Dominantly Inherited Alzheimer Network: Project 2

显性遗传阿尔茨海默病网络：项目 2

• 批准号: 10225489
• 负责人: BRIAN Andrew GORDON
• 金额: $ 99.37万
• 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/10225489
• 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; Induced pluripotent stem cell derived neurons; 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; 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; autosomal dominant Alzheimer' s disease; base; brain tissue; cohort; density; gray matter; high risk; in vivo; 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 阿尔茨海默氏病（AD）是一场日益增长的全球健康危机。开发生物标志物以识别 AD高风险的个体，更好地了解该疾病的生物学基础，并发展 新的治疗剂。常染色体显性AD（ADAD）是疾病的一种罕见形式（<1％） 通过三个基因之一的突变。这些突变的个体在相对年轻的 这是家庭中可遗传的年龄。这提供了一个独特的人群 预测个体相对于症状发作的估计年份（EYO）的疾病阶段 几十年来，它们表现出认知能力下降。在最初的资助期间 绘制出生物标志物的顺序进展；首先，β-淀粉样蛋白的度量异常， 其次是代谢，tau病理学的衡量，灰质的丧失以及最终的认知下降。 Dian研究人员和其他研究人员的工作表明，TAU病理的异常积累可能是 这一级联的关键因素会影响从认知正常到损害的过渡。但是，先验 检查tau的工作以前仅限于在脑脊液中测得的一种生物标志物 （CSF）。虽然信息丰富，但这种孤独措施可能无法充分传达tau病理的作用 广告。 该项目旨在了解Dian队列中TAU病理学的新措施，以进一步阐明 该蛋白在ADAD中的作用。 AIM 1探索使用三个不同正面测量的Tau病理学 发射断层扫描（PET）化合物以绘制tau病理在大脑中的扩散。这将量化 病理负担在大脑中的数量和位置。 AIM 2使用验尸脑组织 验证这些示踪剂，并更多地了解这三种化合物的敏感性和特定性。这是 在这些宠物示踪剂可以广泛用于研究和临床目的之前，至关重要。 AIM 3使用质量 量化具有不同结构特性的新型Tau的光谱法（例如 磷酸化或切割位点）。这些新型的tau将在CSF，脑组织和 AD的人体细胞模型，是对Tau PET成像的强烈称赞。该提议的理由 是更好地理解Tau病理学的时间和空间演变对于理解至关重要 AD的病理生物学和制定成功的治疗试验。这三个目标是高度的 与其他项目和核心合作，并将为Tau病理扮演的角色提供新的见解 在广告中。