Comprehensive diagnosis of Alzheimer's disease by detection of misfolded oligomers in biological fluids

通过检测生物体液中错误折叠的寡聚物来全面诊断阿尔茨海默病

• 批准号: 9766691
• 负责人: CLAUDIO SOTO
• 金额: $ 289.76万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766691
• 关键词: Affect; Alzheimer disease detection; Alzheimer' s Disease; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Appearance; Ataxia; Biochemical; Biological; Biological Assay; Blood; Brain; Brain Injuries; Cause of Death; Cerebrum; Clinical; DNA-Binding Proteins; Dementia; Deposition; Detection; Development; Diagnosis; Disease; Disease Progression; Early Diagnosis; Elderly; Encephalitis; Event; Fingerprint; Frontotemporal Dementia; Functional disorder; Goals; Human; Huntington Disease; Huntington gene; Individual; Inherited; Laboratory Diagnosis; Lead; Lewy Body Dementia; Liquid substance; Medical; Molecular Conformation; Monitor; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathologic; Pathology; Patients; Periodicity; Plasma; Plasma Proteins; Polymers; Population; PrP; Predictive Value; Prion Diseases; Process; Property; Proteins; Sampling; Seeds; Senile Plaques; Sensitivity and Specificity; Structure; Symptoms; Synapses; Tauopathies; Technology; Testing; Time; Urine; Vascular Dementia; alpha synuclein; amplification detection; clinical Diagnosis; disease diagnosis; extracellular; mild cognitive impairment; misfolded protein; neuron loss; noninvasive diagnosis; novel strategies; polymerization; pre-clinical; protein TDP-43; protein aggregate; protein aggregation; protein misfolding; protein misfolding cyclic amplification; response; synucleinopathy; tau Proteins; tau aggregation

ABSTRACT This is a revised application in response to the PAR-15-359, entitled “Novel Approaches to Diagnosing Alzheimer's Disease & Predicting Progression (R01)”. Alzheimer's disease (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, oligomerization and brain accumulation of protein aggregates. Similar to AD several other neurodegenerative disorders are associated to the accumulation of cerebral protein aggregates, including Parkinson disease (PD), amyotrophic lateral sclerosis, prion diseases, and Huntington disease. In AD the most abundant protein aggregates are amyloid plaques and neurofibrillary tangles composed of the amyloid-beta (Aβ) and Tau proteins, respectively. Although the protein involved in the misfolding and aggregation process is different in each disease, the end products and intermediate structures are very similar. Moreover, in all cases, protein misfolding and aggregation follows a seeding-nucleation mechanism in which the limiting step is the formation of small oligomeric intermediates that act as seeds to catalyze the polymerization process. Recent evidence has shown that misfolded oligomers are circulating in biological fluids and these structures appear to be key for inducing brain degeneration. Our working hypothesis is that a sensitive, comprehensive and early biochemical diagnosis of AD may be developed by ultra-sensitive and simultaneous detection of misfolded oligomers composed of the three most common protein aggregating in the human brain (Aβ, Tau, and αSyn) in human biological fluids (CSF and blood plasma). Our approach for detection of these oligomers 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. For this purpose, we invented the protein misfolding cyclic amplification (PMCA), which represents 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 and αSyn oligomers in CSF of AD and PD patients, respectively. The major goal of this project is to adapt the PMCA technology for specific and highly sensitive detection of misfolded Aβ, Tau, and αSyn oligomers in human blood and CSF in order to obtain a fingerprint profile that enable to diagnose AD and distinguish from other diseases with similar clinical presentation. In this project we will perform studies of specificity and sensitivity using large number of samples and evaluate the utility of PMCA for monitoring disease progression and for pre-clinical identification of people in the way to develop AD. The results generated in this project may lead to the development of a comprehensive biochemical test for AD that may be useful not only to aid in the diagnosis of the disease and differentiate it from other diseases with similar clinical presentation, but also to identify people on the way to developing AD pathology before the onset of substantial brain damage and clinical symptoms of the disease.

抽象的 这是针对PAR-15-359的修订应用，题为“新颖的方法 诊断阿尔茨海默氏病并预测进展（R01）”。 阿尔茨海默氏病（AD）是最常见的人口中最常见的痴呆症，也是其中之一 发达国家的主要死亡原因。广告中的主要问题之一是缺乏 早期，敏感和客观的实验室诊断，以识别将发展的个人 大脑损伤之前的疾病。令人信服的证据指出，标志性事件 AD是蛋白质聚集体的错误折叠，寡聚和大脑积累。类似于AD 其他几种神经退行性疾病与脑蛋白的积累有关 骨料，包括帕金森病（PD），肌萎缩性侧面硬化症，病毒疾病和 亨廷顿病。在AD中，最丰富的蛋白质骨料是淀粉样蛋白斑块， 由淀粉样蛋白（Aβ）和tau蛋白分别组成的神经原纤维缠结。 尽管涉及错误折叠和聚集过程的蛋白质在每种过程中都不同 疾病，最终产物和中间结构非常相似。此外，在所有情况下， 蛋白质错误折叠和聚集遵循种子核核酸机制，其中有限 步骤是形成小寡聚中间体，该中间体充当种子催化 聚合过程。最近的证据表明，错误折叠的低聚物正在循环 生物流体和这些结构似乎是诱导脑变性的关键。 我们的工作假设是，敏感，全面和早期的生化诊断 广告可能是通过对错误折叠的低聚物的超敏感和简单检测而开发的 由人脑中三种最常见的蛋白质（Aβ，TAU和αSyn）组成 在人类生物学流体（CSF和血浆）中。我们检测这些低聚物的方法 是利用错误折叠的低聚物的功能特性，能够催化 单体蛋白的聚合是检测它们的一种方式。为此，我们发明了 蛋白质错误折叠环状扩增（PMCA），它代表了平台技术 检测与相关的少量播种失误的寡聚蛋白 各种蛋白质错误折叠疾病。目前，PMCA已被调整为检测错误折叠的Prime 涉及各种生物液中的prion疾病的蛋白质，包括血液和尿液等 最近，AD和PD患者CSF中的固体Aβ和αSyn低聚物。专业 该项目的目标是使PMCA技术适应特定且高度敏感的检测 在人血和CSF中折叠的Aβ，TAU和αSyn低聚物以获得指纹 能够诊断AD并与具有相似临床的其他疾病区分开的轮廓 推介会。在这个项目中，我们将使用大型研究进行特异性和敏感性研究 样品数量，并评估PMCA监测疾病进展的实用性和 在开发广告的方式上对人进行临床前识别。该项目产生的结果 可能导致开发针对AD的全面生化测试，这可能无用 仅是为了帮助诊断疾病，并将其与其他类似疾病区分开 临床表现，但也要在开发AD病理学的途中确定人们 大脑损伤和疾病的临床症状的发作。