1. Academic Validation
  2. 14,15-Epoxyeicosatrienoic Acid Alleviates Pathology in a Mouse Model of Alzheimer's Disease

14,15-Epoxyeicosatrienoic Acid Alleviates Pathology in a Mouse Model of Alzheimer's Disease

  • J Neurosci. 2020 Oct 14;40(42):8188-8203. doi: 10.1523/JNEUROSCI.1246-20.2020.
Wenjun Chen 1 2 Mengyao Wang 1 2 Minzhen Zhu 1 2 Wenchao Xiong 1 2 Xihe Qin 3 Xinhong Zhu 4 2 5 6
Affiliations

Affiliations

  • 1 Institute of Mental Health, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, People's Republic of China.
  • 2 Key Laboratory of Mental Health of the Ministry of Education and Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou 510515, People's Republic of China.
  • 3 Eusyn Medical Technology Company, Guangzhou 510663, People's Republic of China.
  • 4 Institute of Mental Health, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, People's Republic of China zhuxh527@126.com.
  • 5 School of Psychology, Shenzhen University, Shenzhen 518060, People's Republic of China.
  • 6 Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou 510515, People's Republic of China.
Abstract

Alzheimer's disease (AD) is the leading cause of late-onset dementia, and there exists an unmet medical need for effective treatments for AD. The accumulation of neurotoxic Amyloid-β (Aβ) plaques contributes to the pathophysiology of AD. EPHX2 encoding soluble Epoxide Hydrolase (sEH)-a key Enzyme for epoxyeicosatrienoic acid (EET) signaling that is mainly expressed in lysosomes of astrocytes in the adult brain-is cosited at a locus associated with AD, but it is unclear whether and how it contributes to the pathophysiology of AD. In this report, we show that the pharmacologic inhibition of sEH with 1-trifluoromethoxyphenyl- 3-(1-propionylpiperidin-4-yl) urea (TPPU) or the genetic deletion of Ephx2 reduces Aβ deposition in the brains of both male and female familial Alzheimer's disease (5×FAD) model mice. The inhibition of sEH with TPPU or the genetic deletion of Ephx2 alleviated cognitive deficits and prevented astrocyte reactivation in the brains of 6-month-old male 5×FAD mice. 14,15-EET levels in the brains of these mice were also increased by sEH inhibition. In cultured adult astrocytes treated with TPPU or 14,15-EET, astrocyte Aβ clearance was increased through enhanced lysosomal biogenesis. Infusion of 14,15-EET into the hippocampus of 5×FAD mice prevented the aggregation of Aβ. Notably, a higher concentration of 14,15-EET (200 ng/ml) infusion into the hippocampus reversed Aβ deposition in the brains of 6-month-old male 5×FAD mice. These results indicate that EET signaling, especially 14,15-EET, plays a key role in the pathophysiology of AD, and that targeting this pathway is a potential therapeutic strategy for the treatment of AD.SIGNIFICANCE STATEMENT There are limited treatment options for Alzheimer's disease (AD). EPHX2 encoding soluble Epoxide Hydrolase (sEH) is located at a locus that is linked to late-onset AD, but its contribution to the pathophysiology of AD is unclear. Here, we demonstrate that sEH inhibition or Ephx2 deletion alleviates pathology in familial Alzheimer's disease (5×FAD) mice. Inhibiting sEH or increasing 14,15-epoxyeicosatrienoic acid (EET) enhanced lysosomal biogenesis and Amyloid-β (Aβ) clearance in cultured adult astrocytes. Moreover, the infusion of 14,15-EET into the hippocampus of 5×FAD mice not only prevented the aggregation of Aβ, but also reversed the deposition of Aβ. Thus, 14,15-EET plays a key role in the pathophysiology of AD and therapeutic strategies that target this pathway may be an effective treatment.

Keywords

14,15-epoxyeicosatrienoic acid; Alzheimer's disease; astrocyte; lysosomal biogenesis; soluble epoxide hydrolase.

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