Implication de la phospholipase A2 cytoplamique dans la pathogénèse de la maladie d'Alzheimer

Abstract : Soluble beta-amyloid (A-beta) oligomers putatively play a critical role in the early synapse loss and cognitive impairment observed in Alzheimer's disease. We previously demonstrated that A-beta oligomers activate cytosolic phospholipase A2 (cPLA2) which specifically releases arachidonic acid from membrane phospholipids. By using a single A-beta oligomers intra cerebro ventricular injection, we observed that cPLA2 gene suppression prevents both the alterations of cognitive abilities and the reduction of hippocampal synaptic markers levels which are observed in wild type mice. We further demonstrated that the A-beta oligomers-induced sphingomyelinase activation is suppressed and that the phosphorylation of Akt/PKB is preserved in neuronal cells isolated from KO mice. Interestingly, expression of the A-beta precursor protein (APP) is reduced in hippocampus homogenates and neuronal cells from KO mice, but the relationship with the resistance of these mice to the A-beta oligomers toxicity requires further investigation. These results therefore show that cPLA2 plays a key role in the A-beta oligomers-associated neurodegenerative effects, and as such represents a potential therapeutic target for the treatment of Alzheimer's disease
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Cédric Pierre Louis Desbene. Implication de la phospholipase A2 cytoplamique dans la pathogénèse de la maladie d'Alzheimer. Médecine humaine et pathologie. Université de Lorraine, 2012. Français. ⟨NNT : 2012LORR0235⟩. ⟨tel-01749627⟩

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