{
  "abstract": "Traumatic brain injury (TBI) is a major cause of long-term neurological disability, and repeated mild TBI (rmTBI) is increasingly linked to chronic neurodegeneration. Clinical evidence suggests that rmTBI creates a prolonged window of vulnerability to further injury. However, the astrocyte-intrinsic mechanisms that convert repeated mechanical stress into delayed neuronal injury remain poorly defined. In particular, whether rmTBI induces a distinct lipid-mediated neurotoxic programme in human astrocytes is unknown. Using a human astrocyte in vitro platform of rmTBI, we deliver controlled repeated mild injuries to astrocytes. Repeated injury induces a distinctive astrocytic phenotype characterised by cytoskeletal remodelling, reactive oxygen species accumulation, biphasic volume changes, extracellular matrix remodelling and lipid droplet formation. Shotgun lipidomics of astrocyte-conditioned medium reveals selective enrichment of bioactive diacylglycerols (DG) following rmTBI. When applied to human cortical neurons, this conditioned medium impairs neuronal function and morphology, increases apoptosis and activates protein kinase C delta (PKCδ). Pharmacological inhibition of PKC attenuates the neurotoxic effect of rmTBI astrocyte-conditioned medium. These findings support a model in which human astrocytes retain a form of ‘injury memory’ through sustained phenotypic and lipid metabolic remodelling. By implicating the DG-PKCδ axis in delayed neurotoxicity, the study identifies PKC signalling as a tractable target for limiting the long-term consequences of rmTBI.\n\nRepeated mild traumatic brain injury induces astrocytic dysfunction, metabolic imbalance and disrupts lipid homeostasis. This leads to the aberrant release of specific diacylglycerol species which activate protein kinase C signalling in neurons and drive delayed neurotoxic cascades.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK",
    "British Heart Foundation (BHF) - UK Dementia Research Institute (UK DRI) Centre for Vascular Dementia Research (CVDR) at the University of Oxford, Oxford, UK",
    "Kavli Institute for NanoScience Discovery, University of Oxford, Oxford, UK",
    "British Heart Foundation (BHF) Oxford Centre of Research Excellence, University of Oxford, Oxford, UK",
    "Department for Structural Biology, Kiel University, Kiel, Germany",
    "Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands",
    "Institute of Anatomy, Kiel University, Kiel, Germany"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Luise Schlotterose"
    },
    {
      "affs": [
        4
      ],
      "name": "Michel A. Struwe"
    },
    {
      "affs": [
        4
      ],
      "name": "Axel J. Scheidig"
    },
    {
      "affs": [
        5
      ],
      "name": "Niek Blomberg"
    },
    {
      "affs": [
        5
      ],
      "name": "Martin Giera",
      "orcid": "0000-0003-1684-1894"
    },
    {
      "affs": [
        6
      ],
      "name": "Kirsten Hattermann"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Mootaz M. Salman",
      "orcid": "0000-0002-5683-1706"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/94s2az3tw9749.bib",
  "cited_by": 0,
  "doi": "10.1038/s41419-026-09217-8",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13713977/",
  "id": "94s2az3tw9749",
  "issns": [
    "2041-4889"
  ],
  "landing_url": "https://doi.org/10.1038/s41419-026-09217-8",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2728|Traumatic Brain Injury and Neurovascular Disturbances"
    ]
  ],
  "openalex": "W7204125701",
  "pdf_url": "https://www.nature.com/articles/s41419-026-09217-8_reference.pdf",
  "pmcid": "PMC13713977",
  "pmid": "42946721",
  "published": "2026-08-24",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/94s2az3tw9749.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T12:21:33Z",
      "native_id": "PMC13713977",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41419-026-09217-8"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2728|Traumatic Brain Injury and Neurovascular Disturbances",
      "subfield": "neurology"
    }
  ],
  "title": "From injury to degeneration: delayed lipid-mediated neurotoxicity in a human astrocyte traumatic brain injury in-a-dish model",
  "title_text": "From injury to degeneration: delayed lipid-mediated neurotoxicity in a human astrocyte traumatic brain injury in-a-dish model",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:21:33Z",
  "url": "https://research.draconitic.com/paper/94s2az3tw9749",
  "venue": "Cell Death & Disease",
  "versions": []
}