Title: The role of phospholipase D1 in trafficking and processing of amyloid precursor protein
Description: Growing evidence indicates that intracellular signaling lipids control the trafficking and processing of amyloid precursor protein (APP) with major implications for pathological and behavioral manifestations associated with Alzheimer's disease (AD). One such lipid is phosphatidic acid (PA), which mediates membrane trafficking and is produced by a variety of enzymes, including phospholipase D (PLD). We previously demonstrated that a PLD isoform, PLD2, is required for the synaptotoxic and memory-impairing actions of amyloid beta in an AD mouse model. The role that the other PLD isoform, PLD1, plays in AD is unclear, although cell culture studies from other groups have suggested it modulates the trafficking of APP and presenilin 1, the catalytic subunit of gamma secretase. Here, we investigate the role of PLD1 in the biology of APP as well as in an AD mouse model. We report that removing PLD1, unlike PLD2, causes a dramatic decrease in brain levels of PA, indicating that PLD1 is a major source of PA in the brain.

Additionally, removing PLD1 from primary neurons causes a redistribution of APP from endosomes, a primary station for amyloidogenesis, to the Golgi complex, while PLD1 overexpression produces the converse phenotype. Pld1 null mice harboring familial AD-linked (FAD) APP mutations exhibited decreased brain amyloid and an accumulation of APP COOH-terminal fragments. This finding was particularly evident in Pld1 null membrane rafts, whose lipidome was profoundly altered. Acute inhibition of PLD1 reduced APP processing by gamma secretase, consistent with a regulatory role of the lipid raft environment on gamma secretase, a complex highly active in membrane rafts. Finally, Pld1 nullizygosity rescued cognitive deficits in the transgenic model. Thus, PLD1 and its product PA control the metabolism of APP and emerge as potential drug targets for Alzheimer's disease therapy.