title: Cellular prion protein promotes post-ischemic neuronal survival, angioneurogenesis and enhances neural progenitor cell homing via proteasome inhibition.
abstract: Although cellular prion protein (PrP(c)) has been suggested to have physiological roles in neurogenesis and angiogenesis, the pathophysiological relevance of both processes remain unknown. To elucidate the role of PrP(c) in post-ischemic brain remodeling, we herein exposed PrP(c) wild type (WT), PrP(c) knockout (PrP-/-) and PrP(c) overexpressing (PrP+/+) mice to focal cerebral ischemia followed by up to 28 days reperfusion. Improved neurological recovery and sustained neuroprotection lasting over the observation period of 4 weeks were observed in ischemic PrP+/+ mice compared with WT mice. This observation was associated with increased neurogenesis and angiogenesis, whereas increased neurological deficits and brain injury were noted in ischemic PrP-/- mice. Proteasome activity and oxidative stress were increased in ischemic brain tissue of PrP-/- mice. Pharmacological proteasome inhibition reversed the exacerbation of brain injury induced by PrP-/-, indicating that proteasome inhibition mediates the neuroprotective effects of PrP(c). Notably, reduced proteasome activity and oxidative stress in ischemic brain tissue of PrP+/+ mice were associated with an increased abundance of hypoxia-inducible factor 1α and PACAP-38, which are known stimulants of neural progenitor cell (NPC) migration and trafficking. To elucidate effects of PrP(c) on intracerebral NPC homing, we intravenously infused GFP(+) NPCs in ischemic WT, PrP-/- and PrP+/+ mice, showing that brain accumulation of GFP(+) NPCs was greatly reduced in PrP-/- mice, but increased in PrP+/+ animals. Our results suggest that PrP(c) induces post-ischemic long-term neuroprotection, neurogenesis and angiogenesis in the ischemic brain by inhibiting proteasome activity.
authors.affiliation: Department of Neurology, University of Duisburg-Essen Medical School, Essen, Germany.|Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey.
authors.forename: T R
authors.initials: TR
authors.lastname: Doeppner
authors.affiliation: Department of Neurology, University of Duisburg-Essen Medical School, Essen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Kaltwasser
authors.affiliation: Department of Neurology, University of Duisburg-Essen Medical School, Essen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Schlechter
authors.affiliation: Department of Neurology, University of Jena, Jena, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Jaschke
authors.affiliation: Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey.
authors.forename: E
authors.initials: E
authors.lastname: Kilic
authors.affiliation: Department of Neurology, University of Goettingen, Goettingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Bähr
authors.affiliation: Department of Neurology, University of Duisburg-Essen Medical School, Essen, Germany.
authors.forename: D M
authors.initials: DM
authors.lastname: Hermann
authors.affiliation: Department of Neurology, University of Jena, Jena, Germany.|HELIOS Clinic Plauen, Department of Neurology, Plauen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Weise
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D011328:Prions / Q000378:metabolism*
chemical_list: D018696:Neuroprotective Agents; D011328:Prions