1 research outputs found
Soluble Prion Protein Binds Isolated Low Molecular Weight Amyloid‑β Oligomers Causing Cytotoxicity Inhibition
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