Protein variants as blood based biomarkers for diagnosing and staging AD

蛋白质变体作为血液生物标志物用于 AD 诊断和分期

基本信息

批准号：
9977069
负责人：
MICHAEL R SIERKS
金额：
$ 34.96万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977069
关键词：
Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amyloid Amyloid beta-Protein Amyotrophic Lateral Sclerosis Antibodies Aphasia Apraxias Ataxia Binding Biological Assay Biological Markers Blood specimen Brain Cellular Stress Clinical Clinical assessments Cognitive Cohort Studies Collection Confusion DNA-Binding Proteins Diagnosis Diagnostic Disease Disease Outcome Disease Progression Early Diagnosis Effectiveness Environmental Risk Factor Fingerprint Freezing Frontotemporal Dementia Generations Goals Human Immunoglobulin Fragments Individual Injury Length Lewy Body Dementia Link Memory Monitor Morphology Neurodegenerative Disorders Neurons Parkinson Disease Parkinsonian Disorders Patient-Focused Outcomes Patients Performance Plasma Play Population Proteins Protocols documentation Publications Reaction Reagent Research Risk Factors Role Sampling Side Staging Stress Symptoms Tars Therapeutic Time Toxic Environmental Substances Variant Visual Hallucination alpha synuclein base blood-based biomarker cortical visual impairment cost direct application disorder control economic cost effective therapy imaging agent in vivo individual patient nanobodies new technology personalized diagnostics personalized therapeutic protein aggregation radiotracer success tau Proteins therapeutic target tool

项目摘要

ABSTRACT There are over 5 million cases of Alzheimer's Disease (AD) in the US, the number of cases is expected to nearly double over the next 15 years, and the total annual economic costs are over $225 billion. Despite these tremendous costs, there is still no effective treatment for AD. The protein amyloid-beta (Aß) has been linked to AD for many years, but despite thousands of publications on the connection between Aß and AD, there is still much confusion over the role of Aß in AD, and therapeutics targeting Aß have met with very limited success. The protein tau has also been linked to AD. Similar to Aß, tau also exists in a wide variety of different forms in the human brain, so the role of tau in the onset and progression of AD is also not clear. Two other neuronal proteins, alpha-synuclein (a-syn) and Tar-DNA binding protein (TDP-43), have also been implicated in neurodegenerative diseases and play major roles in Parkinson's disease and Amyotrophic lateral sclerosis (ALS), respectively. All four of these key neuronal proteins, Aß, tau, a-syn and TDP-43, are prone to misfolding and aggregation and small toxic aggregates of each of these proteins are thought to play a role in the onset, progression and spread of a number of different neurodegenerative diseases. Cellular stress caused by toxic aggregates of one protein can induce formation of toxic aggregates of other proteins ultimately resulting in a spectrum of neurodegenerative diseases. Clearly generation and accumulation of toxic protein variants of tau, Aß, TDP-43 and a-syn AD play an important role in the onset and progression of neurodegenerative diseases including AD. Because of the important role of these protein variants in different neurodegenerative disease, we hypothesize that there are distinct toxic protein variant profiles that distinguish AD, and that levels of key protein variants in these profiles will change during progression of AD and also from patient to patient. We hypothesize that by determining each individual's toxic protein variant fingerprint using biomarkers present in sera or plasma samples, we can facilitate pre-symptomatic diagnosis and staging of AD, identify appropriate therapeutic strategies for each individual patient, and also monitor effectiveness of different therapeutics in real time. The goal of this proposal is to identify blood based biomarker fingerprints that distinguish different stages AD, including presymptomatic AD, and that identify the most appropriate therapeutic strategy for each individual patient. We developed novel technology that enables us to generate antibody fragments (nanobodies) that selectively bind disease related protein variants. We have a panel of 15 nanobodies to different toxic variants of Aß, tau, a-syn and TDP-43 and have shown that we can detect these variants in blood samples of patients suffering from AD, PD and other neurodegenerative diseases, but not in age-matched cognitively normal cases. The aims of this proposal are to utilize our panel of nanobodies that selectively recognize different disease related forms of Aß, tau, a-syn and TDP-43 to characterize a set of longitudinal plasma samples taken from AD and age-matched control patients. These studies will define protein variant fingerprints that not only distinguish AD from cognitively normal controls, but will define different fingerprints for different stages of AD. We will then characterize a larger set of samples from a clinical population to determine protein variant fingerprints that correlate with different clinical symptoms, such as parkinsonism, aphasia and ataxia. Defining the various protein variant fingerprints associated with different stages and clinical manifestations of AD will provide a very powerful tool to facilitate presymptomatic and personalized diagnoses of AD, indicate the most appropriate therapeutic strategy for each individual patient, and provide a means to monitor the effectiveness of the selected therapeutic in real time.

