911982331, G9000047879, G9000089322, G9000117304, G9000207183, G9000313629, G9000343505, Vascular mechanisms of inhibition of sEH as a novel therapy for AD/ADRD, Bioactive lipids as effectors and indicators of the deleterious effects of environmental exposure on chronic diseases, Mississippi INBRE, Vascular mechanisms of inhibition of sEH as a novel therapy for AD/ADRD, G969388996
OpenAlex ID: W4408276834