Age-dependent Cognitive Impairment, Hydrocephalus and Leukocyte Infiltration in Transgenic Mice with Endothelial Expression of Human EPHX2

Overview

Journal NPJ Aging

Publisher Springer Nature

Specialty Geriatrics

Date 2022 Aug 4

PMID 35927273

Authors

Catherine M Davis

Wenri H Zhang

Thierno M Bah

Natalie E Roese

Elyse M Allen

Philberta Leung

Sydney J Boutros

Tessa Marzulla

Esha Patel

Xiao Nie

Farah N Alkayed

Justin H Huang

Michael A Jensen

Jacob Raber

Martin M Pike

Nabil J Alkayed

Affiliations

Soon will be listed here.

Abstract

Soluble epoxide hydrolase (sEH) is upregulated in microvascular endothelium of human brain with vascular cognitive impairment (VCI). Transgenic endothelial expression of human sEH in mice (Tie2hsEH) induces endothelial dysfunction (ED), a pathogenetic mechanism of VCI. We sought to determine if endothelial upregulation of sEH is sufficient to cause cognitive impairment, and if cognitive impairment due to chronic hypoperfusion induced by unilateral common carotid artery occlusion (CCAO) is exacerbated in Tie2hsEH mice. Behavioral performance was assessed by the open field, rotarod, novel object, Morris water maze and fear conditioning tests. Cerebral blood flow and brain morphology were evaluated by MRI, and inflammatory changes investigated using immunohistochemistry and flow cytometry. We demonstrate that transgenic endothelial expression of sEH is sufficient to induce cognitive impairment, associated with leukocyte infiltration, brain atrophy and accelerated, age-dependent ventriculomegaly, identifying ED and sEH upregulation as potential underlying mechanisms and therapeutic targets for VCI.

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