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

Abstract

Although cellular prion protein (PrPc) has been suggested to have physiological roles in neurogenesis and angiogenesis, the pathophysiological relevance of both processes remain unknown. To elucidate the role of PrPc in post-ischemic brain remodeling, we herein exposed PrPc wild type (WT), PrPc knockout (PrP−/−) and PrPc 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 PrPc. 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 PrPc 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 PrPc induces post-ischemic long-term neuroprotection, neurogenesis and angiogenesis in the ischemic brain by inhibiting proteasome activity.

Protein Profile and Morphological Alterations in Penumbra after Focal Photothrombotic Infarction in the Rat Cerebral Cortex

“…It is involved in cell trafficking, adhesion, protection against oxidative stress, and survival [38][39][40]. In our experiments, PrP was upregulated in penumbra 4 but not 24 h after PTI.…”

“…Overexpression of PrP was also observed in mice 4 and 8 h but not 24 h after focal ischemia [40] that correlated with our data. Upregulation of PrP and PrP mRNA after cerebral ischemia leads to three protective effects: neuroprotection, neurogenesis, and angiogenesis [38][39][40].…”

Cellular Prion Protein (PrPc) and Hypoxia: True to Each Other in Good Times and in Bad, in Sickness, and in Health

“…As PrP c expression level is the highest within the CNS, its functions at this site are presumably of uppermost relevance. Actually, one of the best-supported PrP c functions so far is neuroprotection against hypoxic damage (McLennan et al, 2004; Weise et al, 2004; Mitteregger et al, 2007; Doeppner et al, 2015), implying PrP c capacity for sensing and adequately responding to oxygen deprivation. Thus, PrP c expression is up-regulated following cerebral ischemia, and wild-type (WT) mice display significantly smaller infarct volumes as compared to Prnp -/- mice (McLennan et al, 2004; Weise et al, 2004; Mitteregger et al, 2007).…”

“…Thus, PrP c expression is up-regulated following cerebral ischemia, and wild-type (WT) mice display significantly smaller infarct volumes as compared to Prnp -/- mice (McLennan et al, 2004; Weise et al, 2004; Mitteregger et al, 2007). Moreover, considerably increased long-term neuroprotection, neurogenesis and angiogenesis was reported in the ischemic brains of PrP c -overexpressing (Prnp +/+ ) vs. WT and Prnp -/- mice, accenting the importance of elevated PrP c levels in preventing hypoxia-induced neuronal damage (Doeppner et al, 2015). In other words, it appears that a metabolic switch between oxidative-independent and oxidative-dependent metabolism during hypoxia and subsequent re-oxygenation cannot be efficiently executed when PrP c is absent.…”

“…Expression of HIF-1 target genes, such as for instance LDH-A, correlate with the levels of HIF-1 α (Ke and Costa, 2006). Strikingly, HIF-1α expression is significantly decreased in Prnp -/- and increased in Prnp +/+ mice at 24 h post-stroke (Doeppner et al, 2015) suggesting that PrP c might exert its neuroprotective effects against hypoxic damage in vivo via direct or indirect regulation of HIF-1α and hence LDH-A/lactate.…”