Data Sheet 5_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：tau蛋白（tau）可调控RNA表达。本研究采用两种小鼠模型——表达促聚集型tau的THY-Tau22小鼠，以及tau基因敲除（TauKO）小鼠——以深化对脑内tau蛋白介导的mRNA表达改变的认知。
方法：我们通过空间转录组学技术检测Tau22与TauKO小鼠的区域mRNA表达变化，重点关注阿尔茨海默病早期受累的两个脑区——海马体与脑室的mRNA表达改变。
结果：我们发现转甲状腺素蛋白（transthyretin, Ttr）mRNA的表达呈tau依赖性失调。免疫荧光（IF）实验显示，THY-Tau22小鼠脉络丛上皮细胞内的TTR蛋白表达上调，而TauKO小鼠中该蛋白的表达则显著下调。
结论：鉴于TTR可参与β淀粉样蛋白（Aβ）的清除并抑制其聚集，我们对TauKO小鼠的内源性Aβ进行了检测，观察到小鼠脑内Aβ沉积量增加。本研究揭示了tau蛋白此前未被报道的调控Ttr mRNA及蛋白表达的功能，该调控机制或参与形成促进Aβ相关疾病进展的反馈环路。