Nature communications · 2025
Development of a brain-penetrant G9a methylase inhibitor to target Alzheimer's disease-associated proteopathology.
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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
Аннотация
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.