Tau pathology in Down syndrome and Alzheimer's

唐氏综合症和阿尔茨海默病中的 Tau 蛋白病理学

• 批准号: 10596917
• 负责人: Ann-Charlotte Esther Granholm-Bentley
• 金额: $ 163.71万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10596917
• 关键词: Tau; pathology; Down; syndrome; Alzheimer

Down syndrome (DS) is the most common cause of genetically determined intellectual disability in the United States, affecting approximately 1 in 700 live births and an estimated 350,000 Americans. A close clinical pathologic association has been established between DS and Alzheimer’s disease (AD), which has become a paramount concern since improved medical care has increased the life expectancy of those with DS to close to 60 years of age. Individuals with DS exhibit AD neuropathological hallmarks including amyloid plaques and neurofibrillary tangles as early as 30 years of age. We were the first to demonstrate that AD biomarkers in neuron-derived exosomes in blood were elevated early in life of those with DS, and that phosphorylated Tau (p- Tau) was increased, and amyloid decreased following a diagnosis of dementia in DS-AD. Increased Tauopathy is seen cortico-cortical projection neurons, which form a substrate for memory connectomes in both DS and AD including the neocortical dorsal memory network (DMN) consisting of prefrontal, precuneus and posterior cingulate cortex. These structures form a key cortical network for working/declarative memory, which is dysfunctional in AD and DS. There is virtually no information identifying the molecular and cellular events resulting from trisomy overexpression of HSA21 in the DMN that underlie differences in tau aggregation within selectively vulnerable cortico-cortical neurons in subjects with DS with dementia compared to those without dementia. In the current proposal we will focus on validation of exosomal biomarkers for conversion to dementia in DS-AD and idiopathic AD, as well as examine Tau pathology in exosomes, CSF, and post mortem brain tissue. The Overall Hypothesis for this application is: Tau plays an early role in DS-AD and exosomal Tau properties can predict onset of dementia. To address this hypothesis, we are utilizing blood samples and brain tissue from cognitively well characterized individuals with DS, DS-AD, non-cognitively impaired (NCI) and early onset AD. We will examine exosomal properties related to Tau (Aim 1), p-Tau aggregation and seeding properties (Aim 2), and Tau pathology in the DMN connectome (Aim 3). Our group is uniquely qualified to explore these important translational questions due to the research experience and long-term collaboration of the team. We have involved ADRCs and DS research groups who are already funded to leverage resources in this timely and crucial area of biomedical research.

唐氏综合症（DS）是统一遗传确定智障的最常见原因 各州影响了700名活产中大约1个，估计有350,000名美国人。密切的临床 DS和阿尔茨海默氏病（AD）之间已经建立了病理协会，这已成为 最重要的是，因为改善的医疗服务已提高了DS的人的预期寿命 60岁。具有DS暴露AD神经病理学标志的人，包括淀粉样蛋白斑和 神经原纤维缠结最早30岁。我们是第一个证明广告生物标志物的人 DS患者的早期，血液中的神经来源外泌体升高，并且磷酸化的tau（p- tau）增加了，在DS-AD中诊断为痴呆症后，淀粉样蛋白减少。提高tauopathy 被认为是皮质皮质投射神经元，它形成了DS和AD中的内存连接组的底物 包括由前额叶，前后和后部组成的新皮层背部记忆网络（DMN） 扣带皮质。这些结构构成了用于工作/声明性内存的关键皮层网络，这是 AD和DS功能失调。几乎没有识别分子和细胞事件的信息 DMN中HSA21的三体性过表达导致，这是tau聚集差异的基础 与没有痴呆症的受试者中有选择性易受伤害的皮质皮质神经元相比 失智。在当前的建议中，我们将重点介绍外泌体生物标志物转换为痴呆症的验证 在DS-AD和特发性AD中，以及外泌体，CSF和Mortem脑组织中的TAU病理学。 此应用的总体假设是：TAU在DS-AD和外泌体TAU中起早期作用 特性可以预测痴呆症的发作。为了解决这一假设，我们正在使用血液样本，并且 来自认知表征良好的个体DS，DS-AD，非认知受损（NCI）的脑组织（NCI）和 早发广告。我们将检查与Tau（AIM 1），P-TAU聚集和播种相关的外泌体特性 DMN Connectome中的属性（AIM 2）和Tau病理学（AIM 3）。我们的小组具有独特的资格探索 由于研究经验和团队的长期合作，这些重要的翻译问题。 我们参与了ADRC和DS研究小组，他们已经被资助以及时利用资源 和生物医学研究的关键领域。

项目成果

Small Neuron-Derived Extracellular Vesicles from Individuals with Down Syndrome Propagate Tau Pathology in the Wildtype Mouse Brain.

• DOI: 10.3390/jcm10173931
• 发表时间: 2021-08-31
• 期刊: Journal of clinical medicine
• 影响因子: 3.9
• 作者: Ledreux A;Thomas S;Hamlett ED;Trautman C;Gilmore A;Rickman Hager E;Paredes DA;Margittai M;Fortea J;Granholm AC
• 通讯作者: Granholm AC

A thiol-based intramolecular redox switch in four-repeat tau controls fibril assembly and disassembly.

• DOI: 10.1016/j.jbc.2021.101021
• 发表时间: 2021-09
• 期刊: The Journal of biological chemistry
• 作者: Weismiller HA;Holub TJ;Krzesinski BJ;Margittai M
• 通讯作者: Margittai M