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Wu Y, Dong JH, Dai YF, Zhu MZ, Wang MY, Zhang Y, Pan YD, Yuan XR, Guo ZX, Wang CX, Li YQ, Zhu XH. Hepatic soluble epoxide hydrolase activity regulates cerebral Aβ metabolism and the pathogenesis of Alzheimer's disease in mice. Neuron. 2023 Sep 20;111(18):2847-2862.e10. Epub 2023 Jul 3 PubMed.
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Baylor College of Medicine
Soluble epoxide hydrolase (sEH) is expressed in both peripheral tissues and CNS. Its upregulation has been implicated in multiple neurological conditions, including depression, Parkinson’s disease, and Alzheimer’s disease. Genetic and pharmacological inhibition has been shown to provide therapeutic benefit and these have been attributed to a central mechanism. Here, the authors present an alternative mechanism by which hepatic sEH regulates 14,15-EET, one of the sEH substrates, in the periphery, which then passes the blood-brain barrier to mediate Aβ and tau pathologies and behavior in AD mouse models.
The significance of the work is twofold: One, it reveals a novel liver-brain interaction pathway that modulates AD neuropathology; two, it raises the exciting possibility that peripheral sEH inhibition may provide therapeutic benefit for treating CNS diseases such as AD.
Having said that, the study as presented leaves open several questions that warrant further investigation: 1) We and others have shown that levels of sEH in the brain are increased in AD patients and mouse models (Lee et al., 2019; Ghosh et al., 2020). The strong correlation between sEH inhibition and increased EETs in the brain that we observed supports a central mode of action. Thus the differential contributions of central versus peripheral effects remain to be established. 2) Robust effects of hepatic sEH inhibition on both Aβ and tau pathologies are intriguing and beg the question if these are mediated through common or distinct pathways. 3) A specific increase of 14,15-EET, but not other regioisomers, is also intriguing because these are all sEH substrates and are expected to be affected by sEH inhibition.
References:
Lee HT, Lee KI, Chen CH, Lee TS. Genetic deletion of soluble epoxide hydrolase delays the progression of Alzheimer's disease. J Neuroinflammation. 2019 Dec 17;16(1):267. PubMed.
Ghosh A, Comerota MM, Wan D, Chen F, Propson NE, Hwang SH, Hammock BD, Zheng H. An epoxide hydrolase inhibitor reduces neuroinflammation in a mouse model of Alzheimer's disease. Sci Transl Med. 2020 Dec 9;12(573) PubMed.
View all comments by Hui ZhengOregon Health & Science University
The significance of this study is that peripherally administered sEH inhibitors may benefit CNS disorders, especially AD, i.e., there’s no need for the drug to cross the blood-brain barrier, which is a major challenge in designing CNS-targeting drugs. The observation that sEH increases with age is consistent with our previous observation that sEH is increased in the cerebral microvascular endothelium in postmortem human brains from deceased patients who had vascular-type dementia (Nelson et al., 2014). However, in the current paper, the authors observed an age-dependent increase in sEH in the livers of normal mice, as well as in the liver of an AD mouse model. In contrast, the increase in our study was in diseased brain. Therefore, it seems that changes in liver sEH do not necessarily contribute to AD pathology per se, but rather worsen AD by decreasing levels of the anti-inflammatory 14,15-EET, attenuating microglial phagocytosis. The latter observation is consistent with an earlier report showing that sEH inhibition induces a neuroprotective phenotype in activated microglia in the context of global cerebral ischemia (Wang et al., 2013).
That AD patients have reduced 14,15-EET is interesting, as it may provide a biomarker for the early detection of AD. This finding is also consistent with our recent work showing that human polymorphisms in the newly discovered receptor for 14,15-EET, GPR39, are linked to white-matter hyperintensity, an MRI marker of vascular dementia, and that GPR39 gene deletion causes cognitive deficits in mice (Alkayed et al., 2022; Davis et al., 2021; Bah et al., 2022). The authors’ observation that sEH is protective in models of AD is not novel, as similar observations have been previously reported (Ghosh et al., 2020; Griñán-Ferré et al., 2020). The novel findings are the role of hepatic sEH in setting the levels of plasma 14,15-EET, and its therapeutic targeting.
Some sEH inhibitors have made it to human clinical trials, including GSK2256294, which we have recently shown to be safe and well-tolerated in critically ill patients with subarachnoid hemorrhage, and which decreases inflammatory cytokines in CSF from these patients (Martini et al., 2022). However, long-term safety is unknown, which would be a requirement for an AD drug.
References:
Nelson JW, Young JM, Borkar RN, Woltjer RL, Quinn JF, Silbert LC, Grafe MR, Alkayed NJ. Role of soluble epoxide hydrolase in age-related vascular cognitive decline. Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:30-7. Epub 2014 Sep 30 PubMed.
Wang J, Fujiyoshi T, Kosaka Y, Raybuck JD, Lattal KM, Ikeda M, Herson PS, Koerner IP. Inhibition of soluble epoxide hydrolase after cardiac arrest/cardiopulmonary resuscitation induces a neuroprotective phenotype in activated microglia and improves neuronal survival. J Cereb Blood Flow Metab. 2013 Oct;33(10):1574-81. Epub 2013 Jul 3 PubMed.
Alkayed NJ, Cao Z, Qian ZY, Nagarajan S, Liu X, Nelson JW, Xie F, Li B, Fan W, Liu L, Grafe MR, Davis CM, Xiao X, Barnes AP, Kaul S. Control of coronary vascular resistance by eicosanoids via a novel GPCR. Am J Physiol Cell Physiol. 2022 May 1;322(5):C1011-C1021. Epub 2022 Apr 6 PubMed.
