Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
H3K9me3 inhibition reverses Alzheimer's progression by restoring synaptic and immune proteostasis across the brain-retina axis.
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Fuchs Dieu-Trang, Vit Jean-Philippe, Rentsendorj Altan, Koronyo Yosef, Sheyn Julia, Gaire Bhakta Prasad, Shahin Saba, Shi Haoshen, Chepurna Oksana, Davis Miyah R, Wilson Jered W, Graham Stuart L, Gupta Vivek K, Schneider Lon S, Kleinman Michael T, Sun Tao, Fahnestock Margaret, Horne David A, Mirzaei Mehdi, Black Keith L, Koronyo-Hamaoui Maya
Аннотация
INTRODUCTION: Epigenetic dysregulation is increasingly linked to aging and neurodegeneration, yet its contribution to retinal and brain pathology in Alzheimer's disease (AD) remains unclear.
METHODS: 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/PS1tm1Mpm), we assessed ETP69 effects on cerebral H3 methylation, behavior, AD-like pathology, synaptic integrity, and proteomic profiles.
RESULTS: 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 and remodeled innate immune pathways and brain-derived neurotrophic factor/nerve growth factor-inducible protein (BDNF/VGF)-granin signaling.
DISCUSSION: 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.
METHODS: 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/PS1tm1Mpm), we assessed ETP69 effects on cerebral H3 methylation, behavior, AD-like pathology, synaptic integrity, and proteomic profiles.
RESULTS: 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 and remodeled innate immune pathways and brain-derived neurotrophic factor/nerve growth factor-inducible protein (BDNF/VGF)-granin signaling.
DISCUSSION: 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.