Regulation of prostaglandin F2α, against β amyloid clearance and its inflammation induction through LXR/RXR heterodimer antagonism in microglia

Alzheimer's disease (AD) is characterized by extracellular deposit of beta-amyloid (A beta) and accumulation of intracellular neurofibrillary tangles in the brain. Prostaglandin F-2 alpha, (PGF(2 alpha)) is one of the major metabolites of arachidonic acid (AA), and plays essential roles in a series of key physiological processes like luteolysis and parturition. Additionally, PGF(2 alpha) is also involved in the regulation of chronic and acute inflammation processes. Recent clinical studies have revealed the high content of PGE(2 alpha) metabolite, 15-keto-dihydro-PGF(2 alpha) in AD patients, implying the activation of in vivo PGF(2 alpha) biosynthesis. However, the mechanism underlying the involvement of PGF(2 alpha) in the progression of AD still remains unclear. Here we discovered that PGF(2 alpha) selectively antagonized LXR (liver X receptors)/RXR (retinoid X receptor alpha) and RXR/RXR dimers. Cell based assays indicated that PGF(2 alpha) effectively antagonized the activation of LXR agonist (t0901317) on A beta clearance via inhibiting apolipoprotein E (apoE) expression, and cell apoptosis alleviation by accelerating inflammatory response to A beta or Lipopolysaccharide (LPS) in microglia. Therefore, our current findings have addressed the potential association of PGF(2 alpha) with AD progression, and highlighted that inhibition of PGF(2 alpha) biosynthesis might be a useful therapeutic strategy against AD. (C) 2013 Elsevier Inc. All rights reserved.