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
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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.
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