Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites.
Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites.
复制标题
DOI：
10.1038/ncomms1341
复制
发表时间：
2011-06-07
影响因子：
16.6
通讯作者：
Collinge, John
中科院分区：
文献类型：
--
作者：
Freir, Darragh B.;Nicoll, Andrew J.;Klyubin, Igor;Panico, Silvia;Mc Donald, Jessica M.;Risse, Emmanuel;Asante, Emmanuel A.;Farrow, Mark A.;Sessions, Richard B.;Saibil, Helen R.;Clarke, Anthony R.;Rowan, Michael J.;Walsh, Dominic M.;Collinge, John
已提出PrP在A β寡聚体形式的毒性作用中的作用，其与阿尔茨海默病（AD）有关，但仍存在争议。在这里，我们表明，PrP是所需的离体材料的可塑性损伤的影响，从人类AD脑和标准化的A β衍生的扩散配体（ADDL）制剂破坏海马突触可塑性在PrP依赖的方式。我们筛选了一组抗PrP抗体破坏ADDL-PrP相互作用的能力。针对PrP/A β主要结合位点和PrP螺旋-1的抗体能够阻断A β与PrP结合，表明毒性A β物质具有相对高的分子量和/或可能结合多种PrP分子。针对这些区域的两种代表性和广泛表征的单克隆抗体ICSM-35和ICSM-18显示阻断A β介导的突触可塑性破坏，验证这些抗体单独或组合作为AD的候选治疗剂。先前已经报道了合成淀粉样β蛋白结合朊病毒蛋白并改变突触可塑性的能力。在这里，这种结合的相关性在阿尔茨海默氏病患者的大脑中进行了研究，这种相互作用被朊病毒蛋白的两个不同区域的抗体所阻断。
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. The ability of synthetic amyloid β-protein to bind to prion proteins and alter synaptic plasticity has been previously reported. Here the relevance of this binding is investigated in brains of Alzheimer's disease patients and the interaction is shown to be blocked by antibodies to two distinct regions of prion proteins.
登录
查看更多内容
影响因子：
16.2
作者：
Renner, Marianne;Lacor, Pascale N.;Velasco, Pauline T.;Xu, Jian;Contractor, Anis;Klein, William L.;Triller, Antoine
通讯作者：
Triller, Antoine
影响因子：
11.1
作者：
Calella, Anna Maria;Farinelli, Melissa;Aguzzi, Adriano
通讯作者：
Aguzzi, Adriano
DOI：
10.1073/pnas.0809170106
发表时间：
2009-02-24
影响因子：
11.1
作者：
Antonyuk, S. V.;Trevitt, C. R.;Collinge, J.
通讯作者：
Collinge, J.
DOI：
10.1073/pnas.1009062107
发表时间：
2010-10-12
影响因子：
11.1
作者：
Nicoll, Andrew J.;Trevitt, Clare R.;Collinge, John
通讯作者：
Collinge, John
DOI：
10.1523/jneurosci.3537-10.2010
发表时间：
2010-10-27
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
O'Nuallain B;Freir DB;Nicoll AJ;Risse E;Ferguson N;Herron CE;Collinge J;Walsh DM
通讯作者：
Walsh DM