title: 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.
authors: Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Hertfordshire AL9 7TA, United Kingdom. Electronic address: cbate@rvc.ac.uk.
authors: Clive
authors: C
authors: Bate
authors: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, United Kingdom.
authors: Alun
authors: A
authors: Williams
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000196:embryology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D054467:Phospholipases A2 / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D003432:Cross-Linking Reagents; D011328:Prions; D016708:Synaptophysin; D054467:Phospholipases A2