Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit.
2012
Soluble beta-amyloid (A) 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 oligomers activate cytosolic phospholipase A2 (cPLA2), 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 A oligomers in wild type mice. We further demonstrated that the A 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 A precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA2 / mice, but the relationship with the resistance of these mice to the A oligomer toxicity requires further investigation. These results therefore show that cPLA 2 plays a key role in the A oligomer-associated neurodegeneration, and as such represents a potential therapeutic target for the treatment of Alzheimer’s disease. © 2012 Elsevier Inc. All rights reserved.
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