title: Aβ induces its own prion protein N-terminal fragment (PrPN1)-mediated neutralization in amorphous aggregates.
abstract: Plasma membrane cellular prion protein (PrP(C)) is a high-affinity receptor for toxic soluble amyloid-β (Aβ) oligomers that mediates synaptic dysfunction. Secreted forms of PrP(C) resulting from PrP(C) α-cleavage (PrPN1) or shedding (shed PrP(C)) display neuroprotective activity in neuronal cultures and in mouse models of Aβ-induced neuronal dysfunction. In vitro, recombinant PrPN1 and PrP inhibit Aβ fibrillization. However, the mechanism by which PrPN1 and shed PrP(C) neutralize Aβ oligomers is unclear, and evidence of such neuroprotective activity in Alzheimer's disease (AD) patients is lacking. Here, we show that PrPN1 association with Aβ causes a conformational change resulting in the formation of amorphous and insoluble aggregates that are not compatible with the assembly of Aβs. Using postmortem brain tissues of AD patients, we were able to coimmunoprecipitate Aβ with PrP(C) molecules and observed a coaggregation of Aβ and PrPN1 in the guanidine-extractable fraction presumably representing insoluble amyloid plaques. Furthermore, PrP(C) α-cleavage is increased in AD brains, and we noticed a significant positive correlation between the levels of α-cleavage and of guanidine-extractable Aβ. These data strongly support the hypothesis that PrP(C) α-cleavage is an endogenous neuroprotective mechanism in AD and support the development of PrP(C)-derived peptides as therapeutic molecules for AD.
authors.affiliation: Département de Biochimie (Z8-2001), Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Béland
authors.affiliation: Département de Biochimie (Z8-2001), Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Mikaël
authors.initials: M
authors.lastname: Bédard
authors.affiliation: Département de Biochimie (Z8-2001), Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Tremblay
authors.affiliation: Département de Biochimie (Z8-2001), Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lavigne
authors.affiliation: Département de Biochimie (Z8-2001), Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada. Electronic address: xavier.roucou@usherbrooke.ca.
authors.forename: Xavier
authors.initials: X
authors.lastname: Roucou
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D005260:Female; D051379:Mice; D058990:Molecular Targeted Therapy; D018696:Neuroprotective Agents; D018621:PrPC Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D018621:PrPC Proteins
keywords: Alzheimer; Amorphous aggregates; Aβ; Diffuse plaques; Fibrillization; Neuroprotection; PrPN1; Prion; α-Cleavage