Breaking the Cycle, Cholesterol Cycling, and Synapse Damage in Response to Amyloid-β

Soluble amyloid-β (Aβ) oligomers, a key driver of pathogenesis in Alzheimer disease, bind to cellular prion proteins (PrP^C) expressed on synaptosomes resulting in increased cholesterol concentrations, movement of cytoplasmic phospholipase A₂ (cPLA₂) to lipid rafts and activation of cPLA₂. The formation of Aβ-PrP^C-cPLA₂ complexes was controlled by the cholesterol ester cycle. Thus, Aβ activated cholesterol ester hydrolases which released cholesterol from stores of cholesterol esters; the increased cholesterol concentrations stabilised Aβ-PrP^C-cPLA₂ complexes. Conversely, cholesterol esterification reduced cholesterol concentrations causing the dispersal of Aβ-PrP^C-cPLA₂. In cultured neurons, the cholesterol ester cycle regulated Aβ-induced synapse damage; inhibition of cholesterol ester hydrolases protected neurons, whereas inhibition of cholesterol esterification increased the Aβ-induced synapse damage. Here, I speculate that a failure to deactivate signalling pathways can lead to pathology. Consequently, the esterification of cholesterol is a key factor in the dispersal of Aβ-induced signalling platforms and synapse degeneration.