| First Author | Hoshino T | Year | 2012 |
| Journal | J Neurochem | Volume | 120 |
| Issue | 5 | Pages | 795-805 |
| PubMed ID | 22044482 | Mgi Jnum | J:182717 |
| Mgi Id | MGI:5316362 | Doi | 10.1111/j.1471-4159.2011.07567.x |
| Citation | Hoshino T, et al. (2012) Improvement of cognitive function in Alzheimer's disease model mice by genetic and pharmacological inhibition of the EP(4) receptor. J Neurochem 120(5):795-805 |
| abstractText | Amyloid-beta peptide (Abeta), which is generated by the beta- and gamma-secretase-mediated proteolysis of beta-amyloid precursor protein (APP), plays an important role in the pathogenesis of Alzheimer's disease (AD). We recently reported that prostaglandin E(2) (PGE(2) ) stimulates the production of Abeta through both EP(2) and EP(4) receptors and that activation of the EP(4) receptor stimulates Abeta production through endocytosis and activation of gamma-secretase. We here found that transgenic mice expressing mutant APP (APP23) mice showed a greater or lesser apparent cognitive deficit when they were crossed with mice lacking EP(2) or EP(4) receptors, respectively. Mice lacking the EP(4) receptor also displayed lower levels of Abeta plaque deposition and less neuronal and synaptic loss than control mice. Oral administration of a specific EP(4) receptor antagonist, AE3-208 to APP23 mice, improved their cognitive performance, as well as decreasing brain levels of Abeta and suppressing endocytosis and activation of gamma-secretase. Taken together, these results suggest that inhibition of the EP(4) receptor improves the cognitive function of APP23 mice by suppressing Abeta production and reducing neuronal and synaptic loss. We therefore propose that EP(4) receptor antagonists, such as AE3-208, could be therapeutically beneficial for the prevention and treatment of AD. |
