The phospholipase A2 pathway controls a synaptic cholesterol ester cycle and synapse damage

The cellular prion protein (PrPc) acts as a scaffold protein that organises signalling complexes. In synaptosomes, the aggregation of PrPc by amyloid-beta (A beta) oligomers attracts and activates cytoplasmic phospholipase A(2) (cPLA(2)), leading to synapse degeneration. The signalling platform is dependent on cholesterol released from cholesterol esters by cholesterol ester hydrolases (CEHs). The activation of cPLA(2) requires cholesterol released from cholesterol esters by cholesterol ester hydrolases (CEHs), enzymes dependent upon platelet activating factor (PAF) released by activated cPLA(2). This demonstrates a positive feedback system in which activated cPLA(2) increased cholesterol concentrations, which in turn facilitated cPLA(2) activation. PAF was also required for the incorporation of the tyrosine kinase Fyn and cyclooxygenase (COX)-2 into A beta-PrPc-cPLA(2) complexes. As a failure to deactivate signalling complexes can lead to pathology, the mechanisms involved in their dispersal were studied. PAF facilitated the incorporation of acyl-coenzyme A: cholesterol acyltransferase (ACAT)-1 into A beta-PrPc-cPLA(2)-COX-2-Fyn complexes. The esterification of cholesterol reduced cholesterol concentrations, causing dispersal of A beta-PrPc-cPLA(2) -COX-2-Fyn complexes and the cessation of signalling. This study identifies PAF as a key mediator regulating the cholesterol ester cycle, activation of cPLA(2) and COX-2 within synapses, and synapse damage.