title: Soluble Prion Protein Binds Isolated Low Molecular Weight Amyloid-β Oligomers Causing Cytotoxicity Inhibition.
abstract: A growing number of observations indicate that soluble amyloid-β (Aβ) oligomers play a major role in Alzheimer's disease. Recent studies strongly suggest that at least some of the neurotoxic effects of these oligomers are mediated by cellular, membrane-anchored prion protein and that Aβ neurotoxicity can be inhibited by soluble recombinant prion protein (rPrP) and its fragments. However, the mechanism by which rPrP interacts with Aβ oligomers and prevents their toxicity is largely unknown, and studies in this regard are hindered by the large structural heterogeneity of Aβ oligomers. To overcome this difficulty, here we used photoinduced cross-linking of unmodified proteins (PICUP) to isolate well-defined oligomers of Aβ42 and characterize these species with regard to their cytotoxicity and interaction with rPrP, as well the mechanism by which rPrP inhibits Aβ42 cytotoxicity. Our data shows that the addition of rPrP to the assembling Aβ42 results in a shift in oligomer size distribution, decreasing the population of toxic tetramers and higher order oligomers and increasing the population of nontoxic (and possibly neuroprotective) monomers. Isolated oligomeric species of Aβ42 are cytotoxic to primary neurons and cause permeation of model lipid bilayers. These toxic effects, which are oligomer size-dependent, can be inhibited by the addition of rPrP, and our data suggest potential mechanisms of this inhibitory action. This insight should help in current efforts to develop PrP-based therapeutics for Alzheimer's disease.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University , Cleveland, Ohio 44106, United States.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Williams
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University , Cleveland, Ohio 44106, United States.
authors.forename: Jin-Kyu
authors.initials: JK
authors.lastname: Choi
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University , Cleveland, Ohio 44106, United States.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Surewicz
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University , Cleveland, Ohio 44106, United States.
authors.forename: Witold K
authors.initials: WK
authors.lastname: Surewicz
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D004622:Embryo, Mammalian; D005452:Fluoresceins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018625:Microscopy, Atomic Force; D008970:Molecular Weight; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020349:Surface Plasmon Resonance
chemical_list: D016229:Amyloid beta-Peptides; D005452:Fluoresceins; D011328:Prions; D007770:L-Lactate Dehydrogenase; C007740:fluorexon
keywords: Alzheimer’s disease; Amyloid-β; Neurotoxicity; Oligomers; Prion Protein