Vascular mechanisms of inhibition of sEH as a novel therapy for AD/ADRD

Alzheimer's disease and Alzheimer's disease and related dementias (AD/ADRD) is an emerging global health care crisis. However, underlying mechanisms have not been understood well enough for translation to precision medicine. Understanding vascular contribution to AD/ADRD is imperative since increasing evidence suggests AD and diabetic (DM)-related ADRD are associated with brain hypoperfusion, and 67% of AD GWAS genes are expressed in the cerebral vasculature. Recent studies demonstrated that reduction of soluble epoxide hydrolase (sEH) is beneficial to cognition in AD, DM-ADRD, and cerebral hypoperfusion animal models due to its anti- inflammatory and neuronal protective effects, but vascular contribution has been neglected. sEH is an enzyme that transforms arachidonic acid (AA)-derived EETs and linoleic acid (LA)-derived EpOMEs to their corresponding diols DHETs and DiHOMEs, respectively. Changes in oxylipins, such as the elevated ratio of DHETs/EETs and DiHOMEs/EpOMEs, were found in AD mice and ADRD patients. We preliminary found that SNPs in genes (CYP2J2, 2C8, 2C9) encoding enzymes that catalyze AA and LA to EETs and EpOMEs, and EPHX2 encoding sEH are linked with AD in the ARIC-NCS. We also found that a highly selective sEH inhibitor (sEHi) TPPU reversed cognitive disability, impaired myogenic response (MR) and autoregulation of cerebral blood flow (CBF), and neurovascular unit (NVU) dysfunction in DM-ADRD and AD rats. Moreover, AD/ADRD rats displayed brain hypoperfusion, enhanced blood-brain barrier (BBB) leakage, neurodegeneration, and reduced brain Kir2.1 activity that has been reported to associate with reduced PIP2 levels in cerebral capillary endothelial cells due to enhanced PLA2 activity. This proposal will test the HYPOTHESIS that inhibition of sEH synergistically modulates the PLA2-AA-EETs-DHETS and PLA2-LA-EpOMEs-DiHOMEs pathways to reverse cognitive impairments and enhance brain perfusion by ameliorating CBF autoregulation, maintaining BBB and NVU function. We will compare vascular function (MR, CBF autoregulation, and functional hyperemia), AD phenotypes, regional brain levels of PLA2, sEH, PlP2, Kir2.1, and oxylipins in TPPU-treated both sexes of DM- ADRD and AD rats. We will also compare vascular responses to isomer mixtures of EETs/DHETs, and EpOMEs/DiHOMEs in cerebral arteries and arterioles, and vasodilation responses to elevated potassium and isomer mixtures of oxylipins in arterioles-capillaries isolated from both sexes of control, AD, and ADRD rats to further explore the specific pathways that are affected by inhibition of sEH. This project will address critical knowledge gaps of the vascular contribution of sEHi on cognitive protection and the “next steps” in explaining the biology of the catalytic activity of the sEH. Results generated from this proposal should lay the foundation for the discovery of new drugs targeting these pathways to reverse cerebral vascular dysfunction to prevent the onset and slow the progression of AD/ADRD. .