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.

To investigate whether and how amyloid-β protein (Aβ) is involved in the neurodegenerative changes characteristic of Alzheimer's disease (AD), primary hippocampal neurones from foetal rat brain were exposed acutely and chronically to micromolar concentrations of a synthetic peptide homologous to residues 25–35 of Aβ (β 25–35). A single application of this peptide (25–100 μM) was ineffective but when the neuronal culture were exposed to β 25–35 (25–100 μM) repeatedly every two days for ten days, cell survival was dramatically reduced. The structural changes and the DNA fragmentation of cells chronically exposed to the peptide suggested that neuronal death occurred by apoptosis. Furthermore, β 25–35 showed the intrinsic ability to polymerize into amyloid-like fibrils in vitro. These results confirm the potential pathogenic role of Aβ in AD, and indicate that amyloid fibrils may induce neuronal death through a specific programmed process.