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) 是美国遗传性智力障碍的最常见原因 各州，影响了大约七百分之一的活产儿，估计有 35 万美国人。密切的临床 DS 与阿尔茨海默病 (AD) 之间已建立病理联系，AD 已成为一种 由于医疗保健的改善使 DS 患者的预期寿命延长到接近 60岁。 DS 患者表现出 AD 神经病理学特征，包括淀粉样斑块和 神经原纤维缠结早在30岁时就出现了。我们是第一个证明 AD 生物标志物 DS 患者生命早期血液中神经元衍生的外泌体升高，并且 Tau 磷酸化（p- DS-AD 诊断为痴呆后，Tau 蛋白增加，淀粉样蛋白减少。 tau蛋白病增加 可以看到皮质-皮质投射神经元，它形成 DS 和 AD 中记忆连接体的基质 包括由前额叶、楔前叶和后叶组成的新皮质背侧记忆网络（DMN） 扣带皮层。这些结构形成了工作/陈述性记忆的关键皮层网络， AD 和 DS 功能失调。实际上没有识别分子和细胞事件的信息 由 DMN 中 HSA21 三体性过度表达导致，这是 tau 聚集差异的基础 与没有痴呆的 DS 受试者相比，患有 DS 的痴呆受试者的皮质皮质神经元选择性脆弱 失智。在当前的提案中，我们将重点关注外泌体生物标志物转化为痴呆的验证 DS-AD 和特发性 AD 的研究，以及检查外泌体、脑脊液和死后脑组织中的 Tau 病理学。 该应用的总体假设是：Tau 在 DS-AD 和外泌体 Tau 中发挥早期作用 属性可以预测痴呆症的发作。为了解决这个假设，我们正在利用血液样本 来自认知特征良好的 DS、DS-AD、非认知障碍 (NCI) 和 早发型AD。我们将检查与 Tau（目标 1）、p-Tau 聚集和接种相关的外泌体特性 特性（目标 2）和 DMN 连接组中的 Tau 病理学（目标 3）。我们的团队拥有独特的探索资格 这些重要的转化问题得益于团队的研究经验和长期合作。 我们已经让 ADRC 和 DS 研究小组参与进来，他们已经获得资助，可以及时利用资源 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