Spatial Transcriptomics dataset of Alzheimer's disease mouse models (Tau22 and TauKO). Spatial transcriptomics reveals an unexpected impact of tau and tau pathology on the expression of transthyretin

Gene 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 gene expression in brain. Spatial transcriptomics were used to interrogate regional expression changes. Focusing on the hippocampus and ventricles, two regions altered early in Alzheimer’s disease, we identified the transthyretin gene, 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. As 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 gene and protein expression, which may participate to a feedback loop contributing to Aβ disease progression.

tau蛋白（tau）对基因表达具有调控作用。本研究采用两种小鼠模型——表达促聚集型tau蛋白的THY-Tau22小鼠（THY-Tau22 mice）以及tau基因敲除型TauKO小鼠（TauKO mice），以加深对tau蛋白介导的脑内基因表达改变的认知。我们借助空间转录组学（spatial transcriptomics）解析脑区的基因表达变化。选取阿尔茨海默病早期受累的两个脑区——海马体与脑室，我们发现转甲状腺素蛋白基因（transthyretin gene, Ttr）的表达呈现tau依赖性失调。免疫荧光（immunofluorescence, IF）实验证实，脉络丛上皮细胞中，THY-Tau22小鼠的TTR蛋白表达水平上调，而TauKO小鼠的TTR蛋白表达水平则下调。鉴于TTR参与β淀粉样蛋白（Aβ）的清除与Aβ聚集的抑制，我们对TauKO小鼠的内源性小鼠Aβ进行检测，结果观察到其Aβ沉积量增加。本研究揭示了tau蛋白此前未被报道的对Ttr基因及蛋白表达的调控功能，该调控作用可能参与形成反馈环路，进而推动Aβ相关疾病的病情进展。