Epitope alteration for detecting auto-antibodies of beta-amyloid in serum

阿尔茨海默病（AD）是一种新出现的公共卫生危机，造成了巨大的社会负担。总计 2015 年，美国为所有 AD 患者支付的费用估计为 2,260 亿美元。降低AD成本 初级保健机构的廉价初步筛查是关键之一。然而，目前 现有的成像诊断技术，例如昂贵的 PET 成像，几乎无法实现这一点 需要。显然，快速、廉价且可靠的 AD 患者初步筛查方法迫在眉睫 需要。与PET成像、MRI成像等非侵入性成像相比，生物标志物检测 生物体液中的液体是 AD 诊断的一种非常有前途的替代方案。目前，有多种方法，包括免疫 MS、ELISA、SIMOA，已通过临床试验；然而，这些方法与某些特定的 缺点。例如，免疫-MS操作繁琐，SIMOA准确度低，ELISA检测量大。 不同实验室的差异。 越来越多的证据表明适应性和先天免疫系统在 AD 中发挥着重要作用 病理学。然而，体液免疫在 AD 病理学中的确切作用仍不清楚。积累 β-淀粉样蛋白 (Aβ) 肽的聚集和聚集是 AD 的标志，Aβ 水平的调节 是预防和开发治疗的重要方面之一。这并不奇怪 人类免疫系统天然具有这样的调节系统来控制Aβ水平。自然地 针对 Aβ 的自身抗体 (nAb) (nAbs-Aβ) 是先天免疫系统的一部分 控制大脑和外周系统中 Aβ 物质的代谢和清除的功能。结束 在过去的几年里，一些研究调查了 nAbs-Aβ 滴度及其与各阶段的相关性 AD 或 AD 的严重程度。然而，报道的结果是矛盾的。在此 R21 应用程序中，我们提供 一个新的角度研究人血清中的nAbs-Aβ，希望部分解决不一致的问题。 我们之前发现抗体-表位相互作用可以通过以下方式调整到更高或更低的亲和力 Aβ 和 tau 蛋白的小分子。特别是，我们发现 CRANAD-Xs，一系列 Aβ 成像 PI小组开发的探针可以增强或减弱Aβ与其抗体之间的结合。 在此应用中，我们推测 CRANAD-X 对 Aβ 自身抗体具有类似的调节功能 血清，这种调节能力可用于区分 AD 患者和健康对照者的血清。 我们的方法非常简单，因为 Aβ 抗原和 CRANAD-Xs。

Alzheimer’s disease (AD) is an emerging public health crisis that poses a huge societal burden. The total payments in 2015 for all individuals with AD are estimated at $226 billion in US. To reduce the cost of AD care, inexpensive preliminary screening with a primary-care setting is one of the keys. However, currently available imaging diagnostic technologies, such as expensive PET imaging, are nearly prohibitive for this need. Clearly, fast, cheap, and reliable methods for preliminary screening of AD patients are urgently needed. Compared to non-invasive imaging such as PET imaging and MRI imaging, biomarker detection in biofluids is a very promising alternative for AD diagnosis. Currently, several methods, including immune- MS, ELISA, SIMOA, have been tested in clinical trials; however, these methods are associated with certain drawbacks. For example, immune-MS is tedious, while SIMOA has low accuracy and ELISA has large variations from different labs. Mounting evidence suggest that the adaptive and innate immune systems play essential roles in AD pathology. However, the exact roles of humoral immunity in AD pathology are still not clear. Accumulation and aggregation of Beta-Amyloid (Aβ) peptides are hallmarks of AD, and the regulation of Aβ levels has been one of the essential aspects for prevention and development of therapeutics. It is not surprising that human immunological repertoire naturally has such a regulatory system to control the Aβ levels. Naturally occurring autoantibodies (nAbs) against Aβ (nAbs-Aβ) are a part of the innate immune system with the functions of controlling the metabolism and clearance of Aβ species in brains and periphery systems. Over the past years, several studies have investigated nAbs-Aβ titers and their correlations with the stages of AD or severity of AD. However, the reported results are contradictory. In this R21 application, we provide a new angle to investigate nAbs-Aβ in human serum in hope of partially solving the inconsistence problem. We previously discovered that antibody-epitope interactions can be tuned to higher or lower affinities by small molecules for Aβ and tau proteins. Particularly, we found that CRANAD-Xs, a series of Aβ imaging probes developed by the PI group, could enhance, or weaken the binding between Aβ and its antibodies. In this application, we speculate that CRANAD-Xs have similar tuning function for Aβ auto-antibodies in serum, and this tuning capacity can be used to differentiate sera from AD patients and healthy controls. Our method is very straightforward, due to no modifications are needed for both the Aβ antigens and CRANAD-Xs.