UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

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

Freir, DB; Nicoll, AJ; Klyubin, I; Panico, S; Mc Donald, JM; Risse, E; Asante, EA; ... Collinge, J; + view all (2011) Interaction between prion protein and toxic amyloid beta assemblies can be therapeutically targeted at multiple sites. Nature Communications , 2 , Article 336. 10.1038/ncomms1341. Green open access

[img]
Preview
PDF
ncomms1341.pdf

Download (1MB)
[img]
Preview
Other (JPG Figure 1: Biophysical characterization of Aβ species present in the bADDL preparation.)
ncomms1341-f1.jpg

Download (144kB)
[img]
Preview
Other (JPG Figure 2: PrPC is required for the inhibition of LTP by bADDLs and Aβ-containing extracts of human brain.)
ncomms1341-f2.jpg

Download (68kB)
[img]
Preview
Other (JPG Figure 3: bADDLs avidly bind PrP in a manner that can be blocked by certain anti-PrP antibodies.)
ncomms1341-f3.jpg

Download (93kB)
[img]
Preview
Other (JPG Figure 4: Inhibition of LTP by ADDLs or Aβ-containing AD brain extract is ameliorated by the anti-PrPC antibodies ICSM-35 and ICSM-18. )
ncomms1341-f4.jpg

Download (145kB)
[img]
Preview
PDF (Supplementary Figures S1-S7, Supplementary Methods and Supplementary References.)
ncomms1341-s1.pdf

Download (1MB)

Abstract

A role for PrP in the toxic effect of oligomeric forms of A beta, 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 A beta-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/A beta-binding site and to PrP helix-1, were able to block A beta binding to PrP suggesting that the toxic A beta 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 A beta-mediated disruption of synaptic plasticity validating these antibodies as candidate therapeutics for AD either individually or in combination.

Type: Article
Title: Interaction between prion protein and toxic amyloid beta assemblies can be therapeutically targeted at multiple sites
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/ncomms1341
Publisher version: http://dx.doi.org/10.1038/ncomms1341
Language: English
Additional information: This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. [http://creativecommons.org/licenses/by-nc-nd/3.0/] You are free to share (copy, distribute and transmit the work), but you must attribute the author, you may not use this work for commercial purposes and you may not alter, transform, or build upon this work and distribute any derivative works you create under a similar license.
Keywords: Long-term potentiation, a-beta, monoclonal-antibodies, synaptic plasticity, in-vivo, oligomers, disease, impairment, dimers, memory
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/1319280
Downloads since deposit
2,546Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item