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cells to prevent cell death. To determine if PrP is a cellular component response to
neuronal injury in vivo, Weise et al. [ 57 ] used the thread occlusion stroke mouse
model and detected a significant upregulation of PrP in the ischemic hemisphere at
4 and 8 h after onset of permanent focal ischemia when compared to control ani-
mals. However, significant upregulation of PrP was not detected if the focal isch-
emia is transient. Thus, the extent of upregulation of PrP which is positively
correlated with the severity of ischemia may reflect the protection level required for
neuron cell survival. To further examine if overexpression of PrP may contribute to
transient cerebral ischemia, [ 59 ] subject PrP overexpressing TG35 mice and WT
mice to a 90 min focal cerebral ischemia and found a reduction of early activation
of Erk1/Erk2 in TG35 mice compared to WT mice along with reduced infarct vol-
ume, thus supporting PrP indeed is a pro-survival for neuron cells and implies a
neuroprotection role for PrP-Erk signaling axis. To determine if PrP plays a role in
a short period of ischemia, [ 60 ] performs a 30 min of intraluminal middle cerebral
artery occlusion in PrP null and PrP WT mice and found that increased infarct size
by about 200% in PrP null mice than PrP WT mice, along with increment in activity
of Erk1/Erk2, STAT-1, and caspase-3, thus imitating lack of PrP, may subject neu-
ron cells to apoptosis via Erk1/Erk2-STAT-1-caspase-3 axis. Stress-inducible phos-
phoprotein 1 (STI-1) is a ligand for PrP, in a STI-1 mutation ischemia mouse model,
transgenic expression of STI-1-rescued embryonic lethality in a prion protein-
dependent way [ 61 ]. This result further supports the notion that normal physiologi-
cal function of PrP is neuroprotective, maybe by interacting with STI-1. Besides
interaction with its potential ligand, the octapeptide repeat region at the N-terminus
of PrP together with the PI3K/Akt signaling pathway is important for neuroprotec-
tion when subject to ischemia. Comparing with WT PrP mice, infarct size of PrP
null mice or octapeptide repeat truncation PrP mice is significantly increased [ 62 ].
It is likely that the octapeptide repeat region by modifying SOD activity thus pre-
venting neuron cell death. The aforementioned ischemia models are focusing on
acute injury with maximal 3-day observation. To investigate if PrP participates in
poststroke neurogenesis and angiogenesis in an extended period, Doeppner et al.
induced focal cerebral ischemia by intraluminal middle cerebral artery occlusion in
a post-ischemia mouse model; increased neurogenesis and angiogenesis were
observed in PrP overexpression mice compared with PrP WT mice, whereas exac-
erbated neurological deficits and brain injury were detected in PrP null mice with
increased proteasome activity and oxidative stress [ 63 ]. This result suggests that PrP
is not only neuroprotective but also angiogenetic. Similarly, in a stroke rat model,
PrP expression that mainly occurred in neuron, glia, and vascular endothelial cells
was upregulated significantly in the penumbra of stroke brain compared with the
untreated brain in a time-dependent manner. In addition, the rat showed improved
neurological behavior and reduced cerebral infarction volume when PrP was forced
to express in the ischemic brain [ 64 ], thus further supporting a role for PrP in the
neuroprotection not only in the mouse model but also in the rat model. Most recently,
Guitart showed that it is the exosomal PrP from astrocytes but not neuronal PrP that
improves the neuron cell survival under oxidative stress [ 65 ]. Although PrP has
been shown to protect neuron cells from ischemia, it is not clear that the protection
13 Prion Protein Exacerbates Tumorigenesis