Novel brain-penetrant drugs for translation-targeting therapeutics of Alzheimer’s disease

Abstract Alzheimer's disease (AD), the most common form of dementia in older adults, is a neurodegenerative disorder characterized by progressive decline of memory and cognition. AD is multifaceted and heterogeneous, which prevents clear mechanistic understanding of AD pathogenesis and therefore hinders development of

effective therapeutics. Meanwhile, post-mortem epidemiology indicated that AD onset was associated with elevated activity of the histone methyltransferase G9a (EHMT2) in diseased brain, implicating G9a activity- associated pathways in AD pathogenesis. Using our c hromatin-activity-based chemoproteomic (ChaC)

approach that enables dissection of AD heterogeneity , we (the Chen lab) have discovered a noncanonical, translation regulatory function of G9a in AD pathogenesis. Further, we deduced the mechanism of action of a brain-penetrant G9a-targetd drug, MS1262, w here G9a inhibition by MS1262 reversed AD patient proteomes,

particularly the AD-disturbed expression or phosphorylation of proteins related to cognition and learning, synaptic transmission, synaptogenesis, and hyperactive behavior. Correspondingly, intermittent MS1262 treatment restored cognitive and affective functions in mid/late-stage 5xFAD mice to the healthy level (p