Department of Pharmacology and Therapeutics and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
J Neurosci. 2011 May 18;31(20):7259-63. doi: 10.1523/JNEUROSCI.6500-10.2011.
Synthetic amyloid-β protein (Aβ) oligomers bind with high affinity to cellular prion protein (PrP(C)), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aβ in vitro is controversial. Here we report that intracerebroventricular injection of Aβ-containing aqueous extracts of Alzheimer's disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampus in vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Aβ. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aβ-binding site on PrP(C), prevented the inhibition of LTP by AD brain-derived Aβ. In contrast, R1, a Fab directed to the C terminus of PrP(C), a region not implicated in binding of Aβ, did not significantly affect the Aβ-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aβ dimer and the role of PrP(C) in mediating synaptic plasticity disruption by soluble Aβ.
合成淀粉样蛋白-β 蛋白 (Aβ) 寡聚体与细胞朊蛋白 (PrP(C)) 具有高亲和力，但这种相互作用在体外介导可溶性 Aβ 破坏突触可塑性的作用仍存在争议。本研究报告称，脑室内注射阿尔茨海默病（AD）脑的含有 Aβ 的水性提取物可强烈抑制长时程增强（LTP），而不会显著影响体内大鼠海马中的基础兴奋性突触传递。此外，Aβ 的免疫耗竭可消除 LTP 的破坏。重要的是，针对 PrP(C) 上假定的 Aβ 结合位点的抗原结合抗体片段 D13 的脑室内给药可防止 AD 脑源性 Aβ 抑制 LTP。相比之下，针对 PrP(C) C 末端的 Fab R1 不会显著影响 Aβ 介导的 LTP 抑制，该区域与 Aβ 结合无关。这些数据支持 SDS 稳定的 Aβ 二聚体的病理生理学意义以及 PrP(C) 在介导可溶性 Aβ 破坏突触可塑性中的作用。
