Blood-based diagnostics for Alzheimer's Disease

描述（由申请人提供）：本提案是STTR项目的I/II期快速通道项目，主要目标是开发用于阿尔茨海默病（AD）诊断的血液检测。AD是老年人群中最常见的痴呆症，也是发达国家的主要死亡原因之一。AD的主要问题之一是缺乏早期，敏感和客观的实验室诊断，以确定在严重脑损伤之前将发展该疾病的个体。令人信服的证据表明，AD的标志性事件是淀粉样β（Aβ）蛋白的错误折叠、聚集和脑内积聚。Aβ聚集遵循种子成核机制，并涉及几种中间体，包括可溶性寡聚体和原纤维。最近的证据表明，Aβ寡聚体在生物体液中循环，这些结构似乎是诱导AD脑变性的关键。我们的工作假设是，检测血液中循环的错误折叠Aβ寡聚体可能是AD早期生化诊断的基础。我们的方法是利用错误折叠的寡聚体的功能特性，能够催化单体蛋白质的聚合，作为检测它们的一种方法。我们最近发明了蛋白质错误折叠循环扩增（PMCA），其代表了检测与各种蛋白质错误折叠疾病相关的非常少量的具有播种能力的错误折叠寡聚蛋白的平台技术。目前，PMCA已适用于检测各种生物液体中与朊病毒疾病有关的错误折叠朊病毒蛋白，包括血液和尿液以及最近AD患者脑脊液中的可溶性Aβ寡聚体。本项目的主要目标是采用PMCA技术对人血液中错误折叠的Aβ寡聚体进行特异性和高灵敏度检测，使用大量样本进行特异性和灵敏度研究，并评估Aβ-PMCA在临床前识别AD患者中的实用性。该项目产生的结果可能导致第一个基于血液的AD诊断生化测试。本项目中包含的研究将构成Amprion将商业化的检测的监管批准基础。

DESCRIPTION (provided by applicant): This proposal is for a phase I/II fast track project for the STTR program with the main goal to develop a blood test for Alzheimer's disease (AD) diagnosis. AD is the most common dementia in the elderly population and one of the leading causes of death in the developed world. One of the main problems in AD is the lack of an early, sensitive and objective laboratory diagnosis to identify individuals that will develop the disease before substantial brain damage. Compelling evidences point that the hallmark event in AD is the misfolding, aggregation and brain accumulation of amyloid-beta (Aβ) protein. Aβ aggregation follows a seeding-nucleation mechanism and involves several intermediates, including soluble oligomers and protofibrils. Recent evidence has shown that Aβ oligomers are circulating in biological fluids and these structures appear to be key for inducing brain degeneration in AD. Our working hypothesis is that detection of misfolded Aβ oligomers circulating in blood may be the basis for an early biochemical diagnosis for AD. Our approach is to use the functional property of misfolded oligomers of being capable to catalyze the polymerization of the monomeric protein as a way to detect them. We have recently invented the protein misfolding cyclic amplification (PMCA), which represent a platform technology to detect very small quantities of seeding-competent misfolded oligomeric proteins associated with various protein misfolding diseases. Currently, PMCA has been adapted to detect misfolded prion protein implicated in prion diseases in various biological fluids, including blood and urine and more recently soluble Aβ oligomers in cerebrospinal fluid of AD patients. The major goal of this project is to adapt the PMCA technology for specific and highly sensitive detection of misfolded Aβ oligomers in human blood, perform studies of specificity and sensitivity using large number of samples and evaluate the utility of Aβ-PMCA for pre-clinical identification of people in the way to develop AD. The results generated in this project may lead to the first biochemical test for blood-based diagnosis of AD. The studies included in this project will constitute the basis for regulatory approval of the test that Amprion will commercialize.