美国加州大学Kevin T. Beier等合作团队的一项最新研究发现，阳离子多肽通过内啡肽介导的内吞作用引起记忆丧失。该研究于2025年1月15日发表于国际一流学术期刊《自然》杂志上。

研究表明，zeta抑制肽（ZIP）通过其阳离子电荷去除表面AMPA受体来破坏LTP。这种作用需要内啡肽-A2介导的内吞作用，并被抑制巨噬细胞增多的药物完全阻断。zeta抑制肽及其他阳离子肽能够移除已增强突触中新插入的AMPA受体纳米簇，从而在不改变基础突触功能的情况下消除记忆。

当在体内传递时，阳离子肽可以在局部和全脑范围内调节记忆，这些机制可以用来预防创伤性脑损伤模型中的记忆丧失。他们的发现揭示了一种以前不为人知的突触机制，记忆是通过这种机制维持或丢失的。

研究人员表示，zeta抑制肽（ZIP）干扰小鼠的记忆维持和长期增强（LTP）。然而，缺乏其假定靶点PKMζ蛋白激酶的小鼠表现出正常的学习、记忆以及长期增强，这使得ZIP的机制尚不清楚。

附：英文原文

Title: Cationic peptides cause memory loss through endophilin-mediated endocytosis

Author: Stokes, Eric G., Vasquez, Jose J., Azouz, Ghalia, Nguyen, Megan, Tierno, Alexa, Zhuang, Yinyin, Galinato, Vivienne Mae, Hui, May, Toledano, Michael, Tyler, Isabella, Shi, Xiaoyu, Hunt, Robert F., Aoto, Jason, Beier, Kevin T.

Issue&Volume: 2025-01-15

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.

DOI: 10.1038/s41586-024-08413-w

Source: https://www.nature.com/articles/s41586-024-08413-w