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

• Published in: Cell death & disease 2015-12, Vol.6 (12), p.e2024-e2024
• Main Authors: Doeppner, T R, Kaltwasser, B, Schlechter, J, Jaschke, J, Kilic, E, Bähr, M, Hermann, D M, Weise, J
• Format: Article
• Language: English
• Subjects: 13/1; 13/100; 13/106; 631/378/1689/534; 631/443/592/75/593/15/1939; 631/80/474/2085; 631/80/86; 64/60; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Brain Ischemia - metabolism; Brain Ischemia - pathology; Cell Biology; Cell Culture; Disease Models, Animal; Immunology; Life Sciences; Male; Mice; Mice, Transgenic; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Neurogenesis - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotective Agents - pharmacology; Original; original-article; Prions - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2015.365

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 1 α 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.