An N-terminal Fragment of the Prion Protein Binds to Amyloid-β Oligomers and Inhibits Their Neurotoxicity in Vivo

Abstract

Background: The cellular prion protein (PrPC) could be a toxicity-transducing receptor for amyloid-β (Aβ) oligomers.Results: N1, a naturally occurring fragment of PrPC, binds Aβ oligomers, inhibits their polymerization into fibrils, and suppresses their neurotoxic effects in vitro and in vivo.Conclusion: N1 binds tightly to Aβ oligomers and blocks their neurotoxicity.Significance: Administration of exogenous N1 or related peptides may represent an effective therapy for Alzheimer disease.

Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models

“…When the levels of PrP-interacting A␤ rise as a function of age and eventually hit a critical value, mice demonstrate escalating cognitive decline. Interestingly, the threshold amount of PrP C -interacting A␤o lies close to reported affinity of PrP C toward the A␤ oligomer (K D was determined to be in the low nanomolar range), which could explain why lower concentrations of PLISA-detectable A␤o have little effect on cognitive performance (22,28). The rates of A␤ oligomer accumulation varied dramatically between transgenic AD model mice.…”

“…Interaction between A␤o and PrP C is essential for development of an array of AD features, including activation of certain signaling cascades, synaptotoxicity, inhibition of long term potentiation, memory impairment, and decreased survival in mice (25,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). However, it was also observed that A␤o can induce AD-like phenotypes independently of PrP C in J20 mice (44) and in some in vitro studies (23,24,45).…”

“…For example, experiments with a range of models have shown that A␤o toxicity is critically dependent on cellular prion protein (PrP C ), a cell surface glycoprotein acting as a high affinity receptor with high selectivity for A␤o (21)(22)(23)(24)(25)(26)(27)(28). Interaction between A␤o and PrP C is essential for development of an array of AD features, including activation of certain signaling cascades, synaptotoxicity, inhibition of long term potentiation, memory impairment, and decreased survival in mice (25,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43).…”

Alzheimer's Disease and Prion Protein

“…Synthetic N1 fragment, equivalent of that released by α-cleavage of endogenous PrP C , has been found to bind Aβ oligomers with high affinity, sequester Aβ oligomers in the extracellular space, and hence block the Aβ oligomer-mediated synaptic toxicity (82). Therefore, exogenous administration of N1 or enhancement of endogenous α-cleavage of PrP C represents a brand-new class of therapeutic approaches for AD.…”

“…N1 binds to Aβ oligomers with high affinity, and blocks the neurotoxicity of Aβ oligomers through neutralizing toxic assemblies of Aβ. Therefore, N1 may serve as a potent inhibitor of Aβ oligomer toxicity and represent an entirely new class of therapeutic agents for the treatment of AD (82). N1 is a naturally occurring soluble fragment that is generated by endogenous proteolytic processing of PrP C at the α-site (residues 111 and 112) (83), presumably by ADAM (a disintegrin and metalloprotease) proteases (84)(85)(86)(87).…”