Exosomal cellular prion protein drives fibrillization of amyloid beta and counteracts amyloid beta-mediated neurotoxicity

Clemens Falker, Alexander Hartmann, Inga Guett, Frank Dohler, Hermann Altmeppen, Christian Betzel, Robin Schubert, Dana Thurm, Florian Wegwitz, Pooja Joshi, Claudia Verderio, Susanne Krasemann, Markus Glatzel

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer's disease is a common neurodegenerative, progressive, and fatal disorder. Generation and deposition of amyloid beta (Aβ) peptides associate with its pathogenesis and small soluble Aβ oligomers show the most pronounced neurotoxic effects and correlate with disease initiation and progression. Recent findings showed that Aβ oligomers bind to the cellular prion protein (PrPC) eliciting neurotoxic effects. The role of exosomes, small extracellular vesicles of endosomal origin, in Alzheimer's disease is only poorly understood. Besides serving as disease biomarkers they may promote Aβ plaque formation, decrease Aβ-mediated synaptotoxicity, and enhance Aβ clearance. Here, we explore how exosomal PrPC connects to protective functions attributed to exosomes in Alzheimer's disease. To achieve this, we generated a mouse neuroblastoma PrPC knockout cell line using transcription activator-like effector nucleases. Using these, as well as SH-SY5Y human neuroblastoma cells, we show that PrPC is highly enriched on exosomes and that exosomes bind amyloid beta via PrPC. Exosomes showed highest binding affinity for dimeric, pentameric, and oligomeric Aβ species. Thioflavin T assays revealed that exosomal PrPC accelerates fibrillization of amyloid beta, thereby reducing neurotoxic effects imparted by oligomeric Aβ. Our study provides further evidence for a protective role of exosomes in Aβ-mediated neurodegeneration and highlights the importance of exosomal PrPC in molecular mechanisms of Alzheimer's disease.

Original languageEnglish
JournalJournal of Neurochemistry
DOIs
Publication statusAccepted/In press - 2016

Keywords

  • Alzheimer's disease
  • Amyloid beta
  • Exosomes
  • Neurodegeneration
  • Neurotoxicity
  • Prion protein knockout

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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