10 Nov 2005

Prostaglandin E2 (PGE2) responses could play a role in Alzheimer disease (AD) pathology. That’s the conclusion of a study reported in the current Journal of Neuroscience. Katrin Andreasson and colleagues at Johns Hopkins University, Baltimore, Maryland, found that deleting one form of the PGE2 receptor in mice protects them from oxidative damage and accumulation of amyloid-β (Aβ). The finding adds to the debate over the role of inflammatory responses, particularly prostaglandin synthesis, in AD.

PGE2 stimulates the release of proinflammatory cytokines (see ARF related news story), and researchers have found increased levels of the prostaglandin in the cerebrospinal fluid of AD patients (see Montine et al., 1999). More recently, Andreasson and colleagues found that the EP2 receptor for PGE2 is expressed in the hippocampus and cerebral cortex, areas of the brain particularly affected by AD pathology (see McCullough et al., 2004). This, plus the finding that the EP2 receptor plays a role in microglial activation, prompted the researchers to investigate its potential role in a mouse model of AD.

First author Xibin Liang and colleagues—together with Richard Breyer at Vanderbilt University School of Medicine, Tennessee, and Thomas Montine at the University of Washington, Seattle—deleted the prostaglandin receptor in transgenic mice expressing mutant human genes that cause familial forms of AD—the Aβ precursor protein (APP) harboring the Swedish mutations and human presenilin 1 with deleted glutamic acid 9 (APPSwe-PS1δE9). They then tested the mice for lipid oxidation (a commonly used measure of brain inflammation) and for amyloid burden. Liang and colleagues found that in 12-month-old mice lacking the receptor, F4-neuroprostanes, oxidative derivatives of docosohexanoic acid, were reduced by over half compared to EP2-expressing control animals. F2 isoprostanes were similarly reduced, though this result failed to reach statistical significance.

The authors then used a variety of tests to see how lack of the PGE2 receptor affected Aβ deposition. ELISA and Western blot analysis showed that in both male (12 months) and female (8 months) animals, loss of the receptor reduced the amount of Aβ40 and Aβ42 by about 40-50 percent; the results were highly statistically significant. Histochemical analysis of brain slices showed that the plaque load was also significantly reduced in these animals, again by about 50 percent in the female mice and 70 percent in males.

“Our findings suggest a potential mechanism for the anti-amyloid and proamyloid properties of NSAIDS and COX-2 overexpression, respectively, in transgenic models of mutant APP,” write the authors. They suggest that “the effects of EP2 receptor deletion may also be relevant to the preventive effects of chronic NSAID use against the development of AD.” In this regard it is worth noting that the effects of non-steroidal anti-inflammatory drugs (NSAIDs) are controversial, with data indicating that their main effect in AD patients might be to inhibit γ-secretase, the enzyme that cleaves Aβ from AβPP, rather than COX-2, the enzyme that catalyzes the rate-limiting step in prostaglandin synthesis (see ARF related news story).—Tom Fagan