Yu Xinyuan, Dang Lihong, Dhar Ashis, Zhang Ran, Xu Feng, Spasojevic Ivan, Sheng Huaxin, Yang Wei
Multidisciplinary Brain Protection Program (MBPP), Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.
Department of Medicine - Oncology, Duke University Medical Center, Durham, NC, USA.
Transl Stroke Res. 2025 Apr 21. doi: 10.1007/s12975-025-01351-3.
Ischemic stroke disrupts protein homeostasis in brain cells, causes endoplasmic reticulum (ER) stress, and consequently activates the unfolded protein response (UPR). The primary function of UPR activation is to help cells restore ER function, thereby promoting cell survival. A major adaptive UPR branch is mediated by activating transcription factor 6 (ATF6). We previously provided experimental evidence that activation of ATF6 signaling in neurons improves short-term outcome after both transient and permanent stroke. However, the effect of ATF6 activation in astrocytes on stroke outcome remains undetermined, and critically, the long-term therapeutic potential of targeting this UPR branch in permanent stroke has not been evaluated. The current study aimed to address these two critical unknowns. First, using conditional knock-in mice in which functional short-form ATF6 (sATF6) is specifically expressed in astrocytes, we demonstrated that astrocytic ATF6 activation modestly improved outcome after permanent stroke. Then, our pharmacokinetic analysis indicated that compound AA147, an ATF6-specific activator, can cross the blood-brain barrier. Lastly, we found that post-stroke treatment with AA147 had no significant beneficial effect on short-term outcome, but improved long-term functional recovery in both young and aged mice after permanent stroke. Together with previous findings, our data support the notion that the ATF6 pathway is a promising target for stroke therapy.
缺血性中风会破坏脑细胞中的蛋白质稳态，引发内质网（ER）应激，进而激活未折叠蛋白反应（UPR）。UPR激活的主要功能是帮助细胞恢复内质网功能，从而促进细胞存活。UPR的一个主要适应性分支由激活转录因子6（ATF6）介导。我们之前提供的实验证据表明，神经元中ATF6信号的激活可改善短暂性和永久性中风后的短期预后。然而，星形胶质细胞中ATF6激活对中风预后的影响仍未确定，关键的是，针对永久性中风中这个UPR分支的长期治疗潜力尚未得到评估。当前的研究旨在解决这两个关键的未知问题。首先，使用功能性短型ATF6（sATF6）在星形胶质细胞中特异性表达的条件性敲入小鼠，我们证明星形胶质细胞ATF6激活可适度改善永久性中风后的预后。然后，我们的药代动力学分析表明，ATF6特异性激活剂化合物AA147能够穿过血脑屏障。最后，我们发现中风后用AA147治疗对短期预后没有显著的有益影响，但可改善永久性中风后年轻和老年小鼠的长期功能恢复。结合之前的研究结果，我们的数据支持ATF6通路是中风治疗一个有前景的靶点这一观点。
