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Cationic peptides cause memory loss through endophilin-mediated endocytosis

Author

Listed:
  • Eric G. Stokes

    (University of Colorado Anschutz)

  • Jose J. Vasquez

    (University of California, Irvine)

  • Ghalia Azouz

    (University of California, Irvine)

  • Megan Nguyen

    (University of California, Irvine)

  • Alexa Tierno

    (University of California, Irvine)

  • Yinyin Zhuang

    (University of California, Irvine)

  • Vivienne Mae Galinato

    (University of California, Irvine)

  • May Hui

    (University of California, Irvine)

  • Michael Toledano

    (University of California, Irvine)

  • Isabella Tyler

    (University of California, Irvine)

  • Xiaoyu Shi

    (University of California, Irvine
    University of California, Irvine
    University of California, Irvine)

  • Robert F. Hunt

    (University of California, Irvine
    University of California, Irvine)

  • Jason Aoto

    (University of Colorado Anschutz
    University of Colorado Anschutz)

  • Kevin T. Beier

    (University of California, Irvine
    University of California, Irvine
    University of California, Irvine
    University of California, Irvine)

Abstract

The zeta inhibitory peptide (ZIP) interferes with memory maintenance and long-term potentiation (LTP)1 when administered to mice. However, mice lacking its putative target, protein kinase PKMζ, exhibit normal learning and memory as well as LTP2,3, making the mechanism of ZIP unclear. Here we show that ZIP disrupts LTP by removing surface AMPA receptors through its cationic charge alone. This effect requires endophilin-A2-mediated endocytosis and is fully blocked by drugs suppressing macropinocytosis. ZIP and other cationic peptides remove newly inserted AMPA receptor nanoclusters at potentiated synapses, providing a mechanism by which these peptides erase memories without altering basal synaptic function. When delivered in vivo, cationic peptides can modulate memories on local and brain-wide scales, and these mechanisms can be leveraged to prevent memory loss in a model of traumatic brain injury. Our findings uncover a previously unknown synaptic mechanism by which memories are maintained or lost.

Suggested Citation

  • Eric G. Stokes & Jose J. Vasquez & Ghalia Azouz & Megan Nguyen & Alexa Tierno & Yinyin Zhuang & Vivienne Mae Galinato & May Hui & Michael Toledano & Isabella Tyler & Xiaoyu Shi & Robert F. Hunt & Jaso, 2025. "Cationic peptides cause memory loss through endophilin-mediated endocytosis," Nature, Nature, vol. 638(8050), pages 479-489, February.
    • Handle: RePEc:nat:nature:v:638:y:2025:i:8050:d:10.1038_s41586-024-08413-w
    DOI: 10.1038/s41586-024-08413-w
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