The Role of Phospholipase D in Amyloid Precursor Protein Processing

The generation of a secreted N-terminal fragment of the amyloid precursor protein (A PPs) can be stimulated by a variety of signaling pathways many of which are also known to modulate the activity of the phospholipase D (PLD) enzyme. This study used primary rat neuronal cerebellar granule (CG) cultures and SH-SY5Y human neuroblastoma cell lines to determine the potential role of PLD in the protein kinase C (PKC)-associated generation of A PPs. Protein release was markedly enhanced by direct PKC stimulation following treatment of both cell type with either phorbol ester or indirectly by the muscarinic agonist carbachol and these effects were greatly attenuated by co-incubation with the PKC inhibitor GF109203X. A partial inhibition of PKC- and carbachol-stimulated A PPs secretion was also achieved by pre-treatment of the cells with toxin B, a PLD inhibitor. This suggested that PLD may play a role downstream of PKC in the control of A PPs secretion.