Here we propose to study how brain regional lipid composition contributes to susceptibility to neurodegenerative disorders. We use different approaches to tackle this question, from mass-spectrometry lipidomic analyses, to manipulation of lipid pathways with genetic and pharmacological models. We are particularly interested in the phospholipase D (PLD) pathway, since we have shown that while ablating the PLD1 isoenzyme leads to brain regional dysfunction, the ablation of PLD2 confers protection in an amyloidogenesis model. We are currently exploring how do these PLD dependent mechanisms confer either resistance or susceptibility to neuronal dysfunction.