A role for PrP in the toxic effect of oligomeric forms of Aβ, implicated in Alzheimer's disease (AD), has been suggested but remains controversial. Here we show that PrP is required for the plasticity-impairing effects of ex vivo material from human AD brain and that standardized Aβ-derived diffusible ligand (ADDL) preparations disrupt hippocampal synaptic plasticity in a PrP-dependent manner. We screened a panel of anti-PrP antibodies for their ability to disrupt the ADDL–PrP interaction. Antibodies directed to the principal PrP/Aβ-binding site and to PrP helix-1, were able to block Aβ binding to PrP suggesting that the toxic Aβ species are of relatively high molecular mass and/or may bind multiple PrP molecules. Two representative and extensively characterized monoclonal antibodies directed to these regions, ICSM-35 and ICSM-18, were shown to block the Aβ-mediated disruption of synaptic plasticity validating these antibodies as candidate therapeutics for AD either individually or in combination.

Nonfibrillar, water-soluble low-molecular weight assemblies of the amyloid ␤-protein (A␤) are believed to play an important role in Alzheimer's disease (AD). Aqueous extracts of human brain contain A␤ assemblies that migrate on SDS-polyacrylamide gels and elute from size exclusion as dimers (ϳ8 kDa) and can block long-term potentiation and impair memory consolidation in the rat. Such species are detected specifically and sensitively in extracts of Alzheimer brain suggesting that SDS-stable dimers may be the basic building blocks of AD-associated synaptotoxic assemblies. Consequently, understanding the structure and properties of A␤ dimers is of great interest. In the absence of sufficient brain-derived dimer to facilitate biophysical analysis, we generated synthetic dimers designed to mimic the natural species. For this, A␤(1-40) containing cysteine in place of serine 26 was used to produce disulphide cross-linked dimer, (A␤S26C) 2 . Such dimers had no detectable secondary structure, produced an analytical ultracentrifugation profile consistent for an ϳ8.6 kDa protein, and had no effect on hippocampal long-term potentiation (LTP). However, (A␤S26C) 2 aggregated more rapidly than either A␤S26C or wild-type monomers and formed parastable ␤-sheet rich, thioflavin T-positive, protofibril-like assemblies. Whereas wildtype A␤ aggregated to form typical amyloid fibrils, the protofibril-like structures formed by (A␤S26C) 2 persisted for prolonged periods and potently inhibited LTP in mouse hippocampus. These data support the idea that A␤ dimers may stabilize the formation of fibril intermediates by a process distinct from that available to A␤ monomer and that higher molecular weight prefibrillar assemblies are the proximate mediators of A␤ toxicity.

Growing evidence suggests water-soluble, non-fibrillar forms of amyloid-β protein (Aβ) have important roles in Alzheimer’s disease with toxicities mimicked by synthetic Aβ1–42. However, no defined toxic structures acting via specific receptors have been identified and roles of proposed receptors, such as prion protein (PrP), remain controversial. Here we quantify binding to PrP of Aβ1–42 after different durations of aggregation. We show PrP-binding and PrP-dependent inhibition of long-term potentiation (LTP) correlate with the presence of protofibrils. Globular oligomers bind less avidly to PrP and do not inhibit LTP, whereas fibrils inhibit LTP in a PrP-independent manner. That only certain transient Aβ assemblies cause PrP-dependent toxicity explains conflicting reports regarding the involvement of PrP in Aβ-induced impairments. We show that these protofibrils contain a defined nanotubular structure with a previously unidentified triple helical conformation. Blocking the formation of Aβ nanotubes or their interaction with PrP might have a role in treatment of Alzheimer’s disease.