Genetic deletion of soluble epoxide hydrolase delays the progression of Alzheimer’s disease

Abstract

BackgroundSoluble epoxide hydrolase (sEH) is a bifunctional enzyme with COOH-terminal hydrolase and NH2-terminal lipid phosphatase activities. It is expressed in various cell types in the brain and is involved in the pathogenesis of inflammatory and neurodegenerative diseases. Alzheimer’s disease (AD) is a progressive neuroinflammatory and neurodegenerative disease. However, the pathological significance of sEH and underlying molecular mechanism in AD remain unclear.MethodsTo examine the role of sEH in pathogenesis of AD, we used wild-type (WT) mice, soluble epoxide hydrolase deficient (sEH−/−) and two mouse models of AD, including amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (APP/PS1 Tg) and APP/PS1 Tg/sEH−/− mice. Western blotting analysis and immunohistochemistry assay were performed to evaluate the protein expression. Locomotion, nesting building ability, Y-maze, and Morris water maze tests were conducted to study mouse behavior. The levels of interleukin (IL)-1β, IL-4, IL-6, and IL-10 and the activities of NF-κB and nuclear factor of activated T cells (NFAT) were measured by commercial assay kits. The quantitative protein level profiling in the brain lysate was analyzed using LC-MS/MS approaches.ResultsWe demonstrated that the level of sEH was increased in the brain and predominantly appeared in hippocampal astrocytes of APP/PS1 Tg mice. Genetic ablation of sEH in APP/PS1 Tg mice delayed the progression of AD as evidenced by the alleviation in behavior outcomes and Aβ plaque deposition. In addition, loss of the function of sEH in APP/PS1 Tg mice increased astrogliosis and the production of astrocyte-derived anti-inflammatory cytokines including IL-1β, IL-4, and IL-10, as well as the activity of NF-kB and NFAT. Moreover, analysis of gene ontology in the AD brain revealed that important signaling pathways and processes related to AD pathogenesis such as translational regulation, oxidative stress, cytoskeleton reorganization, and small GTPase signal transduction were altered in APP/PS1 Tg/sEH−/− mice compared with APP/PS1 Tg mice.ConclusionOur results suggest that sEH is a crucial regulator in the progression of AD and might be a potential therapeutic target for the treatment of AD.

Epoxy fatty acid dysregulation and neuroinflammation in Alzheimer’s disease is resolved by a soluble epoxide hydrolase inhibitor

“…2B). We observed elevated expression of sEH predominantly in GFAP-positive astrocytes in Tg samples, with negligible co-staining with Iba1, consistent with previous findings (27). Both the sEH fluorescence intensity and the number of sEH expressing cells were increased significantly in Tg mice compared to N-Tg controls ( Fig.…”

“…However, they are broken down rapidly into their corresponding diols by the soluble epoxide hydrolase (sEH). Genetic deletion of Ephx2 (gene encoding sEH) or pharmacological inhibition of sEH conferred beneficial effects in several disease models, including depression, Parkinson's disease (23)(24)(25)(26), and most recently, APP/PS1 transgenic mouse model of AD (27). However, these studies are restricted to acute model systems or germline deletions.…”

“…Moreover, TPPU reinstates and positively correlates the EpFA levels in the Tg brain, supporting its brain penetration and target engagement.Upregulation of sEH expression has been reported in CNS disorders such as depression(26), schizophrenia(34), and Lewy body dementia and Parkinson's disease(25), and its inhibition has been shown to be beneficial in model systems. Lee et al(27) recently reported that sEH is upregulated in APP/PS1 mice. Our results clearly demonstrate that sEH is not only elevated in multiple transgenic AD mouse models, but also in human AD brains support the idea that it is a conserved and common feature in diseases with neuroinflammatory underpinning.…”

Soluble Epoxide Hydrolase Inhibition to Face Neuroinflammation in Parkinson’s Disease: A New Therapeutic Strategy

“…Interestingly, sEHi impacted on AD hallmarks as amyloid plaques and tau hyperphosphorylation, preventing cognitive decline after oral administration [110]. Additionally, Lee et al (2019) [111] demonstrated that sEH deletion in an AD mice model (APP/PS1) reduced and delayed the development of cognitive impairment and specific markers of the disease such as β-amyloid deposition and apoE expression.…”

“…sEH could likely represent a promising therapeutic target for neurological disorders such as depression, PD, LBD, and AD [108,110,111,147]. In the recent past, several reports demonstrated the usefulness of small molecules for inhibiting sEH activity, which was effective against several illness conditions such as cancer, hypertension, heart diseases (ischemia, cardiac, and renocardiac failures), obesity, and diabetic neuropathy [148][149][150][151][152][153][154][155][156].…”