441
or
the
nor-
rela-
are
and dendritic
age,
juvenile
followed
a
the
relation-
establishmentofcon-
There are several lines of
tile to
receiving
making synapses,
suggesting
length
continuously expanding
betweenneuronaldeathandthe
instead of
a
same
So,
tree,
ship
nectivity.l$
(presumably
pattern.
maldendritic
a
Down
showed
neurons
evidence that Bax
syndrome
age, whichthen
monthsof
4
at
serves
as
a
criti-
by
apparently
perturbations
regulated
neurotrophins)
deathof
tivelyexpandedtree
cal mediatorof
and
andbecomesatrophic.7,27These
naturally
occurring
neurons
peripheral
stops
of
growing
nervous
survival
central
life and
lead to reduced neuronal
system
during embryonic
In
synaptogenesis may
anenhancedextent of
Baxprimarily
neurons as
and
cell loss executed
earlypostnataldevelopment. 18-20
addition,
postmitotic
neuronsand
byapoptosis.
offive Down
lowerinfour
syn-
seems to
the survival of
was
Unexpectedly,p53
regulate
proliferating
of Bcl-2
nervous
to
non-neuronalcells
dromebrainareas. Whether
the central
p53in
opposed
Expression
was studied
sys-
or
in
cell
temis involved
the
death,
familyproteins(Bcl-2, Bcl-x,
Bax, Bak)
cell-cycle checkpoint,
extracts ofrat cerebral cortex
other
Rat
in brain
19 to
at
from
some
function is
from
not known.3°
presently
brains,
post-
96 weeks of
second
14 until the
Bcl-2
postnatal
day
age.
pro-
investigated
embryonic day
embryonic
tein was
E19 and
fromE19to 96weeks.
and
decreased after birth.
natal
exhibited
a
Bcl-x
temporal
spa-
week,
nonoverlapping
of
highest
Bax
tial
its
and
levelsremained
levelswere
transcriptional
high
weeksanddecreasedfrom
atE19anddecreased
expressionpattern
Additionally, p53
indicate role for
target
cells.
p53
wasnot elevated in
atE 19to
2
4
weeksonward.
Bax.
apoptotic
high
Baklevels were
ofcell divi-
in the control
after
This
a
highest
abruptly
p53
might
sion and
death
birth. 21 In
a
in control ofcell
than
Vekrellis et al,2° levels ofBaxin
therat
differentiation rather
studyby
early
during
Heatshock
cerebral cortex and cerebellum were
to
at
brain
highest
in the
postnatal
development. 31
reduced
in
all Down
adult cortex
day 1,
postnatal day 21;
protein 70,
has
syndrome
decreasing
143-fold lower than at
brain
to
been shown
Baxwas
stress-
postnatal day
(3 months),
regions,
protect against
1.
Bax
induced
withstress-activated
paralleledby
caspase-3expres-
and
apoptosisby
tein kinase/c-JunN terminal kinase
expression
sion and endonuclease activation
high
interfering
pro-
High
embryonic
during
coincidedwith
(SAPK/JNK) signaling
cascade.31 Neu-
caspaseproteolytic
occur-
and
the
earlypostnataldevelopment
naturally
whichincreased
pathway
ronal
blocking
inhibitory
in
cell death
the rat cerebral
cortex,
apoptosis
wasreducedinall fetal Down
protein-like immunoreactivity
ring
during
endof
thefirst
weekand
the
brain
The
regions.
c-IAP-
postnatal
syndrome
apoptosis protein genes (NAIP,
disappearedagainby
Bcl-2
first
the
month.20,21
inhibitor
human of
Widespread
proteinexpres-
sioninthe
nervous
declines
are anevolution-
cell death
system
Incontrastto
2/HLkP-1, c-IAP-1/Hiap-2, XIAP,
developing(embryonic)
inthecentralnervous
survivin)
with
conserved
of
that
age
system.22
permissive
Bax,
neu-
ary
family
implying
proteins
prevent
central, highly
Neuronal
Bcl-2 does not
to be
a
factor
con-
for
across
served
sis
that
actata
appear
factorsbut
species,
point
they
seemscrucialforthe maintenanceof
in the
cell-death cascade.32
which is
rotrophic
survival
apopto-
to two
in
selective neurons. 18
inhibitory protein,
homologous
To
there
are
limited humandataof
members.
