{
  "abstract": "While the accumulation of Aβ peptides, derived by proteolytic cleavage from the amyloid precursor protein APP, constitutes a hallmark of Alzheimer’s disease, the question of whether endogenous, physiological APP processing serves an essential role for normal brain function(s) has remained elusive. Here, we modified the mouse APP locus to delete the endogenous α- and β-secretase sites (APP residues S592-G621) while preserving the transmembrane topology and the APP C-terminus. These novel knockin mice (termed APPΔS622) lack APPsα, APPβ, and Aβ production and show only minimal soluble APPs shedding. These APPΔS622 mice provide a unique model to distinguish between functions mediated by unprocessed cell surface APP involved in synaptic adhesion or by proteolytic fragments. Strikingly, APPΔS622 mice exhibit pronounced impairments in both long-term potentiation (LTP) and homeostatic forms of synaptic plasticity. Extracellular field recordings revealed significant deficits in hippocampal LTP, associated with a reduced density of mature spines and reduced spine head size. LTP deficits could be restored by APPsα application, suggesting a requirement for non-amyloidogenic APP processing for LTP. In addition, APPΔS622 mice lacking endogenous Aβ displayed a lack of homeostatic synaptic scaling in response to network impairment that could be specifically rescued by exogenous Aβ. Importantly, these deficits in different forms of synaptic plasticity also led to impairments in cognitive behavior. In summary, our findings reveal an essential role of physiological APP processing products to differentially regulate complementary forms of synaptic plasticity that are critical for network stability, normal brain function and cognition.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Functional Genomics, Institute of Pharmacy and Molecular Biotechnology (IPMB), Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany",
    "Institute for Cell- and Neurobiology, TU Braunschweig, Braunschweig, Germany",
    "Department of Neuroanatomy, Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg, Germany",
    "Department of Anatomy, University of Zürich, Zürich, Switzerland",
    "Institute of Human Movement Sciences and Sport, D-HEST, ETH Zürich, Zürich, Switzerland",
    "Focus Program Translational Neurosciences (FTN), University Medical Center of the Johannes Gutenberg University Mainz, Institute of Pathophysiology, Mainz, Germany",
    "Institute for Clinical Neuroanatomy, Goethe University Frankfurt, Frankfurt/Main, Germany",
    "Neuroinflammation and Neurodegeneration Group, Helmholtz Centre for Infection Research, Braunschweig, Germany"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Lara Kilian"
    },
    {
      "affs": [
        0
      ],
      "name": "Verena Bengelsdorff"
    },
    {
      "affs": [
        1
      ],
      "name": "Jennifer Just"
    },
    {
      "affs": [
        1
      ],
      "name": "Sebastian Stork"
    },
    {
      "affs": [
        2
      ],
      "name": "Christos Galanis",
      "orcid": "0000-0002-6469-7201"
    },
    {
      "affs": [
        0
      ],
      "name": "Marija Banicevic"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Irmgard Amrein"
    },
    {
      "affs": [
        5
      ],
      "name": "Michaela Back"
    },
    {
      "affs": [
        6
      ],
      "name": "Tassilo Jungenitz"
    },
    {
      "affs": [
        6
      ],
      "name": "Meike Fellenz"
    },
    {
      "affs": [
        5
      ],
      "name": "Jakob von Engelhardt"
    },
    {
      "affs": [
        6
      ],
      "name": "Thomas Deller",
      "orcid": "0000-0002-3931-2947"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "David P. Wolfer"
    },
    {
      "affs": [
        2
      ],
      "name": "Andreas Vlachos"
    },
    {
      "affs": [
        1,
        7
      ],
      "name": "Martin Korte"
    },
    {
      "affs": [
        0
      ],
      "name": "Ulrike C. Müller",
      "orcid": "0000-0002-0587-2575"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6hwpw4evvg72v.bib",
  "cited_by": 0,
  "doi": "10.1038/s41419-026-09378-6",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13737196/",
  "id": "6hwpw4evvg72v",
  "issns": [
    "2041-4889"
  ],
  "landing_url": "https://doi.org/10.1038/s41419-026-09378-6",
  "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",
      "2804|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7225245245",
  "pdf_url": "https://www.nature.com/articles/s41419-026-09378-6.pdf",
  "pmcid": "PMC13737196",
  "pmid": "42982811",
  "published": "2026-11-04",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/6hwpw4evvg72v.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:22:28Z",
      "native_id": "PMC13737196",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41419-026-09378-6"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Alzheimer's disease research and treatments",
      "subfield": "neuroscience"
    }
  ],
  "title": "Physiological APP processing is required for synaptic plasticity and cognition",
  "title_text": "Physiological APP processing is required for synaptic plasticity and cognition",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:22:28Z",
  "url": "https://research.draconitic.com/paper/6hwpw4evvg72v",
  "venue": "Cell Death & Disease",
  "versions": []
}