Table 4_Tau mediates the reshaping of the transcriptional landscape toward intermediate Alzheimer’s disease stages.xlsx

IntroductionRecent research revealed that Tau plays critical roles in various neuronal functions. We previously demonstrated that destabilization and nuclear delocalization of Tau alter the expression of glutamatergic genes, mediating early neuronal damage.
MethodsIn this study, we discovered that changes in Tau availability are linked to global alterations in gene expression that affect multiple neuronal pathways. Comparison with the human temporal region showed that the Tau-dependent modulation of gene expression closely resembles the intermediate stages of Alzheimer’s disease (AD) that precede the definitive pathological condition.
ResultsFurthermore, we identified the chromatin remodeling pathway as being significantly affected by Tau in both our cellular model and AD brains, with reductions in heterochromatin markers. Our findings indicate that Tau is able to globally affect the neuronal transcriptome and that its subcellular unbalance changes gene expression in the intermediate stages of AD development. In addition, we found that the chromatin architecture is affected by Tau during the progression of AD.
DiscussionThese results provide new insights into the molecular mechanisms underlying early stages of AD development and highlight the central role of Tau and the contribution of nuclear Tau in this process.

**引言** 近期研究表明，τ蛋白（Tau）在多种神经元功能中发挥关键作用。本团队此前已证实，τ蛋白的不稳定及核定位异常会改变谷氨酸能基因的表达，进而介导早期神经元损伤。
**方法** 本研究发现，τ蛋白丰度的变化与影响多条神经元通路的全基因组基因表达改变密切相关。通过与人类颞叶脑组织样本对比，我们观察到τ蛋白依赖的基因表达调控模式，与确诊前的阿尔茨海默病（AD）中期病理阶段高度相似。
**结果** 此外，我们在细胞模型与AD患者脑组织中均发现，染色质重塑通路受τ蛋白调控的变化极为显著，且异染色质标记物水平出现下降。本研究结果证实，τ蛋白可全局性影响神经元转录组，其亚细胞分布失衡会在AD发展的中期阶段改变基因表达。同时，我们还发现AD进展过程中，染色质结构会受τ蛋白的影响而发生改变。
**讨论** 本研究结果为AD早期发展的分子机制提供了新视角，并凸显了τ蛋白以及核τ蛋白在该过程中的核心作用。