Tau pathology in Down syndrome and Alzheimer's

唐氏综合症（DS）是美国最常见的遗传性智力残疾的原因。 美国，影响大约1 700活产和估计350,000美国人。近距离临床 已经在DS和阿尔茨海默病（AD）之间建立了病理学关联，阿尔茨海默病（AD）已经成为一种 最重要的问题，因为改善的医疗保健增加了那些与DS的预期寿命接近 60岁患有DS的个体表现出AD神经病理学特征，包括淀粉样蛋白斑块， 早在30岁时就出现神经纤维缠结。我们是第一个证明AD生物标志物在 血液中神经元来源的外泌体在患有DS的人的生命早期升高，并且磷酸化Tau（p- 在DS-AD中诊断为痴呆后，Tau）增加，淀粉样蛋白减少。Tau病加重 可见皮质-皮质投射神经元，其形成DS和AD中的记忆连接体的基底 包括由前额叶、楔前叶和后额叶组成的新皮层背侧记忆网络（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， 在AD和DS中功能失调。事实上，没有任何信息可以识别分子和细胞事件 这是由于DMN中HSA 21的三体性过表达导致的，这是DMN内tau聚集差异的基础。 与没有痴呆的受试者相比，患有DS的受试者选择性脆弱的皮质-皮质神经元 痴呆在目前的提案中，我们将重点放在验证外泌体生物标志物转化为痴呆症 以及检查外泌体、CSF和死后脑组织中Tau病理学。 本申请的总体假设是：Tau在DS-AD和外泌体Tau中起早期作用。 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、非认知受损（NCI）和 早发性AD我们将研究与Tau（Aim 1）、p-Tau聚集和播种相关的外泌体性质 目的2）和DMN连接体中的Tau病理学（目的3）。我们的团队是唯一有资格探索 这些重要的翻译问题，由于研究经验和团队的长期合作。 我们已经让已经获得资助的ADRC和DS研究小组参与进来，以便及时利用资源， 也是生物医学研究的关键领域

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.