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

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