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Genetic ablation of Nrf2/antioxidant response pathway in Alexander disease mice reduces hippocampal gliosis but does not impact survival.
[alexander disease]
In
Alexander
disease
(
AxD
)
the
presence
of
mutant
glial
fibrillary
acidic
protein
(
GFAP
)
,
the
major
intermediate
filament
of
astrocytes
,
triggers
protein
aggregation
,
with
marked
induction
of
a
stress
response
mediated
by
the
transcription
factor
,
Nrf
2
.
To
clarify
the
role
of
Nrf
2
in
AxD
,
we
have
crossed
Gfap
mutant
and
transgenic
mouse
models
into
an
Nrf
2
null
background
.
Deletion
of
Nrf
2
eliminates
the
phase
II
stress
response
normally
present
in
mouse
models
of
AxD
,
but
causes
no
change
in
body
weight
or
lifespan
,
even
in
a
severe
lethal
model
.
AxD
astrocytes
without
Nrf
2
retain
features
of
reactivity
,
such
as
expression
of
the
endothelin-
B
receptor
,
but
have
lower
Gfap
levels
,
a
decrease
in
p
62
protein
and
reduced
iron
accumulation
,
particularly
in
hippocampus
.
Microglial
activation
,
indicated
by
Iba
1
expression
,
is
also
diminished
.
Although
the
Nrf
2
response
is
generally
considered
beneficial
,
these
results
show
that
in
the
context
of
AxD
,
loss
of
the
antioxidant
pathway
has
no
obvious
negative
effects
,
while
actually
decreasing
Gfap
accumulation
and
pathology
.
Given
the
attention
Nrf
2
is
receiving
as
a
potential
therapeutic
target
in
AxD
and
other
neurodegenerative
diseases
,
it
will
be
interesting
to
see
whether
induction
of
Nrf
2
,
beyond
the
endogenous
response
,
is
beneficial
or
not
in
these
same
models
.
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"it will be interesting to see whether induction of nrf2"
symptom
alexander disease
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