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

用于检测血清中β-淀粉样蛋白自身抗体的表位改变

• 批准号: 10740080
• 负责人: Chongzhao Ran
• 金额: $ 45.86万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740080
• 关键词: Abeta clearance; Adaptive Immune System; Affinity; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease care; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Antibodies; Antibody titer measurement; Antigens; Autoantibodies; Binding; Biological Markers; Brain; Clinical Trials; Complex; Detection; Diagnosis; Diagnostic Imaging; Diagnostic Procedure; Enzyme-Linked Immunosorbent Assay; Epitopes; Future; Human; Humoral Immunities; Image; Immune; Immunologics; Implant; Individual; Innate Immune System; Laboratories; Literature; Magnetic Resonance Imaging; Mediating; Metabolism; Methods; Modification; Molecular Conformation; Play; Population; Positron-Emission Tomography; Prevention; Public Health; Regulation; Reporting; Role; Sampling; Series; Serum; Severities; System; Technology; Testing; Variant; abeta accumulation; cost; diagnostic technologies; dimer; imaging probe; monomer; non-invasive imaging; novel diagnostics; payment; primary care setting; screening; small molecule; small molecule libraries; tau Proteins; therapeutic development

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.

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。 2015 年，美国为所有 AD 患者支付的费用估计为 2260 亿美元，以降低 AD 成本。 然而，目前关键之一是在初级保健机构进行廉价的初步筛查。 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 显然，迫切需要快速、廉价且可靠的方法来初步筛查 AD 患者。 与 PET 成像和 MRI 成像等非侵入性成像相比，生物标志物检测。 目前，有多种方法，包括免疫法，可用于 AD 诊断。 MS、ELISA、SIMOA等都已在临床试验中进行了测试，但这些方法都与某些特定的因素有关； 例如，免疫-MS 很繁琐，而 SIMOA 的准确性较低，而 ELISA 的准确性较高。 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 然而，体液免疫在AD病理学中的确切作用仍不清楚。 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 已成为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。 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。 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，在该 R21 申请中，我们提供的报告结果是矛盾的。 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 特别是，我们发现了 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。