Novel molecular mechanism driving neuroprotection after soluble epoxide hydrolase inhibition: Insights for Alzheimer's disease therapeutics

Abstract

Background: Neuroinflammation is widely recognized as a significant hallmark of Alzheimer's disease (AD). To combat neuroinflammation, the inhibition of the soluble epoxide hydrolase (sEH) enzyme has been demonstrated crucial. Importantly, sEH inhibition could be related to other neuroprotective pathways described in AD.

Aims: The aim of the study was to unveil new molecular pathways driving neuroprotection through sEH, we used an optimized, potent, and selective sEH inhibitor (sEHi, UB-SCG-51).

Materials and methods: UB-SCG-51 was tested in neuroblastoma cell line, SH-SY5Y, in primary mouse and human astrocytes cultures challenged with proinflammatory insults and in microglia cultures treated with amyloid oligomers, as well as in mice AD model (5XFAD).

Results: UB-SCG-51 (10 and 30 μM) prevented neurotoxic reactive-astrocyte conversion in primary mouse astrocytes challenged with TNF-α, IL-1α, and C1q (T/I/C) combination for 24 h. Moreover, in microglial cultures, sEHi reduced inflammation and glial activity. In addition, UB-SCG-51 rescued 5XFAD cognitive impairment, reducing the number of Amyloid-β plaques and Tau hyperphosphorylation accompanied by a reduction in neuroinflammation and apoptotic markers. Notably, a transcriptional profile analysis revealed a new pathway modulated by sEHi treatment. Specifically, the eIF2α/CHOP pathway, which promoted the endoplasmic reticulum response, was increased in the 5XFAD-treated group. These findings were confirmed in human primary astrocytes by combining sEHi and eIF2α inhibitor (eIF2αi) treatment. Besides, combining both treatments resulted in increased in C3 gene expression after T/I/C compared with the group treated with sEHi alone in cultures.

Discussion: Therefore, sEHi rescued cognitive impairment and neurodegeneration in AD mice model, based on the reduction of inflammation and eIF2α/CHOP signaling pathway.

Conclusions: In whole, our results support the concept that targeting neuroinflammation through sEH inhibition is a promising therapeutic strategy to fight against Alzheimer's disease with additive and/or synergistic activities targeting neuroinflammation and cell stress.

Keywords: 5XFAD; endoplasmic reticulum stress; epoxide hydrolase; glia; neuroinflammation.