1 Institute of Neuropathology, University Medical Centre Hamburg-Eppendorf, D-20246 Hamburg, Germany.
Brain. 2014 Mar;137(Pt 3):873-86. doi: 10.1093/brain/awt375. Epub 2014 Feb 10.
Alzheimer's disease is the most common form of dementia and the generation of oligomeric species of amyloid-β is causal to the initiation and progression of it. Amyloid-β oligomers bind to the N-terminus of plasma membrane-bound cellular prion protein (PrP(C)) initiating a series of events leading to synaptic degeneration. Composition of bound amyloid-β oligomers, binding regions within PrP(C), binding affinities and modifiers of this interaction have been almost exclusively studied in cell culture or murine models of Alzheimer's disease and our knowledge on PrP(C)-amyloid-β interaction in patients with Alzheimer's disease is limited regarding occurrence, binding regions in PrP(C), and size of bound amyloid-β oligomers. Here we employed a PrP(C)-amyloid-β binding assay and size exclusion chromatography on neuropathologically characterized Alzheimer's disease and non-demented control brains (n = 15, seven female, eight male, average age: 79.2 years for Alzheimer's disease and n = 10, three female, seven male, average age: 66.4 years for controls) to investigate amyloid-β-PrP(C) interaction. PrP(C)-amyloid-β binding always occurred in Alzheimer's disease brains and was never detected in non-demented controls. Neither expression level of PrP(C) nor known genetic modifiers of Alzheimer's disease, such as the PrP(C) codon 129 polymorphism, influenced this interaction. In Alzheimer's disease brains, binding of amyloid-β to PrP(C) occurred via the PrP(C) N-terminus. For synthetic amyloid-β42, small oligomeric species showed prominent binding to PrP(C), whereas in Alzheimer's disease brains larger protein assemblies containing amyloid-β42 bound efficiently to PrP(C). These data confirm Alzheimer's disease specificity of binding of amyloid-β to PrP(C) via its N-terminus in a large cohort of Alzheimer's disease/control brains. Differences in sizes of separated protein fractions between synthetic and brain-derived amyloid-β binding to PrP(C) suggest that larger assemblies of amyloid-β or additional non-amyloid-β components may play a role in binding of amyloid-β42 to PrP(C) in Alzheimer's disease.
阿尔茨海默病是最常见的痴呆症形式，淀粉样β寡聚体的产生与该病的起始和进展有关。淀粉样β寡聚体与质膜结合的细胞朊蛋白（PrP(C)）的 N 端结合，引发一系列导致突触退化的事件。与该相互作用相关的结合淀粉样β寡聚体的组成、PrP(C)内的结合区域、结合亲和力和修饰剂，几乎完全在细胞培养或阿尔茨海默病的鼠模型中进行了研究，而我们对阿尔茨海默病患者中 PrP(C)-淀粉样β相互作用的了解仅限于发生情况、PrP(C)中的结合区域和结合的淀粉样β寡聚体的大小。在这里，我们使用 PrP(C)-淀粉样β结合测定法和尺寸排阻层析法，对神经病理学特征明确的阿尔茨海默病和非痴呆对照大脑（n=15，7 名女性，8 名男性，平均年龄：阿尔茨海默病患者 79.2 岁，n=10，3 名女性，7 名男性，平均年龄：对照组 66.4 岁）进行了研究，以调查淀粉样β-PrP(C)相互作用。PrP(C)-淀粉样β结合总是发生在阿尔茨海默病大脑中，而在非痴呆对照中从未检测到。PrP(C)的表达水平或阿尔茨海默病的已知遗传修饰因子，如 PrP(C)密码子 129 多态性，均未影响这种相互作用。在阿尔茨海默病大脑中，淀粉样β与 PrP(C)的结合发生在 PrP(C)的 N 端。对于合成的淀粉样β42，小寡聚体表现出与 PrP(C)的明显结合，而在阿尔茨海默病大脑中，含有淀粉样β42 的较大蛋白质组装有效地与 PrP(C)结合。这些数据在一大群阿尔茨海默病/对照大脑中证实了淀粉样β通过其 N 端与 PrP(C)结合的阿尔茨海默病特异性。在合成和脑源性淀粉样β与 PrP(C)结合的分离蛋白质级分的大小差异表明，较大的淀粉样β组装体或其他非淀粉样β成分可能在阿尔茨海默病中淀粉样β42 与 PrP(C)的结合中起作用。
