Default mode network dysfunction in Down Syndrome

唐氏综合症（DS），智力残疾的最常见的遗传原因，形成最大的人口 在中年时有遗传倾向患上阿尔茨海默病（AD）。几乎所有患有DS的人 到2010年第40年，与AD相似的含有tau和β-淀粉样蛋白（Aβ）斑块的神经元缠结（NFT） 生命，随着年龄的增长而增长。超过70%的DS患者最终会发展为痴呆症，这使得 人群是研究痴呆症发病机制的极好的自然发生的人类模型， 翻译成AD虽然NFT病理学与AD和DS的痴呆程度密切相关， 与Aβ斑块相比，DS认知功能下降的细胞机制在很大程度上尚未探索。 该项目的目标是阐明选择性脆弱性的分子和细胞事件， 额叶皮质（FC）和楔前叶（PreC）锥体神经元。这两个默认模式的互联中心 DMN参与情景记忆和自我意识，在AD和DS中功能障碍。我们 最近报道，患有DS痴呆的人在FC锥体神经元中显示出更多的NFT 与那些没有痴呆症的人相比，含有晚期tau蛋白病理学的人。有趣的是，我们还发现FC 与非痴呆患者相比，DS痴呆患者的NFT阳性神经元显示出不同的转录组学特征。 痴呆DS，尽管有类似的FC斑块负荷之间的DS组。这些发现表明， tau蛋白病理生物学在DS痴呆发病中的作用。有趣的是，神经元变性表现为 细胞内事件的汇合导致tau mRNA剪接的改变，在临床发作之前， 症状最近的证据表明，U1小核核糖核蛋白的错误剪接 （snRNP）与散发性和家族性AD和DS中的NFT相关，但与其他tau蛋白病无关。我们现在 报告了剪接蛋白中更大的缺陷，特别是与tau的选择性剪接相关的那些， 与没有痴呆的DS患者相比，在FC中NFT发展的更晚期阶段， 痴呆在这个项目中，我们将研究选择性脆弱的DMN神经元的分子病理学 使用概念和技术创新的方法： 在tau蛋白进化的翻译后进程中的抗体，单群体微阵列和RNA 转录组学，结合功能基因通路分析。这一提议有望奠定基础 用于设计新型药物和生物标志物的广泛的潜在干预措施， DS痴呆转化为AD。

Down syndrome (DS), the most common genetic cause of intellectual disability, form the largest population with a genetic predisposition in midlife to develop Alzheimer’s disease (AD). Virtually everyone with DS exhibit neurofibrillary tangles (NFTs) containing-tau and β-amyloid (Aβ) plaques similar to AD by the fourth decade of life, which increase with age. Greater than 70% of people with DS ultimately develop dementia, making this population an excellent naturally-occurring human model for the study of the pathogenesis of dementia with translation to AD. Although NFT pathology is tightly linked to the degree of dementia in both AD and DS compared to Aβ plaques, the cellular mechanisms underlying cognitive decline in DS remain largely unexplored. The goal of this project is to elucidate the molecular and cellular events underlying the selective vulnerability of frontal cortex (FC) and precuneus (PreC) pyramidal neurons. These two interconnected hubs of the default mode network (DMN) are involved in episodic memory and self-awareness and are dysfunctional in AD and DS. We recently reported that people with DS with dementia display a greater number of NFTs in FC pyramidal neurons containing advanced tau pathology compared to those without dementia. Interestingly, we also found that FC NFT-positive neurons in DS with dementia display a different transcriptomic signature compared to non- demented DS, despite having similar FC plaque loads between the DS groups. These findings suggest a key role for tau pathobiology in the onset of dementia in DS. Interestingly, neuronal degeneration is manifested by a confluence of intracellular events leading to alterations in tau mRNA splicing before the onset of clinical symptoms. Recent evidence demonstrated that mislocalized splicing of U1 small nuclear ribonucleoproteins (snRNPs) are associated with NFTs in sporadic and familial AD and DS, but not other tauopathies. We now report greater defects in splicing proteins, particularly those associated with alternative splicing of tau, that occur in the more advanced stages of NFT development in the FC in DS with dementia compared to those without dementia. In this project, we will investigate the molecular pathobiology of selectively vulnerable DMN neurons in people with DS with and without dementia using conceptually and technically innovative approaches: splicing antibodies during the post-translational progression of tau evolution, single population microarray and RNA transcriptomics, combined with functional gene pathway analysis. This proposal expects to lay the foundation for a wide range of potential interventions for the design of novel drugs and biomarkers for the prevention of dementia in DS with translation to AD.