抽象的美国有超过 500 万例阿尔茨海默病 (AD) 病例，预计病例数将尽管如此，未来 15 年的经济成本将几乎翻倍，每年的经济成本总额仍将超过 2250 亿美元。尽管花费巨大，但目前仍没有有效的治疗 AD 的方法。 AD 已经存在很多年了，但是尽管有数千篇关于 Aß 和 AD 之间联系的出版物，但仍然存在人们对 Aß 在 AD 中的作用存在很多困惑，并且针对 Aß 的治疗取得的成功非常有限。 tau 蛋白也与 AD 相关，与 Aß 类似，tau 蛋白也以多种不同形式存在于 AD 中。 tau蛋白在人类大脑中的作用，因此tau蛋白在AD发病和进展中的作用还不清楚。蛋白质、α-突触核蛋白 (a-syn) 和 Tar-DNA 结合蛋白 (TDP-43) 也与神经退行性疾病，在帕金森病和肌萎缩侧索硬化症中起重要作用 (ALS)，这四种关键神经元蛋白 Aß、tau、a-syn 和 TDP-43 都容易发生错误折叠。这些蛋白质的聚集和小的有毒聚集体被认为在发病过程中发挥了作用，由毒性引起的多种不同神经退行性疾病的进展和传播。一种蛋白质的聚集体可以诱导其他蛋白质的有毒聚集体的形成，最终导致一系列神经退行性疾病的毒性蛋白变体的明显产生和积累， Aß、TDP-43 和 a-syn AD 在神经退行性疾病的发生和进展中发挥重要作用因为这些蛋白质变体在不同的神经退行性疾病中发挥着重要作用。疾病，我们追求有独特的毒性蛋白变异谱来区分 AD，并且这些谱中关键变异蛋白的水平会在 AD 的进展过程中发生变化，并且从我们通过确定每个人的有毒蛋白质变异体来勇敢地面对这一点。使用血清或血浆样本中存在的生物标志物进行指纹识别，我们可以促进症状前的诊断 AD 的诊断和分期，为每个患者确定适当的治疗策略，以及还实时监测不同疗法的有效性。该提案的目标是确定。基于血液的生物标志物指纹可区分不同阶段的 AD，包括症状前的 AD，并为每个患者确定最合适的治疗策略。新技术使我们能够生成选择性结合疾病的抗体片段（纳米抗体）我们有一组针对 Aß、tau、a-syn 和不同毒性变体的 15 种纳米抗体。 TDP-43 并表明我们可以在患有 AD、PD 的患者的血液样本中检测到这些变异和其他神经退行性疾病，但不适用于年龄匹配的认知正常病例。该提案的目的是利用我们的纳米抗体组选择性地识别不同的疾病相关形式的 Aß、tau、a-syn 和 TDP-43，用于表征采集的一组纵向血浆样本这些研究将定义蛋白质变异指纹，这不仅是来自 AD 和年龄匹配的对照患者。将 AD 与认知正常对照区分开来，但将为 AD 的不同阶段定义不同的指纹。然后，我们将对来自临床人群的更大样本集进行表征，以确定蛋白质变异与不同临床症状相关的指纹，例如帕金森症、失语症和共济失调。与 AD 的不同阶段和临床表现相关的各种蛋白质变异指纹将提供了一个非常强大的工具来促进 AD 的症状前和个性化诊断，表明最为每位患者提供适当的治疗策略，并提供监测有效性的方法实时选择的治疗方法。