Monoacylated Cellular Prion Proteins Reduce Amyloid-β-Induced Activation of Cytoplasmic Phospholipase A(2) 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 (PrP(C)) by Aβ oligomers induced synapse damage in cultured neurons. PrP(C) is attached to membranes via a glycosylphosphatidylinositol (GPI) anchor, the composition of which affects protein targeting and cell signaling. Monoacylated PrP(C) incorporated into neurons bound “natural Aβ”, sequestering Aβ outside lipid rafts and preventing its accumulation at synapses. The presence of monoacylated PrP(C) reduced the Aβ-induced activation of cytoplasmic phospholipase A(2) (cPLA(2)) and Aβ-induced synapse damage. This protective effect was stimulus specific, as treated neurons remained sensitive to α-synuclein, a protein associated with synapse damage in Parkinson’s disease. In synaptosomes, the aggregation of PrP(C) by Aβ oligomers triggered the formation of a signaling complex containing the cPLA(2).a process, disrupted by monoacylated PrP(C). We propose that monoacylated PrP(C) acts as a molecular sponge, binding Aβ oligomers at the neuronal perikarya without activating cPLA(2) or triggering synapse damage.