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-β (Aβ) oligomers attracts and activates cytoplasmic phospholipase A2 (cPLA2), leading to synapse degeneration. The signalling platform is dependent on cholesterol released from cholesterol esters by cholesterol ester hydrolases (CEHs). The activation of cPLA2 requires cholesterol released from cholesterol esters by cholesterol ester hydrolases (CEHs), enzymes dependent upon platelet activating factor (PAF) released by activated cPLA2 This demonstrates a positive feedback system in which activated cPLA2 increased cholesterol concentrations, which in turn facilitated cPLA2 activation. PAF was also required for the incorporation of the tyrosine kinase Fyn and cyclooxygenase (COX)-2 into Aβ-PrPC-cPLA2 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 Aβ-PrPC-cPLA2-COX-2-Fyn complexes. The esterification of cholesterol reduced cholesterol concentrations, causing dispersal of Aβ-PrPC-cPLA2-COX-2-Fyn complexes and the cessation of signalling. This study identifies PAF as a key mediator regulating the cholesterol ester cycle, activation of cPLA2 and COX-2 within synapses, and synapse damage.