Faculty Collaboration Database

Inhibition of soluble epoxide hydrolase ameliorates cerebral blood flow autoregulation and cognition in alzheimer's disease and diabetes-related dementia rat models. Geroscience 2025 Jun;47(3):4429-4449

Date

02/04/2025

Pubmed ID

39903369

Pubmed Central ID

PMC12181608

DOI

10.1007/s11357-025-01550-8

Scopus ID

2-s2.0-85218036037 (requires institutional sign-in at Scopus site)   12 Citations

Abstract

Alzheimer's Disease and Alzheimer's Disease-related dementias (AD/ADRD) pose major global healthcare challenges, with diabetes mellitus (DM) being a key risk factor. Both AD and DM-related ADRD are characterized by reduced cerebral blood flow, although the exact mechanisms remain unclear. We previously identified compromised cerebral hemodynamics as early signs in TgF344-AD and type 2 DM-ADRD (T2DN) rat models. Genome-wide studies have linked AD/ADRD to SNPs in soluble epoxide hydrolase (sEH). This study explored the effects of sEH inhibition with TPPU on cerebral vascular function and cognition in AD and DM-ADRD models. Chronic TPPU treatment improved cognition in both AD and DM-ADRD rats without affecting body weight. In DM-ADRD rats, TPPU reduced plasma glucose and HbA1c levels. Transcriptomic analysis of primary cerebral vascular smooth muscle cells from AD rats treated with TPPU revealed enhanced pathways related to cell contraction, alongside decreased oxidative stress and inflammation. Both AD and DM-ADRD rats exhibited impaired myogenic responses and autoregulation in the cerebral circulation, which were normalized with chronic sEH inhibition. Additionally, TPPU improved acetylcholine-induced vasodilation in the middle cerebral arteries (MCA) of DM-ADRD rats. Acute TPPU administration unexpectedly caused vasoconstriction in the MCA of DM-ADRD rats at lower doses. In contrast, higher doses or longer durations were required to induce effective vasodilation at physiological perfusion pressure in both control and ADRD rats. Additionally, TPPU decreased reactive oxygen species production in cerebral vessels of AD and DM-ADRD rats. These findings provide novel evidence that chronic sEH inhibition can reverse cerebrovascular dysfunction and cognitive impairments in AD/ADRD, offering a promising avenue for therapeutic development.

Author List

Tang C, Border JJ, Zhang H, Gregory A, Bai S, Fang X, Liu Y, Wang S, Hwang SH, Gao W, Morgan GC, Smith J, Bunn D, Cantwell C, Wagner KM, Morisseau C, Yang J, Shin SM, O'Herron P, Bagi Z, Filosa JA, Dong Y, Yu H, Hammock BD, Roman RJ, Fan F

Authors

Seung Min Shin PhD, BS, MS Assistant Professor in the Anesthesiology department at Medical College of Wisconsin
Hongwei Yu MD Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alzheimer Disease
Animals
Cerebrovascular Circulation
Cognition
Diabetes Mellitus, Type 2
Disease Models, Animal
Epoxide Hydrolases
Homeostasis
Male
Rats
Rats, Inbred F344