H3K9me3 inhibition reverses Alzheimer's progression by restoring synaptic and immune proteostasis across the brain-retina axis.
9 affiliations
- 1Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
- 2Macquarie University, Sydney, New South Wales, Australia.
- 3Department of Psychiatry and The Behavioral Sciences, Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
- 4Department of Environmental and Occupational Health, College of Health Sciences, University of California, Irvine, California, USA.
- 5Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada.
- 6Department of Cancer Biology and Molecular Medicine, City of Hope National Medical Center, Duarte, California, USA.
- 7ProHeme Diagnostics Pty Ltd, Sydney, New South Wales, Australia.
- 8Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
- 9Department of Biomedical Sciences, Division of Applied Cell Biology and Physiology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Abstract
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.
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BibTeX
@article{fuchs2026h3k9me3,
title = {{H3K9me3 inhibition reverses Alzheimer's progression by restoring synaptic and immune proteostasis across the brain-retina axis.}},
author = {Dieu-Trang Fuchs and Jean-Philippe Vit and Altan Rentsendorj and Yosef Koronyo and Julia Sheyn and Bhakta Prasad Gaire and Saba Shahin and Haoshen Shi and Oksana Chepurna and Miyah R Davis and Jered W Wilson and Stuart L Graham and Vivek K Gupta and Lon S Schneider and Michael T Kleinman and Tao Sun and Margaret Fahnestock and David A Horne and Mehdi Mirzaei and Keith L Black and Maya Koronyo-Hamaoui},
journal = {Alzheimer's \& dementia : the journal of the Alzheimer's Association},
year = {2026},
month = oct,
doi = {10.1002/alz.71918},
url = {https://europepmc.org/article/MED/42902099},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - H3K9me3 inhibition reverses Alzheimer's progression by restoring synaptic and immune proteostasis across the brain-retina axis.
AU - Dieu-Trang Fuchs
AU - Jean-Philippe Vit
AU - Altan Rentsendorj
AU - Yosef Koronyo
AU - Julia Sheyn
AU - Bhakta Prasad Gaire
AU - Saba Shahin
AU - Haoshen Shi
AU - Oksana Chepurna
AU - Miyah R Davis
AU - Jered W Wilson
AU - Stuart L Graham
AU - Vivek K Gupta
AU - Lon S Schneider
AU - Michael T Kleinman
AU - Tao Sun
AU - Margaret Fahnestock
AU - David A Horne
AU - Mehdi Mirzaei
AU - Keith L Black
AU - Maya Koronyo-Hamaoui
PY - 2026
DA - 2026/10/01
JO - Alzheimer's & dementia : the journal of the Alzheimer's Association
DO - 10.1002/alz.71918
UR - https://europepmc.org/article/MED/42902099
AB - 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.
SN - 1552-5260
SN - 1552-5279
ER -