title: Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit.
abstract: Soluble beta-amyloid (Aβ) oligomers are considered to putatively play a critical role in the early synapse loss and cognitive impairment observed in Alzheimer's disease. We previously demonstrated that Aβ oligomers activate cytosolic phospholipase A(2) (cPLA(2)), which specifically releases arachidonic acid from membrane phospholipids. We here observed that cPLA(2) gene inactivation prevented the alterations of cognitive abilities and the reduction of hippocampal synaptic markers levels noticed upon a single intracerebroventricular injection of Aβ oligomers in wild type mice. We further demonstrated that the Aβ oligomer-induced sphingomyelinase activation was suppressed and that phosphorylation of Akt/protein kinase B (PKB) was preserved in neuronal cells isolated from cPLA(2)(-/-) mice. Interestingly, expression of the Aβ precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA(2)(-/-) mice, but the relationship with the resistance of these mice to the Aβ oligomer toxicity requires further investigation. These results therefore show that cPLA(2) plays a key role in the Aβ oligomer-associated neurodegeneration, and as such represents a potential therapeutic target for the treatment of Alzheimer's disease.
authors.affiliation: Lipidomix (EA 4422), INPL-ENSAIA, Université de Lorraine, Vandœuvre-lès-Nancy, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Desbène
authors.forename: Catherine
authors.initials: C
authors.lastname: Malaplate-Armand
authors.forename: Ihsen
authors.initials: I
authors.lastname: Youssef
authors.forename: Pierre
authors.initials: P
authors.lastname: Garcia
authors.forename: Christophe
authors.initials: C
authors.lastname: Stenger
authors.forename: Mathilde
authors.initials: M
authors.lastname: Sauvée
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fischer
authors.forename: Dorine
authors.initials: D
authors.lastname: Rimet
authors.forename: Violette
authors.initials: V
authors.lastname: Koziel
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Escanyé
authors.forename: Thierry
authors.initials: T
authors.lastname: Oster
authors.forename: Badreddine
authors.initials: B
authors.lastname: Kriem
authors.forename: Frances T
authors.initials: FT
authors.lastname: Yen
authors.forename: Thierry
authors.initials: T
authors.lastname: Pillot
authors.forename: Jean Luc
authors.initials: JL
authors.lastname: Olivier
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000201:enzymology*; D010446:Peptide Fragments / Q000633:toxicity*; D054510:Phospholipases A2, Cytosolic / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D054510:Phospholipases A2, Cytosolic