Characterization of the 18 kDa translocator protein (TSPO) expression in post-mortem normal and Alzheimer's disease brains
Characterization of the 18 kDa translocator protein (TSPO) expression in post-mortem normal and Alzheimer's disease brains
复制标题
DOI：
10.1111/bpa.12763
复制
发表时间：
2019-07-25
期刊：
影响因子：
6.4
通讯作者：
Serrano-Pozo, Alberto
中科院分区：
文献类型：
--
作者：
Gui, Yaxing;Marks, Jordan D.;Serrano-Pozo, Alberto
18 kDa转位蛋白(TSPO)是一种广泛用于小胶质细胞PET成像的放射性配基，但其在死后正常和疾病人脑中的表达尚未得到很好的描述。我们的目的是表征TSPO在人类对照组(CTRL)和阿尔茨海默病(AD)脑中的表达。具体地说，我们试图：(1)确定表达TSPO的细胞类型(S)；(2)比较AD和CTRL脑中TSPO mRNA和TSPO的水平；(3)TSPO水平与反应性胶质细胞和AD神经病理变化的定量神经病理学指标之间的相关性；以及(4)TSPO rs6971 SNP对TSPO mRNA和TSPO水平、胶质反应和AD神经病理变化的影响。我们对CTRL和AD受试者的死后脑样本进行了定量免疫组织化学和Western印迹，并对公开可用的小鼠和人脑RNA-Seq数据集进行了分析。我们发现：(1)TSPO不仅在小胶质细胞中表达，而且在星形胶质细胞、内皮细胞和血管平滑肌细胞中也有表达；(2)在AD和CTRL患者中，TSPO mRNA和TSPO水平存在显著重叠，在两组中，TSPO在颞叶新皮质和白质中的水平存在显著重叠；(3)TSPO皮质负荷与激活的小胶质细胞或反应性星形胶质细胞的负荷、Aβ斑块、神经纤维缠结或皮质厚度无关；(4)TSPO rs6971 SNP对TSPO mRNA或TSPO水平、胶质反应的大小、皮质厚度或AD神经病理变化的负荷没有显著影响。这些结果可能会为正在进行的开发反应性胶质细胞特异性PET放射性配体的努力提供信息。
The 18 kDa translocator protein (TSPO) is a widely used target for microglial PET imaging radioligands, but its expression in post-mortem normal and diseased human brain is not well described. We aimed at characterizing the TSPO expression in human control (CTRL) and Alzheimer's disease (AD) brains. Specifically, we sought to: (1) define the cell type(s) expressing TSPO; (2) compare tspo mRNA and TSPO levels between AD and CTRL brains; (3) correlate TSPO levels with quantitative neuropathological measures of reactive glia and AD neuropathological changes; and (4) investigate the effects of the TSPO rs6971 SNP on tspo mRNA and TSPO levels, glial responses and AD neuropathological changes. We performed quantitative immunohistochemistry and Western blot in post-mortem brain samples from CTRL and AD subjects, as well as analysis of publicly available mouse and human brain RNA-Seq datasets. We found that: (1) TSPO is expressed not just in microglia, but also in astrocytes, endothelial cells and vascular smooth muscle cells; (2) there is substantial overlap of tspo mRNA and TSPO levels between AD and CTRL subjects and in TSPO levels between temporal neocortex and white matter in both groups; (3) TSPO cortical burden does not correlate with the burden of activated microglia or reactive astrocytes, A beta plaques or neurofibrillary tangles, or the cortical thickness; (4) the TSPO rs6971 SNP does not significantly impact tspo mRNA or TSPO levels, the magnitude of glial responses, the cortical thickness, or the burden of AD neuropathological changes. These results could inform ongoing efforts toward the development of reactive glia-specific PET radioligands.