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

The cellular prion protein (PrP) acts as a scaffold protein that organises signalling complexes. In synaptosomes, the aggregation of PrP by amyloid-β (Aβ) oligomers attracts and activates cytoplasmic phospholipase A (cPLA), leading to synapse degeneration. The signalling platform is dependent on cholesterol released from cholesterol esters by cholesterol ester hydrolases (CEHs).

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) resulting in increased cholesterol concentrations, translocation of cytoplasmic phospholipase A (cPLA, also known as PLA2G4A) to lipid rafts, and activation of cPLA The formation of Aβ-PrP 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 complexes, resulting in activated cPLA Conversely, cholesterol esterification reduced cholesterol concentrations causing the dispersal of Aβ-PrP complexes.

Glimepiride protects neurons against amyloid-β-induced synapse damage.

Alzheimer's disease is associated with the accumulation within the brain of amyloid-β (Aβ) peptides that damage synapses and affect memory acquisition. This process can be modelled by observing the effects of Aβ on synapses in cultured neurons. The addition of picomolar concentrations of soluble Aβ derived from brain extracts triggered the loss of synaptic proteins including synaptophysin, synapsin-1 and cysteine string protein from cultured neurons.

Monoacylated Cellular Prion Proteins Reduce Amyloid-β-Induced Activation of Cytoplasmic Phospholipase A2 and Synapse Damage.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) and the loss of synapses. Aggregation of the cellular prion protein (PrPC) by Aβ oligomers induced synapse damage in cultured neurons. PrPC is attached to membranes via a glycosylphosphatidylinositol (GPI) anchor, the composition of which affects protein targeting and cell signaling.