The cellular prion protein (PrPc) acts as a scaffold protein that organises signalling complexes. PrPc has been identified as a receptor for amyloid-β (Aβ) oligomers, the causative agent of Alzheimer's disease. The formation of complexes between Aβ and PrPc triggers the translocation and activation of cytoplasmic phospholipase A2 (cPLA2) in lipid-raft domains, which has been shown to have a role in Aβ-mediated synaptic toxicity. In their paper on page 3050, Clive Bate and colleagues investigate the role of the cholesterol ester cycle in controlling the formation and dissociation of Aβ–PrPc–cPLA2 signalling complexes. The authors show that soluble Aβ increases the concentration of cholesterol in synapses, and this increase is controlled by the hydrolysis of cholesterol esters. Moreover, the cholesterol ester cycle is shown to regulate Aβ–PrPc complexes. The authors demonstrate that the increase in cholesterol induced by Aβ stabilises raft-associated signalling complexes that attract and activate cPLA2. Selective cholesterol ester hydrolase inhibitors reduce the Aβ-induced activation of cPLA2 and synapse damage. Finally, the authors use squalene to increase the concentration of cholesterol esters in synaptosomes, resulting in an increase in Aβ-induced synapse damage. The findings reported here show a key role for the cholesterol ester cycle in controlling the formation and dissociation of Aβ-induced synaptic signalling platforms.
