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

The cellular prion protein (PrP^C) acts as a scaffold protein that organises signalling complexes. In synaptosomes, the aggregation of PrP^C 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-PrP^C-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-PrP^C-cPLA₂-COX-2-Fyn complexes. The esterification of cholesterol reduced cholesterol concentrations, causing dispersal of Aβ-PrP^C-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.