Inhibitors of soluble epoxide hydrolase and cGAS/STING repair defects in amyloid-β clearance underlying vascular complications of Alzheimer's disease.

Abstract

Background: Alzheimer's disease (AD) and its monoclonal antibody therapies are associated with brain vasculitis and amyloid-related imaging abnormalities. The naturally-formed epoxides (EpFAs) of polyunsaturated fatty acids (PUFAs), such as 11,12-epoxyeicosatetraenoic acid (EEQ), are anti-inflammatory and pro-resolution mediators, which are increased by dietary supplementation with ω-3 PUFAs. EpFAs are, however, enzymatically hydrolyzed by soluble epoxide hydrolase (sEH) in AD patients' macrophages in vivo and in vitro.

Objective: To repair amyloid-β 1-42 (Aβ) degradation by AD macrophages using the inhibitors of a) soluble epoxide hydrolase (sEHIs), termed TPPU and EC5026, together with EpFAs, or b) STING pathway termed H-151.

Methods: Immunobiology, immunochemistry, RNA sequencing, and confocal microscopy were used.

Results: In AD brain (examined postmortem), monocyte/macrophages upload Aβ in plaques and transfer it without degradation into brain microvessels, suffer apoptotis, and release Aβ, inducing vasculitis. The EpFAs of epoxyeicosatetraenoic acid (EEQ), along with the inhibitors TPPU and H-151, decrease inflammatory cytokines and regulate macrophage unfolded protein response to endoplasmic reticulum stress. Treatment of AD macrophages by TPPU with EEQ or by STING inhibitor H-151 increased uploading of Aβ after 2 hours and increased degradation of Aβ after 24 hours.

Conclusions: The sEHI inhibitor EC5026 and the STING inhibitor H-151 increased macrophage uptake and degradation of Aβ. EC5026 administration was safe in normal volunteers. EC5026 together with ω-3 PUFA supplementation are indicated for in a clinical trial in patients with mild cognitive impairment.