{
  "abstract": "Introduction\n\nEpigenetic dysregulation is increasingly linked to aging and neurodegeneration, yet its contribution to retinal and brain pathology in Alzheimer's disease (AD) remains unclear.Methods\n\nWe 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\n\nH3K9me3 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\n\nThis 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.",
    "Macquarie University, Sydney, New South Wales, Australia.",
    "Department of Psychiatry and The Behavioral Sciences, Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.",
    "Department of Environmental and Occupational Health, College of Health Sciences, University of California, Irvine, California, USA.",
    "Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada.",
    "Department of Cancer Biology and Molecular Medicine, City of Hope National Medical Center, Duarte, California, USA.",
    "ProHeme Diagnostics Pty Ltd, Sydney, New South Wales, Australia.",
    "Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.",
    "Department of Biomedical Sciences, Division of Applied Cell Biology and Physiology, Cedars-Sinai Medical Center, Los Angeles, California, USA."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 21,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Dieu-Trang Fuchs"
    },
    {
      "affs": [
        0
      ],
      "name": "Jean-Philippe Vit"
    },
    {
      "affs": [
        0
      ],
      "name": "Altan Rentsendorj"
    },
    {
      "affs": [
        0
      ],
      "name": "Yosef Koronyo"
    },
    {
      "affs": [
        0
      ],
      "name": "Julia Sheyn"
    },
    {
      "affs": [
        0
      ],
      "name": "Bhakta Prasad Gaire"
    },
    {
      "affs": [
        0
      ],
      "name": "Saba Shahin"
    },
    {
      "affs": [
        0
      ],
      "name": "Haoshen Shi"
    },
    {
      "affs": [
        0
      ],
      "name": "Oksana Chepurna"
    },
    {
      "affs": [
        0
      ],
      "name": "Miyah R Davis"
    },
    {
      "affs": [
        0
      ],
      "name": "Jered W Wilson"
    },
    {
      "affs": [
        1
      ],
      "name": "Stuart L Graham"
    },
    {
      "affs": [
        1
      ],
      "name": "Vivek K Gupta"
    },
    {
      "affs": [
        2
      ],
      "name": "Lon S Schneider"
    },
    {
      "affs": [
        3
      ],
      "name": "Michael T Kleinman"
    },
    {
      "affs": [
        0
      ],
      "name": "Tao Sun"
    },
    {
      "affs": [
        4
      ],
      "name": "Margaret Fahnestock"
    },
    {
      "affs": [
        5
      ],
      "name": "David A Horne"
    },
    {
      "affs": [
        1,
        6
      ],
      "name": "Mehdi Mirzaei"
    },
    {
      "affs": [
        0
      ],
      "name": "Keith L Black"
    },
    {
      "affs": [
        0,
        7,
        8
      ],
      "name": "Maya Koronyo-Hamaoui",
      "orcid": "0000-0003-2864-8442"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/805p3ts4fv76f.bib",
  "cited_by": 0,
  "doi": "10.1002/alz.71918",
  "fulltext_url": "https://europepmc.org/articles/PMC13683561",
  "id": "805p3ts4fv76f",
  "issns": [
    "1552-5260",
    "1552-5279"
  ],
  "landing_url": "https://europepmc.org/article/MED/42902099",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
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  "openalex": "W7222996639",
  "pdf_url": "https://europepmc.org/articles/PMC13683561?pdf=render",
  "pmcid": "PMC13683561",
  "pmid": "42902099",
  "published": "2026-10-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/805p3ts4fv76f.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:37Z",
      "native_id": "MED:42902099",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42902099"
    }
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Alzheimer's disease research and treatments",
      "subfield": "physiology"
    }
  ],
  "title": "H3K9me3 inhibition reverses Alzheimer's progression by restoring synaptic and immune proteostasis across the brain-retina axis.",
  "title_text": "H3K9me3 inhibition reverses Alzheimer's progression by restoring synaptic and immune proteostasis across the brain-retina axis.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:37Z",
  "url": "https://research.draconitic.com/paper/805p3ts4fv76f",
  "venue": "Alzheimer's & dementia : the journal of the Alzheimer's Association",
  "versions": []
}