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

阿尔茨海默病(AD)是一种新兴的公共卫生危机，给社会造成了巨大的负担。总数 在美国，2015年为所有AD患者支付的费用估计为226亿美元。降低AD的成本 在初级保健环境下进行廉价的初步筛查是关键之一。不过，目前 现有的成像诊断技术，如昂贵的PET成像，几乎令人望而却步 需要。显然，快速、廉价和可靠的AD患者初步筛查方法迫在眉睫 需要的。与PET成像和MRI成像等非侵入性成像相比，生物标志物检测 在生物体液中是诊断AD的一种非常有前途的替代方法。目前，有几种方法，包括免疫- MS、EL ISA、SiMoA已在临床试验中被检测；然而，这些方法与某些 缺点。例如，免疫-MS繁琐，SiMoA准确度低，ELISA法计算量大 来自不同实验室的变化。 越来越多的证据表明，适应性免疫系统和先天免疫系统在阿尔茨海默病中起着重要作用 病理学。然而，体液免疫在AD发病机制中的确切作用尚不清楚。积累 β-淀粉样蛋白(A-β)多肽的聚集是AD的特征，A-β水平的调节 是治疗学预防和发展的重要方面之一。这并不令人惊讶 人类的免疫系统自然就有这样一个控制Aβ水平的调节系统。自然而然 针对Aβ的发生自身抗体(NABS-Aβ)是先天免疫系统的一部分，具有 A-β在脑和外周系统中代谢和清除的调控功能完毕 在过去的几年里，一些研究已经调查了NABS-Aβ滴度及其与疾病分期的相关性 AD或AD的严重性。然而，报道的结果是相互矛盾的。在此R21应用程序中，我们提供 为研究人血清中NABS-Aβ提供一个新的视角，以期部分解决这一矛盾问题。 我们之前发现，抗体-表位的相互作用可以通过以下方式调节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，一系列的β成像 PI小组开发的探针可以增强或削弱Aβ与其抗体的结合。 在这一应用中，我们推测CRANAD-Xs对Aβ自身抗体具有类似的调节功能 血清，这种调节能力可以用来区分AD患者和健康对照的血清。 我们的方法非常简单，因为不需要对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.