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）是一种新兴的公共卫生危机，造成了巨大的社会负担。总 在美国，2015年所有AD患者的付款估计为2260亿美元。降低AD成本 在初级保健环境中进行廉价的初步筛查是关键之一。但目前 可用的成像诊断技术，例如昂贵的PET成像，对此几乎是禁止的 需要的显然，快速，廉价，可靠的方法，初步筛选AD患者迫切需要 needed.与PET成像和MRI成像等非侵入性成像相比， 在生物流体中是AD诊断的非常有前途的替代方案。目前，有几种方法，包括免疫- MS、ELISA、SIMOA已在临床试验中进行了测试;然而，这些方法与某些 缺点.例如，免疫-MS是繁琐的，而SIMOA具有低准确性，而ELISA具有大的准确性。 来自不同实验室的变化。 越来越多的证据表明，适应性和先天性免疫系统在AD中发挥重要作用 病理然而，体液免疫在AD病理中的确切作用尚不清楚。积累 β-淀粉样蛋白（Aβ）肽的聚集是AD的标志，Aβ水平的调节 是预防和开发治疗方法的重要方面之一。也就不足为奇 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 抗Aβ自身抗体（nAbs-Aβ）是先天免疫系统的一部分， 控制脑和外周系统中Aβ类物质的代谢和清除的功能。超过 在过去的几年里，一些研究调查了nAbs-Aβ滴度及其与肿瘤分期的相关性， AD或AD的严重程度。然而，报告的结果是矛盾的。在此R21应用程序中，我们提供 为研究人血清中nAbs-Aβ提供了一个新的视角，以期部分解决目前的不一致问题。 我们以前发现，抗体-表位相互作用可以通过调节抗体-表位相互作用来调节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。 在该应用中，我们推测CRANAD-X对Aβ自身抗体具有类似的调节功能， 血清，并且这种调谐能力可用于区分来自AD患者和健康对照的血清。 我们的方法非常简单，因为Aβ抗原和 CRANAD-Xs。