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

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 omega-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-beta 1-42 (A beta) 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 A beta in plaques and transfer it without degradation into brain microvessels, suffer apoptotis, and release A beta, 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 A beta after 2 hours and increased degradation of A beta after 24 hours. Conclusions The sEHI inhibitor EC5026 and the STING inhibitor H-151 increased macrophage uptake and degradation of A beta. EC5026 administration was safe in normal volunteers. EC5026 together with omega-3 PUFA supplementation are indicated for in a clinical trial in patients with mild cognitive impairment.