单细胞空间转录组学揭示了阿尔茨海默病风险基因突变在非神经元细胞和神经元细胞中诱导的不同失调模式。
Single cell spatial transcriptomics reveals distinct patterns of dysregulation in non-neuronal and neuronal cells induced by the Alzheimer's risk gene mutation.
作者信息
Johnston Kevin, Berackey Bereket B, Tran Kristine Minh, Gelber Alon, Yu Zhaoxia, MacGregor Grant, Mukamel Eran A, Tan Zhiqun, Green Kim, Xu Xiangmin
机构信息
University of California Irvine.
University of California San Diego.
出版信息
Res Sq. 2023 Dec 7:rs.3.rs-3656139. doi: 10.21203/rs.3.rs-3656139/v1.
INTRODUCTION
The R47H missense mutation of the TREM2 gene is a strong risk factor for development of Alzheimer's Disease. We investigate cell-type-specific spatial transcriptomic changes induced by the mutation to determine the impacts of this mutation on transcriptional dysregulation.
METHODS
We profiled 15 mouse brain sections consisting of wild-type, , 5xFAD and ; 5xFAD genotypes using MERFISH spatial transcriptomics. Single-cell spatial transcriptomics and neuropathology data were analyzed using our custom pipeline to identify plaque and induced transcriptomic dysregulation.
RESULTS
The mutation induced consistent upregulation of Bdnf and Ntrk2 across many cortical excitatory neuron types, independent of amyloid pathology. Spatial investigation of genotype enriched subclusters identified spatially localized neuronal subpopulations reduced in 5xFAD and ; 5xFAD mice.
CONCLUSION
Spatial transcriptomics analysis identifies glial and neuronal transcriptomic alterations induced independently by 5xFAD and mutations, impacting inflammatory responses in microglia and astrocytes, and activity and BDNF signaling in neurons.
引言
TREM2基因的R47H错义突变是阿尔茨海默病发生的一个重要风险因素。我们研究了该突变诱导的细胞类型特异性空间转录组变化，以确定此突变对转录失调的影响。
方法
我们使用MERFISH空间转录组学对15个小鼠脑切片进行了分析，这些切片包括野生型、5xFAD和5xFAD基因型。使用我们的定制管道分析单细胞空间转录组学和神经病理学数据，以识别斑块和诱导的转录组失调。
结果
该突变在许多皮质兴奋性神经元类型中一致上调Bdnf和Ntrk2，与淀粉样病理无关。对基因型富集亚群的空间研究确定了在5xFAD和5xFAD小鼠中减少的空间定位神经元亚群。
结论
空间转录组学分析确定了由5xFAD和突变独立诱导的神经胶质和神经元转录组改变，影响小胶质细胞和星形胶质细胞的炎症反应，以及神经元的活性和BDNF信号传导。
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