Synthetic amyloid-β oligomers impair long-term memory independently of cellular prion protein

Abstract

Inability to form new memories is an early clinical sign of Alzheimer's disease (AD). There is ample evidence that the amyloid-β (Aβ) peptide plays a key role in the pathogenesis of this disorder. Soluble, bio-derived oligomers of Aβ are proposed as the key mediators of synaptic and cognitive dysfunction, but more tractable models of Aβ−mediated cognitive impairment are needed. Here we report that, in mice, acute intracerebroventricular injections of synthetic Aβ 1-42 oligomers impaired consolidation of the long-term recognition memory, whereas mature Aβ 1-42 fibrils and freshly dissolved peptide did not. The deficit induced by oligomers was reversible and was prevented by an anti-Aβ antibody. It has been suggested that the cellular prion protein (PrP C ) mediates the impairment of synaptic plasticity induced by Aβ. We confirmed that Aβ 1-42 oligomers interact with PrP C , with nanomolar affinity. However, PrP-expressing and PrP knock-out mice were equally susceptible to this impairment. These data suggest that Aβ 1-42 oligomers are responsible for cognitive impairment in AD and that PrP C is not required.Alzheimer | neurotoxicity | object recognition test | surface plasmon resonance | protein aggregation

Neurotoxic Mutants of the Prion Protein Induce Spontaneous Ionic Currents in Cultured Cells

“…Interestingly, Laurén et al (50) recently identified PrP C as a cell surface receptor for amyloid ␤ oligomers, possibly connecting PrP-induced currents and amyloid ␤ synaptotoxicity. This connection, however, remains controversial as another group reported no difference in amyloid ␤ oligomer-mediated impairment of long term memory between wild-type and PrP knock-out mice (51).…”

The P’s and Q’s of cellular PrP-Aβ interactions

“…51 With regards to memory function in intact animals, Gimbel and coworkers reported that PrP gene deletion improved impairment in the Morris water maze in a transgenic model of AD, 52 a different transgenic AD line did not yield the same effects, 53 and another lab could not score an effect of Prnp genotype on a behavioral task when Aβ oligomers were applied as toxic reagents. 54 …”

Five Questions on Prion Diseases

“…These findings were deemed exciting because they suggest the involvement of PrP C in Alzheimer's disease (AD) pathogenesis. However, others found that the absence of PrP C did not prevent deficits in hippocampal-dependent behavioral tests upon intracerebral Aβ injection [16]. Even more troubling was the report by Malinow [17] that Strittmatter's results could not be reproduced in a virtually identical paradigm.…”