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

ABSTRACT: 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 o

SUBMITTER: Xie L 

PROVIDER: S-EPMC12056044 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature