H3K9me3 inhibition reverses Alzheimer's progression by restoring synaptic and immune proteostasis across the brain-retina axis.

<h4>Introduction</h4>Epigenetic dysregulation is increasingly linked to aging and neurodegeneration, yet its contribution to retinal and brain pathology in Alzheimer's disease (AD) remains unclear.<h4>Methods</h4>We quantified the repressive epigenetic mark histone H3 lysine 9 trimethylation (H3K9me3) in post mortem retinas and brains from donors spanning normal cognition, mild cognitive impairment, and AD dementia. Using a multi-enzyme methyltransferase panel, we characterized the in vitro inhibitory activity of ETP69, an epidithiodiketopiperazine, against suppressor of variegation 3-9 homologue 1 (SUV39H1) and other methyltransferases. In two transgenic AD mouse models (APPswe/PS1dE9 and APPswe/tauP301L/PS1^tm1Mpm), we assessed ETP69 effects on cerebral H3 methylation, behavior, AD-like pathology, synaptic integrity, and proteomic profiles.<h4>Results</h4>H3K9me3 increased early across the AD continuum in both brain and retina, correlating with cognitive impairment and neuropathological burden. H3K9me3 levels were strongly correlated between matched brains and retinas (r = 0.72, p = 0.0002). ETP69 substantially inhibited SUV39H1 and several other methyltransferases in cell-free assays, while consistently reducing cerebral H3K9me3 in vivo relative to other histone marks assessed. In mice, pharmacological H3K9me3 reduction mitigated AD-like pathology, preserved synapses, and improved short- and long-term cognitive and visual performance. Proteomics revealed that H3K9me3 derepression re-established retinal and brain proteostasis(definition) and remodeled innate immune pathways and brain-derived neurotrophic factor/nerve growth factor-inducible protein (BDNF/VGF)-granin signaling.<h4>Discussion</h4>This study identifies H3K9me3 accumulation as a shared, reversible epigenetic contributor to AD across the retina-brain axis; its reduction represents a promising disease-modifying strategy, and the retina may provide an accessible readout of brain epigenetic dysfunction.