title: The role of cytosolic phospholipase A2 α in amyloid precursor protein induction by amyloid beta1-42 : implication for neurodegeneration.
abstract: Amyloid-β peptides generated by proteolysis of the β-amyloid precursor protein (APP) play an important role in the pathogenesis of Alzheimer's disease. The present study aimed to determine whether cytosolic phospholipase A2 α (cPLA2 α) plays a role in elevated APP protein expression induced by aggregated amyloid-β1-42 (Aβ) in cortical neurons and to elucidate its specific role in signal events leading to APP induction. Elevated cPLA2 α and its activity determined by phosphorylation on serine 505 as well as elevated APP protein expression, were detected in primary rat cortical neuronal cultures exposed to Aβ for 24 h and in cortical neuron of human amyloid-β1-42 brain infused mice. Prevention of cPLA2 α up-regulation and its activity by oligonucleotide antisense against cPLA2 α (AS) prevented the elevation of APP protein in cortical neuronal cultures and in mouse neuronal cortex. To determine the role of cPLA2 α in the signals leading to APP induction, increased cPLA2 α expression and activity induced by Aβ was prevented by means of AS in neuronal cortical cultures. Under these conditions, the elevated cyclooxygenase-2 and the production of prostaglandin E2 (PGE2 ) were prevented. Addition of PGE2 or cyclic AMP analogue (dbcAMP) to neuronal cultures significantly increased the expression of APP protein, while the presence protein kinase A inhibitor (H-89) attenuated the elevation of APP induced by Aβ. Inhibition of elevated cPLA2 α by AS prevented the activation of cAMP response element binding protein (CREB) as detected by its phosphorylated form, its translocation to the nucleus and its DNA binding induced by Aβ which coincided with cPLA2 α dependent activation of CREB in the cortex of Aβ brain infused mice. Our results show that accumulation of Aβ induced elevation of APP protein expression mediated by cPLA2 α, PGE2 release, and CREB activation via protein kinase A pathway.
authors.affiliation: Immunology and Infectious Diseases Laboratory, Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev and Soroka University Medical Center, Beer-Sheva, Israel.
authors.forename: Chen
authors.initials: C
authors.lastname: Sagy-Bross
authors.affiliation: Immunology and Infectious Diseases Laboratory, Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev and Soroka University Medical Center, Beer-Sheva, Israel.
authors.forename: Ksenia
authors.initials: K
authors.lastname: Kasianov
authors.affiliation: Immunology and Infectious Diseases Laboratory, Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev and Soroka University Medical Center, Beer-Sheva, Israel.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Solomonov
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Alex
authors.initials: A
authors.lastname: Braiman
authors.affiliation: Department of Physiology and cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Friedman
authors.affiliation: Immunology and Infectious Diseases Laboratory, Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev and Soroka University Medical Center, Beer-Sheva, Israel.
authors.forename: Nurit
authors.initials: N
authors.lastname: Hadad
authors.affiliation: Immunology and Infectious Diseases Laboratory, Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev and Soroka University Medical Center, Beer-Sheva, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Levy
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D054513:Group IV Phospholipases A2 / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D054513:Group IV Phospholipases A2
keywords: APP; cortical neurons; cytosolic phospholipase A2α