IBCN   20355
INSTITUTO DE BIOLOGIA CELULAR Y NEUROCIENCIA "PROFESOR EDUARDO DE ROBERTIS"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
HSV-derived viral vector encoding a dominant-negative RAGE reduces astroglial response to intermittent hypoxia-induced injury.
Autor/es:
ANGELO MF; A. AGUIRRE; LUKIN J; MELENDEZ M; VILLARREAL A; A. EPSTEIN; JERUSALINSKY D; RAMOS J
Lugar:
Lyon
Reunión:
Simposio; 11 Coloque Societe des Neurosciences; 2013
Resumen:
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Glial
cells play a crucial
role in CNS injury since neurodegenerative processes are associated
with neuroinflammation, involving microglial cells and subsequent
activation of astrocytes. Glial activation involves changes in cell
phenotype and gene expression that might trigger neuronal death.
Using Intermittent Hypoxia (IH) to simulate Sleep Apnea as a model of
CNS injury, we have previously demonstrated early reactive gliosis
and neuronal alterations that ranged from decreased dendrite length
and abnormal NeuN staining in hippocampus and brain cortex. We also
demonstrated that IH induces the overexpression of the Receptor for
Advanced Glycation End Products (RAGE) and its ligand S100B as well
as the activation of the downstream NF-B signaling. Mixed culture
(glia and neurons) exposed to IH alsoshowed astrocyte
stellation (the in
vitro version of
reactive gliosis), reduction in neurite length and NF-B
activation.
To
modulate inflammation we developed HSV-derived
amplicon to overexpress
RAGE (RAGE-FL) or its dominant negative (RAGE-Δcyt). In
vitro, astrocytic
stellation was prevented by the overexpression of RAGE-Δcyt.
A similar effect was observed with RAGE-blocking antibodies but not
with unrelated control IgG. Indeed, RAGE blockage has also reduced
neuronal degeneration in
vivo and in
vitro after IH. In
naïve
(non-hypoxic) animals, overexpression of the amplicon-delivered
RAGE-FL, but not RAGE-Δcyt, resulted in alterations of neuronal
morphology similar to those observed in hypoxic animals. In IH
exposed animals RAGE-Δcyt, but not RAGE-FL overexpression prevented
abnormal NeuN distribution which is the first step in the events
leading to neuronal degeneration.
These
results suggest that using viral vectors to block RAGE depending
pathways action may
represent a new promising tool to
diminish inflammation and reactive gliosis in the injured brain.