Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites

Abstract

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.

Specific Soluble Oligomers of Amyloid-β Peptide Undergo Replication and Form Non-fibrillar Aggregates in Interfacial Environments

“…AUC-sedimentation velocity data revealed that LFAOs are mixtures of oligomers with sedimentation coefficients of 5 and 7-12 S and some monomers. This observation is similar to that reported for amyloid-derived diffusible ligands, which were also found to be a heterogeneous mixture containing species larger than 90 kDa that displayed a disperse c(s) distribution between 10 and 25 S in sedimentation velocity experiments (27). A sequential back-to-back SEC fractionation of LFAO samples showed no significant reduction in the concentration of monomers present in the sample, suggesting that LFAOs undergo dissociation upon dilution (supplemental Fig.…”

“…The LFAOs showed a similar distribution of oligomers even after a 10 to 50-fold dilution in AUC (data not shown). It is also noteworthy that recently a similar sedimentation distribution profile was obtained for amyloid-derived diffusible ligands of A␤42 (27). In contrast to the LFAOs, the A␤42 fibril control showed widely disperse sedimentation coefficient values between 50 and 200 S (supplemental Fig.…”

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

“…51,55 However this view of PrP C as a latent pro-pathogenic target molecule is in apparent contradiction with the observation that PrP C is often neuroprotective in whole animal models, and is needed to protect or maintain the adult CNS and PNS, 56 perhaps by mediating stress Extending this discussion to the context of AD it is striking that the 95-105 Aβ binding site for PrP C reported by Lauren et al lies in between the C2 and C1 N-termini. Thus Aβ binding could either alter the balance of proteolytic events affecting PrP, or could alter signaling events by modulating membrane-tethered vs. secreted PrP fragments.…”

Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease Aβ in vivo

“…Soluble extracts of AD brain contain Ab monomers and sodium dodecyl sulfate (SDS)-stable dimers at dramatically higher concentrations than in non-AD controls (figure 5a) [15,51]. Acute application of such Ab-containing soluble extracts of AD brain rapidly and potently inhibits LTP both in vitro [15,52] and in vivo [53,54].…”