title: Prostaglandin I2 upregulates the expression of anterior pharynx-defective-1α and anterior pharynx-defective-1β in amyloid precursor protein/presenilin 1 transgenic mice.
abstract: Cyclooxygenase-2 (COX-2) has been recently identified to be involved in the pathogenesis of Alzheimer's disease (AD). Yet, the role of an important COX-2 metabolic product, prostaglandin (PG) I2 , in the pathogenesis of AD remains unknown. Using human- and mouse-derived neuronal cells as well as amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice as model systems, we elucidated the mechanism of anterior pharynx-defective (APH)-1α and pharynx-defective-1β induction. In particular, we found that PGI2 production increased during the course of AD development. Then, PGI2 accumulation in neuronal cells activates PKA/CREB and JNK/c-Jun signaling pathways by phosphorylation, which results in APH-1α/1β expression. As PGI2 is an important metabolic by-product of COX-2, its suppression by NS398 treatment decreases the expression of APH-1α/1β in neuronal cells and APP/PS1 mice. More importantly, β-amyloid protein (Aβ) oligomers in the cerebrospinal fluid (CSF) of APP/PS1 mice are critical for stimulating the expression of APH-1α/1β, which was blocked by NS398 incubation. Finally, the induction of APH-1α/1β was confirmed in the brains of patients with AD. Thus, these findings not only provide novel insights into the mechanism of PGI2 -induced AD progression but also are instrumental for improving clinical therapies to combat AD.
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, 110819, China.
authors.forename: Pu
authors.initials: P
authors.lastname: Wang
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, 110819, China.
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Guan
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, 110819, China.
authors.forename: Jing-Wen
authors.initials: JW
authors.lastname: Guo
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, 110819, China.
authors.forename: Long-Long
authors.initials: LL
authors.lastname: Cao
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, 110819, China.
authors.forename: Guo-Biao
authors.initials: GB
authors.lastname: Xu
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, 110819, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, 110819, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, 110819, China.
authors.forename: Zhan-You
authors.initials: ZY
authors.lastname: Wang
mesh_terms: D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D011464:Epoprostenol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008565:Membrane Proteins; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009578:Nitrobenzenes / Q000008:administration & dosage / Q000494:pharmacology; D053764:Presenilin-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D016564:Amyloid beta-Protein Precursor; D017362:Cyclic AMP Response Element-Binding Protein; D008565:Membrane Proteins; D009578:Nitrobenzenes; D053764:Presenilin-1; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D011464:Epoprostenol; D017868:Cyclic AMP-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D010450:Endopeptidases; C498194:Aph1a protein, mouse; C498195:Aph1b protein, mouse
keywords: APP/PS1; anterior pharynx-defective-1α/1β; cyclooxygenase-2; prostaglandin I2; β-amyloid protein