Amyloid-β-induced synapse damage is mediated via cross-linkage of cellular prion proteins

Abstract

The cellular prion protein (PrP C), which is highly expressed at synapses, was identified as a receptor for the amyloid-β (Aβ) oligomers that are associated with dementia in Alzheimer disease. Here, we report that Aβ oligomers secreted by 7PA2 cells caused synapse damage in cultured neurons via a PrP C-dependent process. Exogenous PrP C added to Prnp knock-out (0/0) neurons was targeted to synapses and significantly increased Aβ-induced synapse damage. In contrast, the synapse damage induced by a phospholipase A 2-activating peptide was independent of PrP C. In Prnp wild-type (+/+) neurons Aβ oligomers activated synaptic cytoplasmic phospholipase A 2 (cPLA 2). In these cells, the addition of Aβ oligomers triggered the translocation of cPLA 2 in synapses to cholesterol dense membranes (lipid rafts) where it formed a complex also containing Aβ and PrP C. In contrast, the addition of Aβ to Prnp (0/0) neurons did not activate synaptic cPLA 2, which remained in the cytoplasm and was not associated with Aβ. Filtration assays and non-denaturing gels demonstrated that Aβ oligomers cross-link PrP C. We propose that it is the cross-linkage of PrP C by Aβ 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 PrP C also activated synaptic cPLA 2 and caused synapse damage. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.