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<p>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 &amp; 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.</p>

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Development of a brain-penetrant G9a methylase inhibitor to target Alzheimer’s disease-associated proteopathology

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月7日

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  • Ling Xie,
  • Ryan N. Sheehy,
  • Adil Muneer,
  • Yan Xiong,
  • John A. Wrobel,
  • Feng Zhang,
  • Kwang-Su Park,
  • Julia Velez,
  • Jing Liu,
  • Yan-Jia Luo,
  • Brent Asrican,
  • Ping Dong,
  • Ya-Dong Li,
  • Corina Damian,
  • Luis Quintanilla,
  • Yongyi Li,
  • Chongchong Xu,
  • Mohanish Deshmukh,
  • Leon G. Coleman Jr.,
  • Guo-Li Ming,
  • Hongjun Song,
  • Zhexing Wen,
  • Jian Jin,
  • Juan Song,
  • Xian Chen

摘要

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.