| First Author | Chen W | Year | 2020 |
| Journal | J Neurosci | Volume | 40 |
| Issue | 42 | Pages | 8188-8203 |
| PubMed ID | 32973044 | Mgi Jnum | J:296602 |
| Mgi Id | MGI:6468466 | Doi | 10.1523/JNEUROSCI.1246-20.2020 |
| Citation | Chen W, et al. (2020) 14,15-Epoxyeicosatrienoic Acid Alleviates Pathology in a Mouse Model of Alzheimer's Disease. J Neurosci 40(42):8188-8203 |
| abstractText | 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-beta (Abeta) 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 Abeta deposition in the brains of both male and female familial Alzheimer's disease (5xFAD) 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 5xFAD 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 Abeta clearance was increased through enhanced lysosomal biogenesis. Infusion of 14,15-EET into the hippocampus of 5xFAD mice prevented the aggregation of Abeta. Notably, a higher concentration of 14,15-EET (200 ng/ml) infusion into the hippocampus reversed Abeta deposition in the brains of 6-month-old male 5xFAD 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 (5xFAD) mice. Inhibiting sEH or increasing 14,15-epoxyeicosatrienoic acid (EET) enhanced lysosomal biogenesis and amyloid-beta (Abeta) clearance in cultured adult astrocytes. Moreover, the infusion of 14,15-EET into the hippocampus of 5xFAD mice not only prevented the aggregation of Abeta, but also reversed the deposition of Abeta. 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. |
