{
  "abstract": "Extensive synaptic loss and progressive neurodegeneration are defining pathological hallmarks of Alzheimer's disease (AD), primarily driven by soluble A{beta} oligomers and neurofibrillary tangles. The apolipoprotein E4 (APOE4) isoform further aggravates these pathological cascades, yet the precise molecular mechanisms underlying AD pathogenesis remain poorly elucidated. Store-operated calcium entry (SOCE) deficiency in neurons has been proven to exert a detrimental effect on dendritic spine integrity and function. Herein, we investigated whether SOCE dysregulation contributes to A{beta}O-induced synaptotoxicity and how APOE4 modulates this pathological process. In primary neuronal cultures, co-treatment with A{beta}O and APOE4 markedly reduced synapse density and impaired dendritic arbor complexity, compared with A{beta}O treatments combined with APOE3 or APOE2 isoforms. Consistently, neurons exposed to A{beta}O plus APOE4 exhibited significantly lower SOCE amplitudes than those treated with A{beta}O and APOE3. In line with SOCE suppression, the A{beta}O/APOE4 combination specifically downregulated stromal interaction molecule 1 (STIM1) protein expression, with no observable change in STIM2 levels. Mechanistically, A{beta}O/APOE4-mediated STIM1 reduction was dependent on p62-selective autophagic degradation. Notably, exogenous STIM1 overexpression effectively rescued the deficits in dendritic arbor complexity. Furthermore, STIM1 downregulation induced by A{beta}O and APOE4 initiated the autophagic degradation of glutathione peroxidase 4 (Gpx4). This autophagy activation was attributed to decreased Bcl2 expression and occurs independently of STING accumulation. Subsequent Gpx4 insufficiency further triggered excessive accumulation of reactive oxygen species and disrupted mitochondrial cristae morphology in neurons. Collectively, our findings uncover a previously unrecognized mechanism whereby APOE4 exacerbates A{beta}O-induced synaptotoxicity. Specifically, the combination facilitates p62-mediated selective autophagic degradation of STIM1, which suppresses Bcl2 expression and ultimately promotes robust Gpx4 autophagic degradation, driving neuronal synaptic damage.",
  "abstract_shown": true,
  "affiliations": [
    "Wenzhou Medical University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "name": "J. Zhou"
    },
    {
      "name": "H. Liao"
    },
    {
      "name": "W. Liang"
    },
    {
      "name": "S. Liu"
    },
    {
      "name": "J. Cai"
    },
    {
      "name": "Y. Liu"
    },
    {
      "name": "Y. Liu"
    },
    {
      "name": "Z. Zhou"
    },
    {
      "affs": [
        0
      ],
      "name": "S. Wu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/87akffkhzmhhr.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.11.01.763365",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.11.01.763365v1.full",
  "id": "87akffkhzmhhr",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.11.01.763365v1",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.11.01.763365v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/87akffkhzmhhr.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T00:21:31Z",
      "native_id": "10.64898/2026.11.01.763365",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.11.01.763365v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Apolipoprotein E4 Exacerbates Aβ Oligomer-Induced Synaptotoxicity through Promoting Autophagic Degradation of Glutathione Peroxidase 4",
  "title_text": "Apolipoprotein E4 Exacerbates Aβ Oligomer-Induced Synaptotoxicity through Promoting Autophagic Degradation of Glutathione Peroxidase 4",
  "type": "preprint",
  "updated_at": "2026-11-05T00:20:54Z",
  "url": "https://research.draconitic.com/paper/87akffkhzmhhr",
  "venue": "bioRxiv",
  "versions": []
}