Amyloid-β-induced Synapse Damage Is Mediated via Cross-linkage of Cellular Prion Proteins

The cellular prion protein (PrPC), which is highly expressed at synapses, was identified as a receptor for the amyloid-beta (A beta) oligomers that are associated with dementia in Alzheimer disease. Here, we report that A beta oligomers secreted by 7PA2 cells caused synapse damage in cultured neurons via a PrPC-dependent process. Exogenous PrPC added to Prnp knock-out((0/0)) neurons was targeted to synapses and significantly increased A beta-induced synapse damage. In contrast, the synapse damage induced by a phospholipase A(2)-activating peptide was independent of PrPC. In Prnp wild-type((+/+)) neurons A beta oligomers activated synaptic cytoplasmic phospholipase A(2) (cPLA(2)). In these cells, the addition of A beta oligomers triggered the translocation of cPLA(2) in synapses to cholesterol dense membranes (lipid rafts) where it formed a complex also containing A beta and PrPC. In contrast, the addition of A beta to Prnp((0/0)) neurons did not activate synaptic cPLA(2), which remained in the cytoplasm and was not associated with A beta. Filtration assays and non-denaturing gels demonstrated that A beta oligomers cross-link PrPC. We propose that it is the cross-linkage of PrPC by A beta oligomers that triggers abnormal activation of cPLA(2) and synapse damage. This hypothesis was supported by our observation that monoclonal antibody mediated cross-linkage of PrPC also activated synaptic cPLA(2) and caused synapse damage.