H3K9me3 epigenetic derepression reverses Alzheimer’s-like pathology and improves cognition via immunomodulation and Vgf network activation

ABSTRACT: Alzheimer's disease (AD) is associated with excessive epigenome histone 3 lysine 9 trimethylation (H3K9me3), repressing genes involved in synaptic plasticity and memory. In this study, we explored the therapeutic potential of ETP69, an inhibitor of the H3K9me3 methyltransferase SUV39H1, in both old wild type and transgenic APPSWE/PS1dE9 (AD+) mice. We found that intraperitoneal ETP69 administration rapidly and persistently reduced neuronal and myelomonocytic H3K9me3, mitigating AD-related neuropathology and enhancing dendritic spine formation and cognitive function. ETP69 had immunomodulatory effects manifested by limiting microgliosis and increasing blood and brain-infiltrating monocytes correlated with Aβ-plaque clearance. Brain proteomics revealed that 84% of proteins dysregulated in AD+ mice were reversed by ETP69 and enriched for synaptic plasticity and learning. Importantly, ETP69 activated the brain-derived neurotrophic factor (Bdnf) pathways and related neurosecretory protein Vgf network, associating with improved cognition. These results support the pharmacological inhibition of H3K9me3 gene silencing to reverse aging and AD-related cognitive decline

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Retina

DISEASE(S): Alzheimer's Disease

SUBMITTER: Shahab Mirshahvaladi  

LAB HEAD: Maya Koronyo-Hamaoui

PROVIDER: PXD041527 | Pride | 2026-10-26

REPOSITORIES: Pride