Dominantly Inherited Alzheimer Network: Project 2

显性遗传阿尔茨海默病网络：项目 2

• 批准号: 10017844
• 负责人: BRIAN Andrew GORDON
• 金额: $ 31.61万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017844
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antibodies; Autopsy; Behavioral Genetics; Binding; Biological; Biological Markers; Biology; Brain; Cell Line; Cell model; Cerebrospinal Fluid; Characteristics; Clinical; Cognitive; Collaborations; Data; Data Collection; Dementia; Development; Disease; Disease Marker; Disease Progression; Elements; Evaluation; Evolution; Family; Freezing; Funding; Genes; Genetic; Health; Heritability; Human; Immunohistochemistry; Impaired cognition; Impairment; Individual; Inherited; Late Onset Alzheimer Disease; Lead; Learning; Ligand Binding; Ligands; Liquid substance; Location; Magnetic Resonance Imaging; Maps; Mass Spectrum Analysis; Measures; Metabolism; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Neuropsychological Tests; Normalcy; Observational Study; Pathogenesis; Pathologic; Pathology; Phosphorylation; Phosphorylation Site; Play; Population; Positron-Emission Tomography; Process; Property; Proteins; Quantitative Autoradiography; Research; Research Personnel; Role; Sensitivity and Specificity; Site; Slice; Structure; Symptoms; Techniques; Therapeutic Agents; Therapeutic Trials; Time; Tissues; Tracer; Uncertainty; Work; base; brain tissue; cohort; density; gray matter; high risk; in vivo; induced pluripotent stem cell; innovation; insight; mutation carrier; mutational status; neuroimaging; neuropathology; novel; novel therapeutics; presenilin-1; presenilin-2; progression marker; tau Proteins; tau aggregation; tau-1; therapeutic target

Project 2: Tau SUMMARY Alzheimer's disease (AD) is a growing worldwide health crisis. It is critical to develop biomarkers to identify individuals at high risk for AD, better understand the biological underpinnings of the disease, and to develop new therapeutic agents. Autosomal dominant AD (ADAD) is a rare form of the disease (<1%) that is caused by mutations in one of three genes. Individuals with these mutations develop dementia at a relatively young age that is heritable within families. This provides a unique cohort of individuals where it is possible to predict the disease stage of individuals relative to their estimated years to symptom onset (EYO) even decades before they show cognitive decline. During the initial funding periods DIAN investigators have mapped out a sequential progression of biomarkers; first, measures of beta-amyloid become abnormal, followed by metabolism, measures of tau pathology, loss of grey matter, and eventually cognitive decline. Work by DIAN investigators and others suggests that the abnormal accumulation of tau pathology may be a key factor in this cascade that impacts the transition from cognitive normality to impairment. However, prior work examining tau has previously been limited only to one biomarker measured in the cerebrospinal fluid (CSF). While informative, this solitary measure may not adequately convey the role tau pathology plays in AD. This project seeks to understand new measures of tau pathology in the DIAN cohort to further elucidate the role this protein plays in ADAD. Aim 1 explores tau pathology measured using three different positron emission tomography (PET) compounds to map the spread of tau pathology in the brain. This will quantify the amount as well as location of pathological burden in the brain. Aim 2 uses post mortem brain tissue to validate these tracers and learn more about the sensitivity and specific of these three compounds. This is critical before these PET tracers can be used broadly for research and clinical purposes. Aim 3 uses mass spectrometry to quantify novel forms of tau which have distinct structural properties (e.g. different phosphorylation or cleavage sites). These novel forms of tau will be measured in the CSF, brain tissue, and human cell models of AD and is a strong compliment to the tau PET imaging. The rationale for this proposal is that better understanding the temporal and spatial evolution of tau pathology is critical to understanding the pathobiology of AD and for formulating successful therapeutic trials. These three Aims are highly collaborative with the other Projects and Cores, and will provide new insights in the role tau pathology plays in AD.

项目2：Tau摘要 阿尔茨海默病（AD）是一种日益严重的全球性健康危机。开发生物标志物来识别 AD高风险个体，更好地了解疾病的生物学基础， 新的治疗剂。常染色体显性AD（ADAD）是一种罕见的疾病（<1%）， 通过三种基因中的一种突变。具有这些突变的个体在相对年轻的时候就会患上痴呆症。 在家庭中可以遗传的年龄。这提供了一个独特的人群，在那里可以 预测个体相对于其估计的症状发作年数（EYO）的疾病阶段， 在他们出现认知能力下降之前的几十年。在最初的供资期间，国家税务和海关局的调查人员 绘制了生物标志物的连续进展;首先，β-淀粉样蛋白的测量变得异常， 随后是代谢、tau病理学的测量、灰质的损失以及最终的认知衰退。 DIAN研究人员和其他人的工作表明，tau蛋白病理学的异常积累可能是一个重要的因素。 这是影响从认知正常到认知障碍转变的级联反应中的关键因素。但是现有 研究tau蛋白的工作以前仅限于在脑脊液中测量的一种生物标志物 （CSF）。虽然信息量大，但这种单独的测量可能无法充分传达tau病理学在细胞凋亡中所起的作用。 AD. 该项目旨在了解DIAN队列中tau病理学的新指标，以进一步阐明 这种蛋白质在ADAD中的作用。目的1探索使用三种不同的正电子探针测量的tau病理学 发射断层扫描（PET）化合物来绘制脑中tau病理学的传播。这将量化 大脑中病理负荷的数量和位置。Aim 2使用死后脑组织 验证这些示踪剂，并了解更多关于这三种化合物的敏感性和特异性。这是 在这些PET示踪剂可以广泛用于研究和临床目的之前，这是至关重要的。目标3使用质量 用于定量具有不同结构特性（例如，不同的 磷酸化或切割位点）。这些新形式的tau蛋白将在CSF、脑组织和脑组织中进行测量。 AD的人类细胞模型，并且是对tau PET成像的有力补充。这项建议的理由是， 更好地理解tau蛋白病理学的时间和空间演变对于理解 AD的病理生物学和制定成功的治疗试验。这三个目标高度 与其他项目和核心合作，并将提供tau病理学所起作用的新见解 在AD中。