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The activity of hepatic epoxide hydrolase regulates amyloid-β in the brain



Epoxyeicosatrienoic acids (EETs) play a central role as lipid messengers in the maintenance of homeostasis. These compounds are formed from arachidonic acid by cytochrome P450 enzymes and subsequently converted to dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH).

EETs and sEH have become the focus of scientific interest as potential therapeutic targets for chronic diseases such as diabetes, metabolic syndrome or inflammatory pain. In particular, administration of small molecule sEH inhibitors has been shown to reduce amyloid-β (Aβ) pathology in the brain and improve both synaptic integrity and cognitive function in Alzheimer's (5xFAD) mice.


In a paper published last year in Neuron, Yu Wu and colleagues investigated the effects of hepatic sEH and EETs on the pathogenesis of Alzheimer's disease in more detail. For their study, they used inducible and liver-specific epoxide hydrolase knockout mice and found that while sEH is expressed in various peripheral organs, its removal in the liver led to a significant increase in certain EETs (14,15-EET). Interestingly, experiments in which the liver-specific sEH knockout mice were crossed with Alzheimer's animal models showed that deletion of hepatic sEH decreased both soluble and insoluble Aβ levels in the brain and reduced the overall amyloid burden, suggesting significant therapeutic potential.

In their paper, the authors outline three possible mechanisms by which deletion of epoxide hydrolase could reduce the deposition of Aβ in the brain. Firstly, they discovered that the cleavage of the amyloid precursor protein (APP) is reduced in the animals. Secondly, a reduction in hepatic sEH activity promotes Aβ clearance by microglia. Indeed, deletion of hepatic sEH resulted in increased accumulation of microglial cells around amyloid plaques. Remarkably, sEH deletion also reduced apolipoprotein E (ApoE) protein levels in the brain without altering ApoE mRNA expression. In addition, cell culture experiments showed that 14,15-EET, but not other EETs, directly interacts with Aβ and inhibits its oligomerisation in a dose-dependent manner.

The authors also demonstrated that administration of 14,15-EET via intracerebroventricular infusion using an osmotic pump significantly reduced levels of amyloid-β and phosphorylated tau while improving cognitive function in Alzheimer's mice. In addition to 14,15-EET, the deletion of sEH in the liver also increased the levels of other epoxy fatty acids, which also have an influence on Aβ pathology and the phenotype of Alzheimer's disease.

There is also the possibility that circulating 14,15-EET acts directly on the cerebrovascular system by promoting endothelial cell proliferation and vasodilation, which may be critical given the role of cerebrovascular dysfunction in AD. Therefore, by increasing 14,15-EET plasma levels, deletion of sEH in the liver may improve blood-brain barrier integrity, neurovascular coupling and thus cognitive abilities. In addition, elevated levels of 14,15-EET in plasma may promote the clearance of Aβ by peripheral organs such as the liver and kidney after its transport from the brain into the bloodstream.

Taken together, the liver-brain axis appears to have an increasing influence not only on various metabolic processes and the immune system, but also on neurodegenerative diseases. It is noteworthy that plasma levels of 14,15-EET are significantly reduced in Alzheimer's patients compared to patients without cognitive impairment, which emphasises its potential as a new plasma biomarker for Alzheimer's disease.


It is known that liver-specific expression of ApoE4, in contrast to ApoE3, can worsen synaptic plasticity and Aβ pathology in the brain. Current research suggests that soluble epoxide hydrolase is relevant in a number of neurological diseases, such as vascular dementia, Parkinson's disease and traumatic brain injury. It is therefore very welcome that several sEH inhibitors such as GSK2256294, EC5026 and AR9281 are currently in clinical trials (NCT03318783, NCT04228302, NCT00847899).

References:

Inoue Y, Bamkole M, Kanekiyo T (2023) Hepatic soluble epoxide hydrolase: A promising target for unveiling the liver-brain axis in Alzheimer's disease. Neuron 111:2775


Wu Y, Dong J-H, Dai Y-F, Zhu M-Z, Wang M-Y, Zhang Y, Pan Y-D, Yuan X-R, Guo Z-X, Wang C-X, Li Y-Q, Zhu X-H (2023) Hepatic soluble epoxide hydrolase activity regulates cerebral Aβ metabolism and the pathogenesis of Alzheimer's disease in mice. Neuron 111:2847

Image credit: iStock/Mohammed Haneefa Nizamudeen

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