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<p>The Amyloid Precursor Protein (APP), a genetic cause of Alzheimer’s disease (AD), is a type-I transmembrane protein that is metabolized by proteolysis in the endolysomal system. APP and its metabolites are secreted by cells in extracellular vesicles (EVs). To study the function of APP-containing EVs, we isolated App-EVs from rat primary neuronal conditioned media and proteomic analysis identified the Valosin-containing protein (Vcp) as molecular cargo. Pharmacological modulation of Vcp activity was found to alter App processing and global EV secretion in rat primary neurons. AD-associated knock-in <i>App</i> mutations were found to alter the abundance of App-EVs and the trafficking of App metabolites within App-EVs, in a manner related to the epitopes generated by the nonamyloidogenic processing of App.</p>

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Valosin-containing Protein is cargo in Amyloid Precursor Protein extracellular vesicles

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Yue Lu,
  • Mohammad Abdullah,
  • Liam R. Healy,
  • Tao Yin,
  • Metin Yesiltepe,
  • Luciano D’Adamio,
  • Marc D. Tambini

摘要

The Amyloid Precursor Protein (APP), a genetic cause of Alzheimer’s disease (AD), is a type-I transmembrane protein that is metabolized by proteolysis in the endolysomal system. APP and its metabolites are secreted by cells in extracellular vesicles (EVs). To study the function of APP-containing EVs, we isolated App-EVs from rat primary neuronal conditioned media and proteomic analysis identified the Valosin-containing protein (Vcp) as molecular cargo. Pharmacological modulation of Vcp activity was found to alter App processing and global EV secretion in rat primary neurons. AD-associated knock-in App mutations were found to alter the abundance of App-EVs and the trafficking of App metabolites within App-EVs, in a manner related to the epitopes generated by the nonamyloidogenic processing of App.