Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer’s disease proteopathology for precision medication

Abstract

Current amyloid beta-targeting approaches for Alzheimer disease (AD) therapeutics only slow cognitive decline for small numbers of patients. This limited efficacy exists because AD is a multifactorial disease whose pathological mechanism(s) and diagnostic biomarkers are largely unknown. Here we report a new mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of a hippocampal proteome that defines the proteopathic nature of AD. Accordingly, we developed a novel brain-penetrant inhibitor of G9a, MS1262, across the blood-brain barrier to block this G9a-regulated, proteopathologic mechanism. Intermittent MS1262 treatment of multiple AD mouse models consistently restored both cognitive and noncognitive functions to healthy levels. Comparison of proteomic/phosphoproteomic analyses of MS1262-treated AD mice with human AD patient data identified multiple pathological brain pathways that elaborate amyloid beta and neurofibrillary tangles as well as blood coagulation, from which biomarkers of early stage of AD including SMOC1 were found to be affected by MS1262 treatment. Notably, these results indicated that MS1262 treatment may reduce or avoid the risk of blood clot burst for brain bleeding or a stroke. This mouse-to-human conservation of G9a-translated AD proteopathology suggests that the global, multifaceted effects of MS1262 in mice could extend to relieve all symptoms of AD patients with minimum side effect. In addition, our mechanistically derived biomarkers can be used for stage-specific AD diagnosis and companion diagnosis of individualized drug effects

Targeting G9a translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae

“…In addition, we identified multiple G9a-regulated, inhibitor-reversed pathways characteristic of long COVID or COVID neurological symptoms. Importantly, akin to our finding that a brain-penetrant inhibitor of G9a, MS1262, reversed brain neuropathological pathways associated with Alzheimer’s disease pathogenesis 45 , we found that MS1262 suppressed SARS-CoV2 replication, suggesting a therapeutic effect of G9a inhibition on long-lasting COVID neurological symptoms.…”

“…Similarly, the exact function of EZH2 during the process requires further investigation. COVID-19 accelerates Alzheimer's-related symptoms and dementia 103,104 , and we recently reported on development of a blood-brain-barrier penetrant G9a inhibitor that reversed cognitive and noncognitive effects of Alzheimer's in multiple mouse models 45 . Thus, it will be interesting to study the effects of G9a inhibition in Alzheimer's mouse models of COVID-19.…”