Critical role of cPLA<sub>2sub> in A尾 oligomer-induced neurodegeneration and memory deficit
- 作者：Cé ; dric Desbè ; ne<sup>asup><sup> ; sup><sup>bsup><sup> ; sup><sup>1sup> ; Catherine Malaplate-Armand<sup>asup><sup> ; sup><sup>bsup> ; Ihsen Youssef<sup>asup> ; Pierre Garcia<sup>asup> ; Christophe Stenger<sup>asup> ; Mathilde Sauvé ; e<sup>asup><sup> ; sup><sup>csup> ; Nicolas Fischer<sup>asup> ; Dorine Rimet<sup>asup> ; Violette Koziel<sup>asup> ; Marie-Christine Escanyé ; <sup>asup><sup> ; sup><sup>bsup> ; Thierry Oster<sup>asup><sup> ; sup><sup>dsup> ; Badreddine Kriem<sup>asup> ; Frances T. Yen<sup>asup> ; Thierry Pillot<sup>asup> ; Jean Luc Olivier<sup>asup><sup> ; sup><sup>bsup><sup> ; sup><sup>Jean-Luc.Olivier@medecine.uhp-nancy.frsup>
- 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 A<sub>2sub> (cPLA<sub>2sub>), which specifically releases arachidonic acid from membrane phospholipids. We here observed that cPLA<sub>2sub> 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 cPLA<sub>2sub><sup>鈭?鈭?/sup> mice. Interestingly, expression of the A尾 precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA<sub>2sub><sup>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 cPLA<sub>2sub> 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.