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)是美国遗传决定的智力残疾的最常见原因 在美国各州，大约每700名活产儿中就有1名受到影响，估计有350,000名美国人受到影响。一个亲密的诊所 DS和阿尔茨海默病(AD)之间的病理联系已经建立，阿尔茨海默病已经成为一种 最令人担忧的是，由于改善了医疗保健，DS患者的预期寿命增加到接近 60岁。DS患者表现出AD神经病理特征，包括淀粉样斑块和 神经纤维缠绕早在30岁时就会出现。我们是第一个证明AD生物标志物在 DS患者早期血液中神经元来源的外切体升高，使Tau磷酸化(p-1)。 在DS-AD中被诊断为痴呆症后，Tau)增加，淀粉样蛋白减少。增加的紧张症 可见皮质-皮质投射神经元，它构成了DS和AD记忆连接的底物 包括由前额叶、楔前核和后叶组成的新皮质背侧记忆网络(DMN 扣带回皮质。这些结构形成了工作/陈述性记忆的关键皮层网络，这是 阿尔茨海默病和阿尔茨海默病功能障碍。事实上，没有任何信息可以识别分子和细胞事件 由于HSA21在DMN中的三体过度表达，这是导致tau聚集在 痴呆症患者与非痴呆者的选择性易损皮质神经元比较 痴呆症。在目前的提案中，我们将重点验证转化为痴呆症的外体生物标志物 在DS-AD和特发性AD中，以及检查外显体、脑脊液和尸检脑组织中的Tau病理。 关于这一应用的总体假设是：tau在DS-AD和外体Tau中起早期作用 这些特性可以预测痴呆症的发病。为了解决这一假设，我们使用了血液样本和 来自认知特征良好的DS、DS-AD、非认知损害(NCI)和 早发性AD。我们将研究与Tau(目标1)、p-Tau聚集和种子相关的外体属性 属性(目标2)和DMN连接体中的Tau病理(目标3)。我们的团队是唯一有资格探索的人 这些重要的翻译问题源于团队的研究经验和长期合作。 我们让ADRC和DS研究小组参与进来，他们已经获得了资金，以便及时利用资源 也是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