baculovirus
inhibitors of
and
date,
only
ofbcl-2
develop-
apoptosis proteins
(Cp-IAP
muscular
mental
tothe
chro-
on
changes
family
Op-IAP), maps
spinal
atrophyregion
Bcl-2
ofthe normalcerebral
mosome
Neuronal
is
immunoreactivity
cortex,
5q 13.1. 33
apoptosis inhibitoryprotein
andbrainstemdecreasesto weakandeven
in
motor
as
hippocampus,
undetectable
expressedparticularly
neurons, probably
acting
In
levels between 14 and 39 weeks of
gesta-
a
ofmotor-neuron
negative regulator
muscular
apoptosis.34
spinal
model
is that
tion .23,24
bcl-2
observedin
one
Although
is frequently
potential
pathogenic
staining
gan-
activities
atrophy,
brain
with
deletion oftelomeric survival motorneuron
gliogliomas,25
regions
high apoptotic
gene (SMlVte’)
werenot
correlatedwithdecreasedBcl-2
acts as the
tosis
neurotoxic
withneuronal
always
expression,
indicate
primary
insult,
apop-
or
and
levels ofBcl-2
did not
a
high
necessarily
of
sup-
inhibitory protein
depletion,
down-regulation,
of
in
Bak
absence
to an attenuated
resistance.35
pression
apoptosis.23
Expression
the cerebrumandcerebellumwas
proapoptotic
in
fetuses
apoptotic
apoptosisproteins
members
leading
members
fam-
oftheinhibitorof
high
(studied
but low
Although
24
to
weeks of
and
were
cas-
foundto bind to and inhibit
ofthe
up
elderly subjects
gestation)
ily
youngadults.z6
pase protease family,
in
the mode of neuronal
apoptosis
neuronal
Down
In
late
actionis unknown.
syndrome
previous studies,
inhibitory
apoptosis
of certain
gestational
protein
Theoretically,
brainshavebeenshownto exhibitaltereddendritictrees,’~2’
couldalso
a
inhibitor
be
inhibitoryprotein
potent
activation
in
visual
a
decreased number of cells
the
has
the
cortex,28 poorly
electrophysiologic
to increased
proapop-
caspases.32
Recently, caspase-3
and altered
beenshown
defined cortical cell
to occur
in
cell death
layers,7
duringprogrammed
With
nervous
membraneproperties.29
in
the
Vekrel-
over-
respect
system.36
Again
developing
studyby
blocked
in
of
Down
lis et
totic
alterations
Bax-induced
apoptosis
couldbe
al,2°
proteins,
synaptogenesis
synaptic
syn-
by
wasreduced
interest:
ofthe
baculovirus
dromeare of
an inhibitor of
density
expression
special
weeks’ gestation;
40
p35 protein,
at32
thenumberofdendritic
Reducedlevels of
heat
and34
shock
70andneu-
spines
but was
caspases.
protein
weeks of
syndrome
remained
until
ronal
could lead to increased
gestation
apoptosis inhibitory protein
ofneurons
unchanged
visual
Down
cortex
by
numbers of
4
in the
lower
to
Bax-induced
sensitivity
apoptosis,
(caspase
functional
significantly
months of
activation)
and
to
of
controls,
higher
compared
disturbing
in Down
fetal
age;
temporal
longevity
in
intersections
infantile Downsyn-
and
neurons
dendritic branches
brain
syndrome
(eg, exaggerated
decreased
fromthe
infan-
drome
6monthsof
steadily
age)
developmentalapoptosis).
(<