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

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.