Alzheimer’s disease (AD) is the most common neurodegenerative disorder. Along with an increasing number of elderly worldwide, it poses a great challenge for the society and health care. Although sporadic AD is the common form of AD, 2–3% of the AD cases are expected to be due to mutations in the β region of the amyloid precursor protein, which is referred to as autosomal dominant AD (ADAD). These mutations may cause changes in the secondary structure of the amyloid β fibrils and may alter the fibrillization rate leading to changes in the disease development and could also affect the binding to tracers used in diagnosis. In particular, from some recent clinical studies using PET tracers for detection of fibrillar amyloids, it is evident that in ADAD patients with Arctic mutation no amyloid plaque binding can be detected with the ¹¹C-Pittsburgh Compound B (¹¹C-PIB). However, for in vitro conditions, significant binding of ³H-PIB has been reported for the amyloid fibrils carrying the Arctic mutation. The aim of the present study is to investigate if there is any mutation specific binding of commonly used amyloid tracers, namely, florbetaben, florbetapir, FPIB, AZD4694, and AZD2184, by means of molecular modeling techniques. Other than Arctic, ADAD mutations, such as the Dutch, Italian, Iowa, and Flemish mutations, are considered in this study. We report that all tracers except florbetapir show reduced binding affinity toward amyloid β fibrils with the Arctic mutation when compared to the native type. Moreover, florbetapir is the only tracer that binds to all mutants with increased affinity when compared to the native fibril. The results obtained from these studies could increase the understanding of the structural changes caused by mutation and concomitant changes in the interaction pattern of the PET tracers with the mutated variants, which in turn can be useful in selecting the appropriate tracers for the purpose of diagnosis as well as for designing new tracers with desirable properties.

中文翻译：

---

阿尔茨海默氏症家族染色体突变对淀粉样蛋白原纤维与不同PET示踪剂相互作用的影响：分子建模研究的见解。

阿尔茨海默氏病（AD）是最常见的神经退行性疾病。随着世界范围内越来越多的老年人，这对社会和医疗保健构成了巨大的挑战。尽管偶发性AD是AD的常见形式，但预计2-3％的AD病例归因于淀粉样蛋白前体蛋白β区的突变，这被称为常染色体显性AD（ADAD）。这些突变可能会导致淀粉样蛋白β原纤维的二级结构发生变化，并可能改变原纤维化率，从而导致疾病发展变化，还可能影响与诊断所用示踪剂的结合。特别是，从最近的一些使用PET示踪剂检测原纤维淀粉样蛋白的临床研究中，很明显，在具有北极突变的ADAD患者中，使用淀粉样蛋白检测不到淀粉样蛋白斑块结合。¹¹ C-匹兹堡化合物B（¹¹ C-PIB）。但是，对于体外条件，^3的显着结合已经报道了H-PIB用于携带北极突变的淀粉样蛋白原纤维。本研究的目的是通过分子建模技术研究常用淀粉样蛋白示踪剂，即florbetaben，florbetapir，FPIB，AZD4694和AZD2184是否存在任何突变特异性结合。除北极以外，本研究还考虑了ADAD突变，例如荷兰，意大利，爱荷华州和佛兰德斯突变。我们报道，与天然类型相比，除florbetapir以外的所有示踪剂均显示出对具有北极突变的β淀粉样蛋白原纤维的结合亲和力降低。此外，与天然纤维相比，florbetapir是唯一以增加的亲和力结合所有突变体的示踪剂。