Data Sheet 6_Spatial transcriptomics reveals an unexpected impact of tau and tau pathology on the expression of transthyretin.pdf

IntroductionRNA expression is modulated by tau. We used two mouse models, THY-Tau22 mice, which express pro-aggregation tau, and TauKO mice, which are null for tau, to improve our understanding of tau-altered mRNA expression in brain.
MethodsSpatial transcriptomics on Tau22 and TauKO mice were used to interrogate regional mRNA expression changes. We focused on mRNA expression changes in the hippocampus and ventricles; two regions altered early in Alzheimer’s disease.
ResultsWe identified the transthyretin mRNA, Ttr, as being dysregulated in a tau-dependent manner. Immunofluorescence (IF) revealed increased TTR protein expression in THY-Tau22 mice and lowered expression in TauKO mice in the choroid plexus epithelial cells.
ConclusionAs TTR is involved in the clearance of Aβ and the prevention of Aβ aggregation, we evaluated endogenous mouse Aβ in TauKO mice and observed increased Aβ deposits. Our study reveals a hitherto unknown regulatory role of tau on Ttr mRNA and protein expression, which may participate in a feedback loop contributing to Aβ disease progression.

引言：RNA表达受tau蛋白调控。本研究使用两种小鼠模型：表达促聚集型tau蛋白的THY-Tau22小鼠（THY-Tau22 mice）以及tau基因敲除的TauKO小鼠（TauKO mice），以期加深对大脑中tau蛋白介导的mRNA表达改变的认知。
方法：本研究采用空间转录组学（spatial transcriptomics）技术，对Tau22及TauKO小鼠进行分析，以探究不同脑区的mRNA表达变化。研究重点聚焦于阿尔茨海默病（Alzheimer’s disease）早期即出现病理改变的两个脑区——海马体与脑室的mRNA表达差异。
结果：本研究鉴定出运甲状腺素蛋白mRNA（transthyretin mRNA，Ttr）的表达以tau蛋白依赖性方式出现失调。免疫荧光（immunofluorescence，IF）实验显示，在脉络丛上皮细胞（choroid plexus epithelial cells）中，THY-Tau22小鼠的TTR蛋白表达水平升高，而TauKO小鼠的TTR蛋白表达水平显著降低。
结论：鉴于TTR参与β淀粉样蛋白（Aβ）的清除过程以及Aβ聚集的抑制作用，我们对TauKO小鼠的小鼠内源性Aβ进行了检测，观察到其Aβ沉积量有所增加。本研究揭示了tau蛋白此前未被报道的对Ttr mRNA及蛋白表达的调控功能，该调控机制可能参与构建促进Aβ相关疾病进展的反馈环路。