Davis CM, Bah TM, Zhang WH, Nelson JW, Golgotiu K, Nie X, Alkayed FN, Young JM, Woltjer RL, Silbert LC, Grafe MR, Alkayed NJ. GPR39 localization in the aging human brain and correlation of expression and polymorphism with vascular cognitive impairment. Alzheimers Dement (N Y). 2021;7(1):e12214. Epub 2021 Oct 14 PubMed.
Bah TM, Allen EM, Garcia-Jaramillo M, Perez R, Zarnegarnia Y, Davis CM, Bloom MB, Magana AA, Choi J, Bobe G, Pike MM, Raber J, Maier CS, Alkayed NJ. GPR39 Deficiency Impairs Memory and Alters Oxylipins and Inflammatory Cytokines Without Affecting Cerebral Blood Flow in a High-Fat Diet Mouse Model of Cognitive Impairment. Front Cell Neurosci. 2022;16:893030. Epub 2022 Jul 6 PubMed.
Ghosh A, Comerota MM, Wan D, Chen F, Propson NE, Hwang SH, Hammock BD, Zheng H. An epoxide hydrolase inhibitor reduces neuroinflammation in a mouse model of Alzheimer's disease. Sci Transl Med. 2020 Dec 9;12(573) PubMed.
Griñán-Ferré C, Codony S, Pujol E, Yang J, Leiva R, Escolano C, Puigoriol-Illamola D, Companys-Alemany J, Corpas R, Sanfeliu C, Pérez B, Loza MI, Brea J, Morisseau C, Hammock BD, Vázquez S, Pallàs M, Galdeano C. Pharmacological Inhibition of Soluble Epoxide Hydrolase as a New Therapy for Alzheimer's Disease. Neurotherapeutics. 2020 Jun 2; PubMed.
Martini RP, Siler D, Cetas J, Alkayed NJ, Allen E, Treggiari MM. A Double-Blind, Randomized, Placebo-Controlled Trial of Soluble Epoxide Hydrolase Inhibition in Patients with Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care. 2022 Jun;36(3):905-915. Epub 2021 Dec 6 PubMed.
View all comments by Nabil AlkayedThis is the third paper that has shown sEH inhibition is beneficial in preventing cognitive decline in Alzheimer’s disease. Importantly, this is the first paper to link sEH in the liver to Alzheimer’s in the brain, though unrelated studies have found connections between liver function and AD progression (Nho et al., 2019). The etiology of AD is largely unknown, though there are known risk factors, such as ApoE4 mutations, diabetes, chronic inflammation, and vascular disease.
The promise of sEH inhibitors in Alzheimer’s is that they have proven beneficial in several of these underlying conditions and hence can target multiple pathways to prevent end-organ damage, in this case, in the brain. Thus, this paper opens the door to a better understanding of the pathogenesis of AD and offers a possible new treatment for the disorder. The sEH inhibitors that have been shown to be safe and effective in early phase human trials should now be tested in an AD population.
References:
Nho K, Kueider-Paisley A, Ahmad S, MahmoudianDehkordi S, Arnold M, Risacher SL, Louie G, Blach C, Baillie R, Han X, Kastenmüller G, Trojanowski JQ, Shaw LM, Weiner MW, Doraiswamy PM, van Duijn C, Saykin AJ, Kaddurah-Daouk R, Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium. Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers. JAMA Netw Open. 2019 Jul 3;2(7):e197978. PubMed.
View all comments by Darryl ZeldinUCLA/VA
This paper has a wealth of data on the 5xFAD and 3xAD Tg models. Overall, it teaches us that manipulation of the peripheral production of specific arachidonic acid-derived oxylipins can ameliorate Alzheimer’s pathology by pleiotropic activities, including reducing BACE1 and Aβ oligomers, with possible direct inhibition of aggregate formation, while also increasing TREM2 and phagocytic amyloid clearance. The most impressive effects come from selectively ablating hepatic Ephx2 after pathology is present: five months in 5xFAD, and 14 months in 3xAD mice. They show a dramatic reduction in pathology to very low levels consistent with clearance and effective treatment of behavioral deficits. These effects are reminiscent of reports from our group and others on curcumin and other immunomodulatory lipid mediators, and highlight the potential of pleiotropic, small molecule interventions in an era of inherently expensive FDA-approved antibody infusions.
This paper does more than this in establishing the impact of bidirectional manipulations of the arachidonic acid/Ephx2 pathway and products that increase or decrease pathology. It shows age-related alterations in hepatic production and circulating levels of 14,15-EET and in DHET/EET ratios in the two animal models, which argue for a treatable, primary, hepatic age change. They also add some data comparing normal control and AD patient levels of these oxylipins to suggest “translational relevance.”
The study has some limitations. 1) It doesn’t include ApoE4 interactions with major effects on TREM2 and lipid mediators. 2) The age-related changes in mice show a jump between ages 5 and 7 months, which equates to normal adults, and only go out to 18 months, while studies on aging mice typically include endpoints at 24 months, or even 28 months and beyond as in the recent paper on taurine and aging (Jun 2023 news). 3) The human data needs to be bolstered, including on MCI measures and aging. I would like a discussion of how their findings relate to multiple, large, unbiased plasma lipidomics studies in humans and mouse models. I am not clear that these unbiased studies have measured these lipids and found, or not found, age or AD changes. In general, they don’t highlight them. 4) Apart from Aβ, the direct targets, vis -à- vis receptors, for the lipid mediators are not identified or discussed.
Despite the limitations, this study adds 3xAD mice and tauopathy data to previous papers from this group, reporting large effects in 5xFAD mice that linked their intervention efficacy to increased lysosomal biogenesis and amyloid clearance in astrocytes.
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