Abstract
BackgroundAlzheimer’s disease (AD) causes substantial medical and societal burden with no therapies ameliorating cognitive deficits. Centralized pathologies involving amyloids, neurofibrillary tangles, and neuroinflammatory pathways are being investigated to identify disease-modifying targets for AD. Cyclooxygenase-2 (COX-2) is one of the potential neuroinflammatory agents involved in AD progression. However, chronic use of COX-2 inhibitors in patients produced adverse cardiovascular effects. We asked whether inhibition of EP2 receptors, downstream of the COX-2 signaling pathway, can ameliorate neuroinflammation in AD brains in presence or absence of a secondary inflammatory stimuli.MethodsWe treated 5xFAD mice and their non-transgenic (nTg) littermates in presence or absence of lipopolysaccharide (LPS) with an EP2 antagonist (TG11-77.HCl). In cohort 1, nTg (no-hit) or 5xFAD (single-hit—genetic) mice were treated with vehicle or TG11-77.HCl for 12 weeks. In cohort 2, nTg (single-hit—environmental) and 5xFAD mice (two-hit) were administered LPS (0.5 mg/kg/week) and treated with vehicle or TG11-77.HCl for 8 weeks.ResultsComplete blood count analysis showed that LPS induced anemia of inflammation in both groups in cohort 2. There was no adverse effect of LPS or EP2 antagonist on body weight throughout the treatment. In the neocortex isolated from the two-hit cohort of females, but not males, the elevated mRNA levels of proinflammatory mediators (IL-1β, TNF, IL-6, CCL2, EP2), glial markers (IBA1, GFAP, CD11b, S110B), and glial proteins were significantly reduced by EP2 antagonist treatment. Intriguingly, the EP2 antagonist had no effect on either of the single-hit cohorts. There was a modest increase in amyloid–plaque deposition upon EP2 antagonist treatment in the two-hit female brains, but not in the single-hit genetic female cohort.ConclusionThese results reveal a potential neuroinflammatory role for EP2 in the two-hit 5xFAD mouse model. A selective EP2 antagonist reduces inflammation only in female AD mice subjected to a second inflammatory insult.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder that is the leading cause of dementia in the elderly [1]
We report that chronic Prostaglandin-E2 receptor-2 (EP2) antagonism is beneficial only in the two-hit 5xFAD model by attenuating neuroinflammation and gliosis when the genetic insult was combined with the external inflammatory insult
Mice in cohort 1 had both sexes of 5xFAD and their non-transgenic littermates treated with either EP2 antagonist TG11-77.HCl (58.1 mg/kg/day) or its vehicle for 12 weeks starting at 8 weeks of age
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder that is the leading cause of dementia in the elderly [1]. The last two decades of drug discovery efforts for AD have mainly focused on the amyloid cascade hypothesis [5, 6], which involves targeting the removal of amyloid plaques from the brain of AD patients with active or passive immunization (e.g., bapineuzumab), decreasing total Aβ production with γ-secretase inhibitors (e.g., semagacestat), or decreasing Aβ42 levels with γ-secretase modulators (e.g., tarenflurbil). These agents have not yet provided a clinical benefit [7,8,9] suggesting anti-amyloid therapeutics alone may not be sufficient to ameliorate the disease pathology. We asked whether inhibition of EP2 receptors, downstream of the COX-2 signaling pathway, can ameliorate neuroinflammation in AD brains in presence or absence of a secondary inflammatory stimuli
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