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 (PrPC ) 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-PrPC -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-PrPC -cPLA2 complexes. Conversely, cholesterol esterification reduced cholesterol concentrations causing the dispersal of Aβ-PrPC -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.