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; Kevin T Beier

doi:10.1038/s41586-024-08413-w

Cationic peptides cause memory loss through endophilin-mediated endocytosis

Nature. 2025 Jan 15. doi: 10.1038/s41586-024-08413-w. Online ahead of print.

Authors

Eric G Stokes¹, Jose J Vasquez², Ghalia Azouz², Megan Nguyen², Alexa Tierno³, Yinyin Zhuang⁴, Vivienne Mae Galinato², May Hui², Michael Toledano², Isabella Tyler², Xiaoyu Shi^{4

5

6}, Robert F Hunt^{3

7}, Jason Aoto^{1

8}, Kevin T Beier^{9

10

11

12}

Affiliations

¹ Pharmacology Graduate Program, University of Colorado Anschutz, Aurora, CO, USA.
² Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
³ Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA, USA.
⁴ Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA.
⁵ Department of Chemistry, University of California, Irvine, Irvine, CA, USA.
⁶ Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, USA.
⁷ Epilepsy Research Center, University of California, Irvine, Irvine, CA, USA.
⁸ Department of Pharmacology, University of Colorado Anschutz, Aurora, CO, USA.
⁹ Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA. [email protected].
¹⁰ Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, USA. [email protected].
¹¹ Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA. [email protected].
¹² Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA. [email protected].

PMID: 39814881
DOI: 10.1038/s41586-024-08413-w

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 LTP^2,3, 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.