title: Exosomal cellular prion protein drives fibrillization of amyloid beta and counteracts amyloid beta-mediated neurotoxicity.
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 (PrP(C) ) 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 PrP(C) connects to protective functions attributed to exosomes in Alzheimer's disease. To achieve this, we generated a mouse neuroblastoma PrP(C) knockout cell line using transcription activator-like effector nucleases. Using these, as well as SH-SY5Y human neuroblastoma cells, we show that PrP(C) is highly enriched on exosomes and that exosomes bind amyloid beta via PrP(C) . Exosomes showed highest binding affinity for dimeric, pentameric, and oligomeric Aβ species. Thioflavin T assays revealed that exosomal PrP(C) 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 PrP(C) in molecular mechanisms of Alzheimer's disease. We show that the prion protein (PrP(C) ) on exosomes captures neurotoxic species of amyloid beta (Aβ) promoting its fibrillization. Our study provides evidence for a protective role of exosomes in Alzheimer`s disease and suggests that, depending on its membrane topology, PrP(C) holds a dual function: when expressed at the neuronal surface it acts as receptor for Aβ leading to neurotoxic signaling, whereas it detoxifies Aβ when present on exosomes. This provides further support for key roles of PrP(C) in Alzheimer's disease.
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Falker
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Guett
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Dohler
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Altmeppen
authors.affiliation: Laboratory of Structural Biology of Infection and Inflammation, Institute of Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany.|The Hamburg Centre for Ultrafast Imaging, Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Betzel
authors.affiliation: Laboratory of Structural Biology of Infection and Inflammation, Institute of Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany.|The Hamburg Centre for Ultrafast Imaging, Hamburg, Germany.
authors.forename: Robin
authors.initials: R
authors.lastname: Schubert
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Dana
authors.initials: D
authors.lastname: Thurm
authors.affiliation: Department of Translational Cancer Research, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wegwitz
authors.affiliation: IRCCS Humanitas, Rozzano, Italy.
authors.forename: Pooja
authors.initials: P
authors.lastname: Joshi
authors.affiliation: IRCCS Humanitas, Rozzano, Italy.|CNR-Institute of Neuroscience, Milano, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Verderio
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Krasemann
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D045744:Cell Line, Tumor; D055354:Exosomes / Q000502:physiology*; D055786:Gene Knockout Techniques; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity; D018621:PrPC Proteins / Q000502:physiology*; D012995:Solubility; D014162:Transfection
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D018621:PrPC Proteins; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; amyloid beta; exosomes; neurodegeneration; neurotoxicity; prion protein knockout