Critical role of cPLA₂ in A尾 oligomer-induced neurodegeneration and memory deficit

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• 作者：C&#233 ; dric Desbè ; ne^a ; ^b ; ¹ ; Catherine Malaplate-Armand^a ; ^b ; Ihsen Youssef^a ; Pierre Garcia^a ; Christophe Stenger^a ; Mathilde Sauv&#233 ; e^a ; ^c ; Nicolas Fischer^a ; Dorine Rimet^a ; Violette Koziel^a ; Marie-Christine Escany&#233 ; ^a ; ^b ; Thierry Oster^a ; ^d ; Badreddine Kriem^a ; Frances T. Yen^a ; Thierry Pillot^a ; Jean Luc Olivier^a ; ^b ; ^{Jean-Luc.Olivier@medecine.uhp-nancy.fr}
• 关键词：Alzheimer's disease ; Cytosolic phospholipase A2 ; Soluble beta-amyloid oligomers ; Memory ; Apoptosis ; Synaptotoxicity ; Amyloid precursor protein
• 刊名：Neurobiology of Aging
• 出版年：2012
• 期刊代码：202_01974580
• 类别：med
• 出版时间：June, 2012
• 卷：33
• 期：6
• 页码：1123.e17-1123.e29
• 文件大小：1855 K

摘要

Soluble beta-amyloid (A尾) 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 A尾 oligomers activate cytosolic phospholipase A₂ (cPLA₂), which specifically releases arachidonic acid from membrane phospholipids. We here observed that cPLA₂ gene inactivation prevented the alterations of cognitive abilities and the reduction of hippocampal synaptic markers levels noticed upon a single intracerebroventricular injection of A尾 oligomers in wild type mice. We further demonstrated that the A尾 oligomer-induced sphingomyelinase activation was suppressed and that phosphorylation of Akt/protein kinase B (PKB) was preserved in neuronal cells isolated from cPLA₂^{鈭?鈭?/sup> mice. Interestingly, expression of the A尾 precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA₂鈭?鈭?/sup> mice, but the relationship with the resistance of these mice to the A尾 oligomer toxicity requires further investigation. These results therefore show that cPLA₂ plays a key role in the A尾 oligomer-associated neurodegeneration, and as such represents a potential therapeutic target for the treatment of Alzheimer's disease.}