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bioRxiv · 10.1101/2025.01.20.633888

Valosin-containing Protein is Cargo in Amyloid Precursor Protein Extracellular Vesicles

Lue, Y.·Abdullah, M.·Healy, L. R.·Tambini, M. D.
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Abstract

The Amyloid Precursor Protein (APP), a genetic cause of Alzheimers 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. The presence of Vcp suggests a role for App-EVs in the clearance of protein aggregates.

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Lue, Y., Abdullah, M., Healy, L. R., Tambini, M. D.. 2025-01-22. Valosin-containing Protein is Cargo in Amyloid Precursor Protein Extracellular Vesicles. https://doi.org/10.1101/2025.01.20.633888

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