The role of the phospholipase D pathway in neurodegeneration
Tiago Gil Oliveira
Lipids are not only one of the main constituents of the brain, but are also involved in the pathogenesis of various neurodegenerative diseases. Importantly, genetic studies have implicated lipid related genes as major risk factors for Alzheimer’s disease (AD), and blood lipid signatures have been proposed as future biomarkers. In the past few years, using new techniques to study lipids, such as high profile liquid chromatography (HPLC) and LC-mass spectrometry (LC-MS) lipidomic analysis, we have identified lipid metabolic dysregulation in brain samples from both AD patients and rodent models. Moreover, we showed that chronic stress, one of the main risk factors for sporadic AD, induces significant alterations in the rat brain lipidome. Lipids can be interconverted by different enzymes, and in the context of AD, we showed that amyloid beta (Aβ) leads to increased activity of the lipid-modulating enzyme, phospholipase D (PLD). There are two main PLD isoenzymes in mammals, PLD1 and PLD2, and one PLD in simple organisms such as nematodes, that produce phosphatidic acid from the hydrolysis of phosphatidylcholine. Specifically, we showed that the ablation of PLD2 blocks Aβ pathological signaling and prevents behavioral deficits induced by Aβ overexpression. In order to gain mechanistic insight, we recently showed that PLD ablation in worms also blocks Aβ pathological effects, including decreasing Aβ-induced susceptibility to pharmacological-induced seizures. Since AD patients have been reported to have increased levels of epileptiform activity associated with memory deficits, we are now using a combination of nematode and rodent models to understand the role of the PLD pathway in Aβ-induced hyperexcitability.