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唐氏综合征患者伴或不伴痴呆的额皮质和纹状体的细胞和分子病理生物学。

Frontal cortex and striatal cellular and molecular pathobiology in individuals with Down syndrome with and without dementia.

机构信息

Department of Neurobiology and Neurology, Barrow Neurological Institute, 350 W. Thomas St, Phoenix, AZ, 85013, USA.

School of Life Sciences, College of Liberal Arts and Sciences, Arizona State University, Tempe, AZ, 85287, USA.

出版信息

Acta Neuropathol. 2019 Mar;137(3):413-436. doi: 10.1007/s00401-019-01965-6. Epub 2019 Feb 7.

DOI:10.1007/s00401-019-01965-6
PMID:30734106
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6541490/
Abstract

Although, by age 40, individuals with Down syndrome (DS) develop amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles (NFTs) linked to cognitive impairment in Alzheimer's disease (AD), not all people with DS develop dementia. Whether Aβ plaques and NFTs are associated with individuals with DS with (DSD +) and without dementia (DSD -) is under-investigated. Here, we applied quantitative immunocytochemistry and fluorescent procedures to characterize NFT pathology using antibodies specific for tau phosphorylation (pS422, AT8), truncation (TauC3, MN423), and conformational (Alz50, MC1) epitopes, as well as Aβ and its precursor protein (APP) to frontal cortex (FC) and striatal tissue from DSD + to DSD - cases. Expression profiling of single pS422 labeled FC layer V and VI neurons was also determined using laser capture microdissection and custom-designed microarray analysis. Analysis revealed that cortical and striatal Aβ plaque burdens were similar in DSD + and DSD - cases. In both groups, most FC plaques were neuritic, while striatal plaques were diffuse. By contrast, FC AT8-positive NFTs and neuropil thread densities were significantly greater in DSD + compared to DSD -, while striatal NFT densities were similar between groups. FC pS422-positive and TauC3 NFT densities were significantly greater than Alz50-labeled NFTs in DSD + , but not DSD - cases. Putaminal, but not caudate pS422-positive NFT density, was significantly greater than TauC3-positive NFTs. In the FC, AT8 + pS422 + Alz50, TauC3 + pS422 + Alz50, pS422 + Alz50, and TauC3 + pS422 positive NFTs were more frequent in DSD + compared to DSD- cases. Single gene-array profiling of FC pS422 positive neurons revealed downregulation of 63 of a total of 864 transcripts related to Aβ/tau biology, glutamatergic, cholinergic, and monoaminergic metabolism, intracellular signaling, cell homeostasis, and cell death in DSD + compared DSD - cases. These observations suggest that abnormal tau aggregation plays a critical role in the development of dementia in DS.

摘要

虽然唐氏综合征（DS）患者到 40 岁时会出现与阿尔茨海默病（AD）认知障碍相关的淀粉样β（Aβ）斑块和含有 tau 的神经原纤维缠结（NFT），但并非所有 DS 患者都会发展为痴呆。目前，对于 DS 患者中是否存在 Aβ斑块和 NFT 与有痴呆（DSD+）和无痴呆（DSD-）的个体有关，还需要进一步研究。在这里，我们使用针对 tau 磷酸化（pS422、AT8）、截断（TauC3、MN423）和构象（Alz50、MC1）表位以及 Aβ及其前体蛋白（APP）的特异性抗体，通过定量免疫细胞化学和荧光程序，对来自 DSD+至 DSD-病例的额皮质（FC）和纹状体组织中的 NFT 病理进行了特征描述。还使用激光捕获显微解剖和定制的微阵列分析方法，对单个 pS422 标记的 FC 层 V 和 VI 神经元的表达谱进行了确定。分析显示，DSD+和 DSD-病例的皮质和纹状体 Aβ斑块负担相似。在两组中，大多数 FC 斑块都是神经纤维的，而纹状体斑块是弥漫性的。相比之下，FC AT8 阳性 NFT 和神经原纤维缠结密度在 DSD+中明显高于 DSD-，而纹状体 NFT 密度在两组之间相似。在 DSD+中，FC pS422 阳性和 TauC3 NFT 密度明显高于 Alz50 标记的 NFT，但 DSD-病例中并非如此。在壳核，pS422 阳性 NFT 密度明显高于 TauC3 阳性 NFT，但尾状核无此现象。在 FC 中，AT8+ pS422+ Alz50、TauC3+ pS422+ Alz50、pS422+ Alz50 和 TauC3+ pS422 阳性 NFT 在 DSD+中比 DSD-病例更常见。FC pS422 阳性神经元的单个基因芯片分析显示，在 DSD+中与 Aβ/tau 生物学、谷氨酸能、胆碱能和单胺能代谢、细胞内信号转导、细胞内稳态和细胞死亡相关的总共 864 个转录本中的 63 个下调。这些观察结果表明，异常 tau 聚集在 DS 痴呆的发展中起着关键作用。

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