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 β-amyloid (Aβ) and accumulation of intracellular neurofibrillary tangles in the brain. Prostaglandin F2α (PGF2α) 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, PGF2α is also involved in the regulation of chronic and acute inflammation processes. Recent clinical studies have revealed the high content of PGF2α metabolite, 15-keto-dihydro-PGF2α in AD patients, implying the activation of in vivo PGF2α biosynthesis. However, the mechanism underlying the involvement of PGF2α in the progression of AD still remains unclear. Here we discovered that PGF2α selectively antagonized LXR (liver X receptors)/RXR (retinoid X receptor α) and RXR/RXR dimers. Cell based assays indicated that PGF2α effectively antagonized the activation of LXR agonist (t0901317) on Aβ clearance via inhibiting apolipoprotein E (apoE) expression, and cell apoptosis alleviation by accelerating inflammatory response to Aβ or Lipopolysaccharide (LPS) in microglia. Therefore, our current findings have addressed the potential association of PGF2α with AD progression, and highlighted that inhibition of PGF2α biosynthesis might be a useful therapeutic strategy against AD.
School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Jingjing
J
Zhuang
Haikun
H
Zhang
Rong
R
Zhou
Lili
L
Chen
Jing
J
Chen
Xu
X
Shen
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D002460:Cell Line; D015237:Dinoprost / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D000071518:Liver X Receptors; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry*; D010446:Peptide Fragments / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D047488:Retinoid X Receptors / Q000737:chemistry*; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D016229:Amyloid beta-Peptides; D015237:Dinoprost; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010446:Peptide Fragments; D047488:Retinoid X Receptors; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C075222:amyloid beta-protein (1-42)
Alzheimer's disease; Aβ clearance; Inflammation; Microglia; Prostaglandin F(2α)