DEVELOPMENT OF NOVEL BIOMARKERS FOR ALZHEIMER'S DISEASE

描述（由申请人提供）：对阿尔茨海默病（AD）早期发病鉴别诊断和疾病进展分期的新型生物标志物的需求尚未得到满足。目前，阿尔茨海默病的明确诊断需要组织活检或大脑尸检，这只能在患者死亡后进行。目前，在脑脊液（CSF）、血液和尿液等患者样本中，还没有经过验证的生物标志物可用于明确监测AD的进展或消退。大多数方法侧重于个体蛋白如tau和A2在患者样本中作为生物标志物的定量变化。这些研究得出了一个共识，即脑脊液中总蛋白和p-tau蛋白的增加以及伴随的A21-42蛋白的减少可能表明神经退行性变。然而，这些变化并不是阿尔茨海默病的具体指标，也可能发生在其他形式的痴呆症中。因此，这些生物标志物不能用于早期AD的鉴别诊断和疾病进展分期。基于蛋白质-蛋白质相互作用范式而非特定蛋白质水平的新型生物标志物的开发，可能为更早、更具体的诊断和疾病监测创造机会，从而更好地管理患者。利用测量蛋白质之间病理相互作用的方法可能提供迫切需要的新型AD生物标志物。这些生物标志物还可以作为药物靶点，用于识别治疗阿尔茨海默病的新药物疗法，并监测用于治疗阿尔茨海默病的不同治疗效果。OLIGOMERIX正在评估基于含有tau低聚物的可溶性复合物和含有tau和A21-42的复合物的新型AD生物标志物。有限数量脑脊液样本的初步可行性研究表明，与非AD对照相比，AD患者脑脊液中的tau低聚物和tau- A21-42复合物增强。开发了不同格式的elisa来测量CSF中的这些参数。该项目的目的是扩大初步研究，使用具有统计学意义的临床腰椎CSF样本，包括严重，轻度和年龄匹配的非AD对照，以评估tau低聚物tau A2和tau apoe复合物作为AD早期检测和进展的特异性生物标志物的潜力。这项工作将与博士合作进行。Richard Mayeux和Lawrence Honig在哥伦比亚大学医学中心的陶布研究所研究阿尔茨海默病和大脑老化。该计划的具体目标如下：“开发用于AD的生物标志物分析，测量脑脊液中tau寡聚物和tau与A2或apoE的复合物。”利用临床脑脊液样本对开发的生物标志物分析进行可行性研究。为此，Honig博士将提供约250个脑脊液样本，用于生物标志物的统计显著研究。OLIGOMERIX将对去鉴定的盲法样本进行elisa， Honig博士将分析数据。这些生物标记物可能被授权给制药行业，用于针对tau低聚物、tau a2或tau apocomplex的化合物的临床评估。关键词阿尔茨海默病，生物标志物，tau, A2, apoE，寡聚物公共卫生相关性：拟议项目的重点是基于蛋白质-蛋白质相互作用的范式，识别和开发阿尔茨海默病（AD）的新型生物标志物。目前，AD生物标志物的研究主要集中在与AD病因相关的蛋白水平的定量变化上。除阿尔茨海默病外，这些变化也可能发生在其他形式的痴呆症中，因此不是阿尔茨海默病的具体指标。在这里，我们建议基于含有AD关键蛋白的可溶性复合物来评估新的AD生物标志物：tau， A21-42和apoE。我们的目标是1)开发生物标志物检测方法来测量人类脑脊液样本中tau蛋白与自身（tau寡聚物）、A2或apoE的相互作用，2)使用大量脑脊液样本评估使用tau寡聚物或tau复合物与A2或apoE作为AD生物标志物的可行性。

DESCRIPTION (provided by applicant): There is a critical unmet need for novel biomarkers for differential diagnosis of Alzheimer's disease (AD) at early onset and to stage disease progression. Presently, definitive diagnosis of AD requires tissue biopsy or autopsy of the brain, which can occur only after the patient dies. Currently, there are no validated biomarkers identified in patient samples such as cerebrospinal fluid (CSF), blood, and urine that can be used to definitely monitor the progression or regression of AD. Most approaches focus on quantitative changes of individual proteins such as tau and A2 in patient samples as biomarkers. These studies have led to a consensus that an increase in total and p-tau and a concomitant decrease in A21-42 in CSF may be indicative of neurodegeneration. However, these changes are not specific indicators of AD and may also occur in some other forms of dementia. Therefore, these biomarkers cannot be used for differential diagnosis of AD at early onset and to stage disease progression. The development of novel biomarkers based on the paradigm of protein-protein interactions, rather than on specific protein levels, may create opportunity for earlier and more specific diagnosis and disease monitoring for better patient management. Using the approach of measuring pathological interactions between proteins may provide urgently needed novel AD biomarkers. These biomarkers can also serve as drug targets for the identification of new medication therapies to treat AD and to monitor different therapeutic effects when used to treat AD. OLIGOMERIX is evaluating novel AD biomarkers based on soluble complexes containing tau oligomers and complexes containing both tau and A21-42. Preliminary feasibility studies with a limited number of CSF samples have indicated that tau oligomers and tau- A21-42 complexes are enhanced in CSF from AD compared to non-AD controls. ELISAs of different formats were developed to measure these parameters in CSF. The objective of this project is to expand the preliminary studies using a statistically significant number of clinical lumbar CSF samples that include severe, mild and age-matched non-AD controls to assess the potential of tau oligomers tau A2, and tau-apoE complexes as specific biomarkers for early detection and progression of AD. This work will be performed in collaboration with Drs. Richard Mayeux and Lawrence Honig at the Taub Institute for Research on Alzheimer's disease and the Aging Brain at Columbia University Medical Center. The specific aims of the proposed program are as follows: " Develop biomarker assays for AD measuring tau oligomers and complexes of tau with A2 or apoE in CSF " Conduct feasibility study of developed biomarker assays using clinical CSF samples Towards this end Dr. Honig will provide about 250 CSF samples for a statistically significant study of the biomarkers. OLIGOMERIX will perform ELISAs on de-identified blinded samples, and Dr. Honig will analyze the data. The biomarkers may be out-licensed to the pharmaceutical industry for clinical evaluation of compounds targeting tau oligomers, tau-A2, or tau-apoEcomplexes. Key Words Alzheimer's disease, biomarker, tau, A2, apoE, oligomer. PUBLIC HEALTH RELEVANCE: The proposed program is focused on the identification and development of novel biomarkers for Alzheimer's disease (AD), based on the paradigm of protein-protein interactions. Presently, AD biomarker studies are primarily focused on the quantitative changes in the levels of protein involved in AD etiology. In addition to AD, these changes may also occur in some other forms of dementia, therefore, are not specific indicators of AD. Here we propose to evaluate novel AD biomarkers based on soluble complexes containing key protein players in AD: tau, A21-42 and apoE. Our goal is to 1) develop biomarker assays to measure the interactions of tau protein with itself (tau oligomers), A2 or apoE in human CSF samples, 2) evaluate the feasibility of using tau oligomers, or tau complexes with A2 or apoE as biomarkers for AD using a significantly large number of CSF samples.