Cited by 84Alzheimer's disease research and treatmentsEicosanoids and Hypertension PharmacologyCholinesterase and Neurodegenerative Diseases

Hepatic soluble epoxide hydrolase activity regulates cerebral Aβ metabolism and the pathogenesis of Alzheimer’s disease in mice

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Wu, Yu, Dong, Jing-Hua, Dai, Yong-Feng, Zhu, Min-Zhen, Wang, Meng-Yao, Zhang, Yuan, Pan, Yi-Da, Yuan, Xin-Rui +4 more·2023·Neuron

Abstract

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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Crossref · 10.1016/j.neuron.2023.06.002

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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”

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Authors
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.
Affiliations
Shenzhen University (CN)
Venue
Neuron
Publisher
Elsevier BV
Published
2023-09
Volume
111
Issue
18
Pages
2847-2862.e10
ISSN
0896-6273 (ISSN-L)
OpenAlex
W4382987966
Cited by
84
References
74
Citations by year
2026: 21 · 2025: 35 · 2024: 20 · 2023: 8
FWCI
14.80
Type
journal article
Language
en
Open access
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

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