Xie Ling, Sheehy Ryan N, Muneer Adil, Xiong Yan, Wrobel John A, Zhang Feng, Park Kwang-Su, Velez Julia, Liu Jing, Luo Yan-Jia, Asrican Brent, Dong Ping, Li Ya-Dong, Damian Corina, Quintanilla Luis, Li Yongyi, Xu Chongchong, Deshmukh Mohanish, Coleman Leon G, Ming Guo-Li, Song Hongjun, Wen Zhexing, Jin Jian, Song Juan, Chen Xian
Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Nat Commun. 2025 May 7;16(1):4222. doi: 10.1038/s41467-025-59128-z.
Current Aβ-targeting therapeutics for Alzheimer's disease (AD) only slow cognitive decline due to poor understanding of AD pathogenesis. Here we describe a mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of hippocampal proteins associated with AD pathology. Correspondingly, we developed a brain-penetrant inhibitor of G9a, MS1262, which restored both age-related learning & memory and noncognitive functions in multiple AD mouse models. Further, comparison of AD pathology-correlated mouse proteomes with those of AD patients found G9a regulates pathological pathways that promote Aβ and neurofibrillary tangles. This mouse-to-human overlap of G9a regulated AD-associated pathologic proteins supports at the molecular level the efficacy of targeting G9a translational mechanism for treating AD patients. Additionally, MS1262 treatment reversed the AD-characteristic expression or phosphorylation of multiple clinically validated biomarkers of AD that have the potential to be used for early-stage AD diagnosis and companion diagnosis of individualized drug effects.
由于对阿尔茨海默病（AD）发病机制的了解不足，目前用于治疗AD的靶向淀粉样前体蛋白（Aβ）的疗法只能减缓认知衰退。在此，我们描述了一种AD发病机制，其中组蛋白甲基转移酶G9a以非经典方式调节与AD病理相关的海马蛋白的翻译。相应地，我们开发了一种G9a的脑渗透性抑制剂MS1262，它在多个AD小鼠模型中恢复了与年龄相关的学习和记忆以及非认知功能。此外，将与AD病理相关的小鼠蛋白质组与AD患者的蛋白质组进行比较发现，G9a调节促进Aβ和神经原纤维缠结的病理途径。G9a调节的AD相关病理蛋白在小鼠和人类之间的这种重叠在分子水平上支持了靶向G9a翻译机制治疗AD患者的疗效。此外，MS1262治疗逆转了多种经临床验证的AD生物标志物的AD特征性表达或磷酸化，这些生物标志物有可能用于AD的早期诊断和个体化药物疗效的伴随诊断。
