Dominantly Inherited Alzheimer Network: Project 2

项目2：Tau总结 阿尔茨海默病(AD)是一个日益严重的世界性健康危机。开发生物标记物来识别 AD的高危人群，更好地了解疾病的生物学基础，并发展 新的治疗剂。常染色体显性遗传性阿尔茨海默病(ADAD)是一种罕见的疾病(&lt；1%) 通过三种基因中的一种发生突变。携带这些突变的人在相对年轻的时候就会患上痴呆症。 在家庭内可遗传的年龄。这提供了一个独特的个人队列，在那里有可能 预测个人的疾病阶段与其症状出现(EYO)的估计年限相关 几十年后他们才会表现出认知能力下降。在最初的资金阶段，DIAN的调查人员 绘制了一系列生物标志物的序列；首先，β-淀粉样蛋白的测量变得异常， 紧随其后的是新陈代谢、tau病理指标、灰质丢失，最终是认知能力下降。 DIAN调查人员和其他人的工作表明，tau病理的异常积累可能是 这一级联反应中的关键因素影响了从认知正常到损害的转变。然而，之前 以前检查tau的工作仅限于在脑脊液中测量到的一个生物标志物。 (CSF)。虽然提供了信息，但这种单独的措施可能不能充分传达tau病理在 广告。 本项目旨在了解DIAN队列中tau病理的新指标，以进一步阐明 该蛋白在ADAD中起作用。目标1探索用三种不同正电子测量的tau病理 发射断层扫描(PET)化合物，以绘制tau病理在大脑中的传播情况。这将量化 病理性负担在大脑中的数量和位置。Aim 2使用尸检脑组织 验证这些示踪剂，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示踪剂能够广泛用于研究和临床目的之前是至关重要的。目标3使用质量 光谱以量化具有不同结构特性(例如，不同的)的新型tau 磷酸化或裂解位点)。这些新形式的tau将在脑脊液、脑组织和 AD的人体细胞模型，是对tau PET成像的有力补充。这项提议的理由是 更好地理解tau病理的时间和空间演变对于理解 阿尔茨海默病的病理生物学和制定成功的治疗试验。这三个目标是高度一致的 与其他项目和核心合作，并将为tau病理学所扮演的角色提供新的见解 在公元后。

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.