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.

阿尔茨海默氏病（AD）是邮政的新兴公共心脏危机。 2015年，所有广告中的人的付款估计为2260亿美元。 护理，廉价的初步筛查是主要护理设置的钥匙。 可用的成像诊断技术（例如昂贵的宠物成像）几乎是对此的极限 需要清楚，快速，便宜和可靠的广告患者筛查 需要。 在生物流体中，目前是AD诊断的一种非常有希望的替代方法。 MS，ELISA，SIMOA在临床试验中已进行了测试； 例如，缺点。 来自不同实验室的变体。 越来越多的证据表明，适应性囊泡免疫系统在AD中起重要作用 然而，病理学中的精确作用在AD病理学中的确切作用尚不清楚 β-淀粉样蛋白（Aβ）肽的聚集是AD的标志，Aβ水平的调节具有 是预防和发展治疗学的基本方面之一。 人类的Imunologice曲目自然具有控制Aβ水平的调节系统。 发生针对Aβ（NABS-Aβ）的自身抗体（NABS）是先天免疫系统的一部分 控制大脑和周围系统中Aβ物种的新陈代谢和清除的功能 过去几年，严重性研究研究了NABS-Aβ滴度及其与阶段的相关性 AD或AD的严重性。 一个新的角度来研究人血清中的NABS-Aβ，希望部分解决不一致问题。 我们以前发现，可以通过通过 Aβ和Tau蛋白的小分子。 PI组开发的探针可以增强或削弱Aβ和IS抗体之间的结合。 在此应用中，我们认为Cranad-Xs在Aβ抗体中具有相似 血清和这种调整能力可用于将血清与AD患者和健康对照区分开。 我们的方法非常简单 Cranad-XS。