Comerota, M. | Search bioRxiv

bioRxiv2026

Astrocytic sEH-EET signaling regulates microglial lysosomal function and suppresses the STING-Type I interferon pathway in Alzheimer's disease

Background: The development of {beta}-amyloid (A{beta}) pathology in Alzheimer's disease (AD) is accompanied by profound changes in astrocytes and microglia and associated neuroinflammation. Soluble epoxide hydrolase (sEH), which degrades anti-inflammatory epoxyeicosatrienoic acids (EETs), is elevated in the AD brain, yet how EETs restrain inflammation remains poorly understood. Methods: We performed single-nucleus RNA sequencing (snRNA-seq) on brains from wild-type, sEH knockout, 5xFAD, and 5xFAD; sEH knockout mice, and used primary mouse microglia and human induced pluripotent stem cell (iPSC)-derived microglia to define the underlying mechanism. To test cell-type-specific contributions, we generated astrocyte- and endothelial-specific she knockout mice and crossed them with 5xFAD mice. Results: Genetic disruption of sEH in 5xFAD mice markedly reduced the abundance of a type I interferon (IFN)-responsive microglial subcluster and lowered phospho-STING (pSTING) levels. In primary microglia, supplementation with 11,12-EET attenuated STING activation and IFN target gene expression; blocking lysosomal acidification abolished this effect and caused pSTING to accumulate, identifying lysosomal degradation as a critical route for terminating STING signaling. 11,12-EET also enhanced microglial lysosomal acidification and A{beta} phagocytosis. Astrocytic, but not endothelial, disruption of sEH recapitulated the reductions in A{beta} pathology and microglial STING activation seen in global sEH-deficient mice, identifying astrocytes as the major cellular source of EETs regulating this pathway. Conclusion: We define an astrocyte-microglia axis in which astrocytic sEH limits EET availability and thereby sustains microglial STING signaling. By promoting lysosomal clearance of pSTING, EETs suppress type I IFN signaling and enhance microglial A{beta} clearance, highlighting sEH inhibition as a therapeutic strategy targeting both neuroinflammation and lysosomal dysfunction in AD.

neuroscience↗

bioRxiv2020

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

Neuroinflammation has been increasingly recognized to play critical roles in Alzheimers disease (AD). The epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by the soluble epoxide hydrolase (sEH). We found that sEH is predominantly expressed in astrocytes where its levels are significantly elevated in postmortem human AD brains and in {beta}-amyloid mouse models, and the latter is correlated with drastic reductions of brain EpFA levels. Using a highly potent and specific small molecule sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we report here that TPPU treatment potently protected against LPS-induced inflammation in vitro and in vivo. Long-term administration of TPPU to the 5xFAD mouse model via drinking water reversed microglia and astrocyte reactivity and immune pathway dysregulation, and this is associated with reduced {beta}-amyloid pathology and improved synaptic integrity and cognitive function. Importantly, TPPU treatment reinstated and positively correlated EpFA levels in the 5xFAD mouse brain, demonstrating its brain penetration and target engagement. These findings support TPPU as a novel therapeutic target for the treatment of AD and related disorders. One Sentence SummaryWe show that soluble epoxide hydrolase is upregulated in AD patients and mouse models, and that inhibition of this lipid metabolic pathway using an orally bioavailable small molecule inhibitor is effective in restoring brain epoxy fatty acids, ameliorating AD neuropathology and improving synaptic and cognitive function.

neuroscience↗