Clinical and Translational Science Award

由于21号染色体上淀粉样前体蛋白基因和其他基因的三倍和过表达，唐氏综合征(DS)患者表现出比正常人群更早的AD神经病理，大约一半的DS成人患者发展为AD。然而，在患有DS的成年人中有广泛的表型差异，许多人没有发展为AD。这项研究建议使用以前的生物库样本来确定有助于成人DS患者对AD的复原力的因素。该项目将把患有和不伴有AD的老年DS患者的已建立的成纤维细胞系重新编程为诱导多能干细胞(IPSCs)，然后将这些IPSCs分化为神经元，然后再分化为皮质类器官(混合皮质神经元和星形胶质细胞3D培养)。这些有机化合物将被用来进行转录分析，并检查神经元发育和功能的差异。 具体地说，这个项目将使用生物库样本的子集，对500多名患有DS的成年人进行纵向检查，以调查DS-AD。我们将：(1)将已建立的来自患有或不患有DS-AD的老年DS患者的成纤维细胞系重新编程为IPSCs，然后使用这些IPSCs来研究：(1)神经元发育对DS-AD的影响；(2)差异基因表达和eQTL；(3)新基因WWOX在DS-AD中的作用。这项研究将产生资源，使研究人员能够在鉴定DS-AD的保护性和推定基因后进行功能基因组研究。

Due to triplication and overexpression of the gene for amyloid precursor protein and other genes on chromosome 21, individuals with Down Syndrome (DS) show neuropathologies of AD at an earlier age than the typical population, and about half of adults with DS develop AD. Yet there is wide phenotypic variation in adults with DS and many do not develop AD. This study proposes to use previously biobanked samples towards identifying factors that contribute to resilience to AD in adults with DS. The project will reprogram established fibroblast lines from older DS subjects with and without concomitant AD into induced pluripotent stem cells (iPSCs) and then differentiate these iPSCs into neurons and then into cortical organoids (mixed cortical neuron and astrocyte 3D culture). These organoids will be used to perform transcriptomic analysis and to examine differences in neuronal development and function. Specifically, this project will use a subset of the biobanked samples that examined over 500 adults with DS longitudinally to investigate DS-AD. We will: (1) reprogram established fibroblasts lines from older DS subjects with or without DS-AD into iPSCs, and then use these iPSCs to investigate: (1) the effects of neuronal development on DS-AD; (2) differential gene expressions and eQTL; and (3) the role of a novel gene, WWOX, in DS-AD. This study will generate resources that will enable researchers to perform functional genomic studies following identification of protective and putative genes in DS-AD.