The cholesterol ester cycle regulates signalling complexes and synapse damage caused by amyloid-β

Cholesterol is required for the formation and function of some signalling platforms. In synaptosomes, amyloid-β (Aβ) oligomers, the causative agent in Alzheimer's disease, bind to cellular prion proteins (PrP^C) resulting in increased cholesterol concentrations, translocation of cytoplasmic phospholipase A₂ (cPLA₂, also known as PLA2G4A) to lipid rafts, and activation of cPLA₂ The formation of Aβ-PrP^C complexes is controlled by the cholesterol ester cycle. In this study, Aβ activated cholesterol ester hydrolases, which released cholesterol from stores of cholesterol esters and stabilised Aβ-PrP^C complexes, resulting in activated cPLA₂ Conversely, cholesterol esterification reduced cholesterol concentrations causing the dispersal of Aβ-PrP^C complexes. In cultured neurons, the cholesterol ester cycle regulated Aβ-induced synapse damage; cholesterol ester hydrolase inhibitors protected neurons, while inhibition of cholesterol esterification significantly increased Aβ-induced synapse damage. An understanding of the molecular mechanisms involved in the dispersal of signalling complexes is important as failure to deactivate signalling pathways can lead to pathology. This study demonstrates that esterification of cholesterol is a key factor in the dispersal of Aβ-induced signalling platforms involved in the activation of cPLA₂ and synapse degeneration.