皮质免疫网络图谱鉴定出与β-淀粉样蛋白和 Tau 病理相关的不同小胶质细胞转录程序。
A cortical immune network map identifies distinct microglial transcriptional programs associated with β-amyloid and Tau pathologies.
机构信息
School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, Australia.
The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia.
出版信息
Transl Psychiatry. 2021 Jan 14;11(1):50. doi: 10.1038/s41398-020-01175-9.
Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer's disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five modules of co-expressed genes related to microglia and assess their role in the neuropathologic features of AD in 540 subjects from two cohort studies of brain aging. Two of these transcriptional programs-modules 113 and 114-relate to the accumulation of β-amyloid, while module 5 relates to tau pathology. We replicate these associations in brain epigenomic data and in two independent datasets. In terms of tau, we propose that module 5, a marker of activated microglia, may lead to tau accumulation and subsequent cognitive decline. We validate our model further by showing that three representative module 5 genes (ACADVL, TRABD, and VASP) encode proteins that are upregulated in activated microglia in AD.
小胶质细胞功能障碍被认为是导致阿尔茨海默病（AD）发生的众多细胞机制之一。在这里，我们利用人类前额叶皮质的转录组网络图谱，鉴定出与小胶质细胞相关的五个共表达基因模块，并在两个大脑老化队列研究的 540 名受试者中评估其在 AD 神经病理学特征中的作用。这两个转录程序模块——模块 113 和 114——与β-淀粉样蛋白的积累有关，而模块 5 与 tau 病理学有关。我们在脑表观基因组数据和两个独立的数据集上复制了这些关联。就 tau 而言，我们提出模块 5（激活小胶质细胞的标志物）可能导致 tau 积累和随后的认知能力下降。我们通过进一步展示三个代表性模块 5 基因（ACADVL、TRABD 和 VASP）编码的蛋白在 AD 中激活的小胶质细胞中上调，进一步验证了我们的模型。
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