Cationic peptides cause memory loss through endophilin-mediated endocytosis

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, Jason Aoto and Kevin T. Beier ()
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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
Robert F. Hunt: University of California, Irvine
Jason Aoto: University of Colorado Anschutz
Kevin T. Beier: University of California, Irvine

Nature, 2025, vol. 638, issue 8050, 479-489

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-024-08413-w

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