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Cellular prion protein promotes post-ischemic neuronal survival, angioneurogenesis and enhances neural progenitor cell homing via proteasome inhibition

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...

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Autores principales: Doeppner, T R, Kaltwasser, B, Schlechter, J, Jaschke, J, Kilic, E, Bähr, M, Hermann, D M, Weise, J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720898/
https://www.ncbi.nlm.nih.gov/pubmed/26673668
http://dx.doi.org/10.1038/cddis.2015.365
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author Doeppner, T R
Kaltwasser, B
Schlechter, J
Jaschke, J
Kilic, E
Bähr, M
Hermann, D M
Weise, J
author_facet Doeppner, T R
Kaltwasser, B
Schlechter, J
Jaschke, J
Kilic, E
Bähr, M
Hermann, D M
Weise, J
author_sort Doeppner, T R
collection PubMed
description 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.
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spelling pubmed-47208982016-01-26 Cellular prion protein promotes post-ischemic neuronal survival, angioneurogenesis and enhances neural progenitor cell homing via proteasome inhibition Doeppner, T R Kaltwasser, B Schlechter, J Jaschke, J Kilic, E Bähr, M Hermann, D M Weise, J Cell Death Dis Original Article 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. Nature Publishing Group 2015-12 2015-12-17 /pmc/articles/PMC4720898/ /pubmed/26673668 http://dx.doi.org/10.1038/cddis.2015.365 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Doeppner, T R
Kaltwasser, B
Schlechter, J
Jaschke, J
Kilic, E
Bähr, M
Hermann, D M
Weise, J
Cellular prion protein promotes post-ischemic neuronal survival, angioneurogenesis and enhances neural progenitor cell homing via proteasome inhibition
title Cellular prion protein promotes post-ischemic neuronal survival, angioneurogenesis and enhances neural progenitor cell homing via proteasome inhibition
title_full Cellular prion protein promotes post-ischemic neuronal survival, angioneurogenesis and enhances neural progenitor cell homing via proteasome inhibition
title_fullStr Cellular prion protein promotes post-ischemic neuronal survival, angioneurogenesis and enhances neural progenitor cell homing via proteasome inhibition
title_full_unstemmed Cellular prion protein promotes post-ischemic neuronal survival, angioneurogenesis and enhances neural progenitor cell homing via proteasome inhibition
title_short Cellular prion protein promotes post-ischemic neuronal survival, angioneurogenesis and enhances neural progenitor cell homing via proteasome inhibition
title_sort cellular prion protein promotes post-ischemic neuronal survival, angioneurogenesis and enhances neural progenitor cell homing via proteasome inhibition
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720898/
https://www.ncbi.nlm.nih.gov/pubmed/26673668
http://dx.doi.org/10.1038/cddis.2015.365
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