Antagonism of the EP2 Receptor Reveals Sex-Specific Protection in a Two-Hit Mouse Model of Alzheimer’s Disease

TL;DR

Blocking the EP2 receptor in male mice with Alzheimer's disease improved memory and reduced brain inflammation, but effects varied by sex.

Contribution

This study demonstrates sex-specific therapeutic effects of EP2 receptor antagonism in an Alzheimer's disease mouse model.

Findings

EP2 antagonism improved spatial memory in male 5xFAD mice but not females.

Treatment reduced proinflammatory gene expression in the neocortex of male 5xFAD mice.

Amyloid load and glial activation were reduced in male and female 5xFAD mice.

Abstract

Neuroinflammation is evident in Alzheimer’s disease
(AD)
brains, exacerbating the pathology and ensuing cognitive deficits
in patients. The prostaglandin-E2 receptor EP2 emerged as a neuroinflammatory
target in several neurodegenerative diseases, including AD. Antagonism
of EP2 mitigates neuroinflammation and cognitive deficits in status
epilepticus and stroke models. Here, we investigated the efficacy
of a potent and selective EP2 antagonist TG11–77.HCl on the
cognitive behavior and neuroinflammation in a two-hit 5xFAD mouse
model of AD. We exposed adult 5xFAD mice on B6SJL genetic background
and their nontransgenic littermates to a low dose of lipopolysaccharide
and administered TG11–77.HCl or the vehicle in the drinking
water for 12 weeks. Mice were subjected to Morris water maze and Y-maze
testing during their last week of drug treatment. Blood samples were
subjected to complete blood count (CBC) analysis and brain tissues
were processed to examine the levels of inflammatory transcripts and
glial marker expression (mRNA), followed by the quantification of
congophilic amyloid deposition and microglial activation (IBA+) in the brain by immunohistochemistry. TG11–77.HCl
treatment enhanced the spatial memory performance and ameliorated
mRNA expression of proinflammatory mediators, chemokines, and cytokines
in the neocortex of 5xFAD males only and attenuated astroglia and
microglia activation in both male and female 5xFAD mice and the congophilic
amyloid load in 5xFAD males only. CBC analysis revealed no changes
in peripheral inflammation, irrespective of sex, on treatment with
TG11–77.HCl. This study reveals sex-specific protection of
selective EP2 antagonism in a two-hit mouse model of AD and supports
a prudent therapeutic strategy against neuroinflammation and associated
cognitive impairment in AD.

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