title: Improvement of neuronal cell survival by astrocyte-derived exosomes under hypoxic and ischemic conditions depends on prion protein.
abstract: Prion protein (PrP) protects neural cells against oxidative stress, hypoxia, ischemia, and hypoglycemia. In the present study we confirm that cultured PrP-deficient neurons are more sensitive to oxidative stress than wild-type neurons and present the novel findings that wild-type, but not PrP-deficient astrocytes protect wild-type cerebellar neurons against oxidative stress and that exosomes released from stressed wild-type, but not from stressed PrP-deficient astrocytes reduce neuronal cell death induced by oxidative stress. We show that neuroprotection by exosomes of stressed astrocytes depends on exosomal PrP but not on neuronal PrP and that astrocyte-derived exosomal PrP enters into neurons, suggesting neuronal uptake of astrocyte-derived exosomes. Upon exposure of wild-type astrocytes to hypoxic or ischemic conditions PrP levels in exosomes were increased. By mass spectrometry and Western blot analysis, we detected increased levels of 37/67 kDa laminin receptor, apolipoprotein E and the ribosomal proteins S3 and P0, and decreased levels of clusterin/apolipoprotein J in exosomes from wild-type astrocytes exposed to oxygen/glucose deprivation relative to exosomes from astrocytes maintained under normoxic conditions. The levels of these proteins were not altered in exosomes from stressed PrP-deficient astrocytes relative to unstressed PrP-deficient astrocytes. These results indicate that PrP in astrocytes is a sensor for oxidative stress and mediates beneficial cellular responses, e.g. release of exosomes carrying PrP and other molecules, resulting in improved survival of neurons under hypoxic and ischemic conditions.
authors.affiliation: Zentrum Für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Guitart
authors.affiliation: Zentrum Für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Loers
authors.affiliation: Institut Für Klinische Chemie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Buck
authors.affiliation: Zentrum Für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Bork
authors.affiliation: Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey.|Center for Neuroscience, Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.affiliation: Zentrum Für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Kleene
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D055354:Exosomes / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D000072002:Prion Proteins / Q000378:metabolism*
chemical_list: D000072002:Prion Proteins
keywords: PrP; apolipoprotein E; clusterin; exosomes; hypoxia; ischemia; oxidative stress