Hepatic soluble epoxide hydrolase activity regulates cerebral Aβ metabolism and the pathogenesis of Alzheimer’s disease in mice
Open accessAbstract
Alzheimer's disease (AD) is caused by a complex interaction between genetic and environmental factors. However, how the role of peripheral organ changes in response to environmental stimuli during aging in AD pathogenesis remains unknown. Hepatic soluble epoxide hydrolase (sEH) activity increases with age. Hepatic sEH manipulation bidirectionally attenuates brain amyloid-β (Aβ) burden, tauopathy, and cognitive deficits in AD mouse models. Moreover, hepatic sEH manipulation bidirectionally regulates the plasma level of 14,15-epoxyeicosatrienoic acid (-EET), which rapidly crosses the blood-brain barrier and modulates brain Aβ metabolism through multiple pathways. A balance between the brain levels of 14,15-EET and Aβ is essential for preventing Aβ deposition. In AD models, 14,15-EET infusion mimicked the neuroprotective effects of hepatic sEH ablation at biological and behavioral levels. These results highlight the liver's key role in AD pathology, and targeting the liver-brain axis in response to environmental stimuli may constitute a promising therapeutic approach for AD prevention.
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Hepatic soluble epoxide hydrolase activity increases with age, decreasing the brain level of 14,15-epoxyeicosatrienoic acid, which directly binds to Aβ to prevent its deposition and indirectly enhances microglial TREM2-dependent Aβ phagocytosis, further delaying cognitive decline.
“In addition, hepatic soluble epoxide hydrolase activity increases with age, decreasing the brain level of 14,15-epoxyeicosatrienoic acid, which directly binds to Aβ to prevent its deposition and indirectly enhances microglial TREM2-dependent Aβ phagocytosis, further delaying cognitive decline.230”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [230]
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Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances
Jiang, Q., Liu, J., Huang, S., Wang, X.-Y., Chen, X., Liu, G.-H., Ye, K., Song, W., Masters, C. L., Wang, J., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02145-7 · Cited by 165 · see citing works
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- 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.
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- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 385 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81930034, 2022ZD0211700)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- Alzheimer's disease, soluble epoxide hydrolase, amyloid-beta metabolism, 14,15-epoxyeicosatrienoic acid, liver-brain axis, tauopathy, cognitive impairment, blood-brain barrier, neuroprotection
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Epoxide Hydrolases, Liver, Amyloid beta-Peptides, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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