Dominantly Inherited Alzheimer Network: Project 2

显性遗传阿尔茨海默病网络：项目 2

• 批准号: 10462566
• 负责人: BRIAN Andrew GORDON
• 金额: $ 78.66万
• 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/10462566
• 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; 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 阿尔茨海默病 (AD) 是一场日益严重的全球健康危机。开发生物标志物来识别至关重要 患有 AD 高风险的个体，更好地了解该疾病的生物学基础，并开发 新的治疗剂。常染色体显性 AD (ADAD) 是一种罕见的疾病形式 (<1%)，由 通过三个基因之一的突变。携带这些突变的个体在相对年轻的时候就会患上痴呆症 家族内可遗传的年龄。这提供了一个独特的个人群体，可以在其中 预测个体相对于症状出现的估计年数 (EYO) 的疾病阶段，甚至 几十年前他们就表现出认知能力下降。在最初的资助期间，DIAN 研究人员已经 绘制出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， 接下来是新陈代谢、tau蛋白病理学测量、灰质损失，以及最终认知能力下降。 DIAN 研究人员和其他人的工作表明，tau 病理学的异常积累可能是 这一级联中影响认知正常向损伤转变的关键因素。然而，之前 此前，检测 tau 蛋白的工作仅限于脑脊液中测量的一种生物标志物 （脑脊液）。虽然信息丰富，但这种单独的测量可能无法充分传达 tau 病理学在 广告。 该项目旨在了解 DIAN 队列中 tau 病理学的新测量方法，以进一步阐明 该蛋白在 ADAD 中发挥作用。目标 1 探索使用三种不同正电子测量的 tau 蛋白病理学 发射断层扫描 (PET) 化合物可绘制 tau 蛋白病理学在大脑中的传播情况。这将量化 大脑中病理负担的数量和位置。目标 2 使用死后脑组织 验证这些示踪剂并了解有关这三种化合物的敏感性和特异性的更多信息。这是 在这些 PET 示踪剂广泛用于研究和临床目的之前，这一点至关重要。目标 3 使用质量 光谱测定法来量化具有独特结构特性（例如不同结构）的新型 tau 蛋白 磷酸化或切割位点）。这些新型 tau 蛋白将在脑脊液、脑组织和 AD 的人类细胞模型，是对 tau PET 成像的有力补充。此提案的理由 更好地理解 tau 病理学的时间和空间演变对于理解 AD 的病理学并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，将为 tau 病理学的作用提供新的见解 在公元。