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Fibrillar amyloid beta-protein binds protease nexin-2/amyloid beta-protein precursor: stimulation of its inhibition of coagulation factor XIa.
[hereditary cerebral hemorrhage with amyloidosis]
Cerebrovascular
deposition
of
fibrillar
39
-
42
amino
acid
amyloid
beta
-protein
(
Abeta
)
,
a
condition
known
as
cerebral
amyloid
angiopathy
(
CAA
)
,
is
a
key
pathological
feature
of
Alzheimer
's
disease
and
related
disorders
including
hereditary
cerebral
hemorrhage
with
amyloidosis
-
Dutch
type
(
HCHWA-D
)
.
Severe
cases
of
CAA
,
particularly
in
HCHWA-D
,
lead
to
recurrent
and
often
fatal
hemorrhagic
strokes
.
Although
the
reasons
for
this
pathological
consequence
remain
unclear
,
alterations
in
proteolytic
hemostasis
mechanisms
have
been
implicated
.
For
example
,
the
Abeta
parent
molecule
protease
nexin-
2
/
amyloid
beta
-protein
precursor
(
PN
-
2
/
AbetaPP
)
,
which
is
elevated
in
HCHWA-D
cerebral
vessels
with
Abeta
deposits
,
is
a
potent
inhibitor
of
coagulation
factor
XIa
(
FXIa
)
.
Here
we
show
that
fibrillar
HCHWA-D
Abeta
binds
PN
-
2
/
AbetaPP
,
but
not
its
isolated
Kunitz-
type
proteinase
inhibitor
(
KPI
)
domain
,
in
a
saturable
,
dose-dependent
manner
with
a
K
(
d
)
of
approximately
28
nM
.
Neither
PN
-
2
/
AbetaPP
nor
its
KPI
domain
bound
to
nonfibrillar
HCHWA-D
Abeta
.
The
fibrillar
Abeta
binding
domain
on
PN
-
2
/
AbetaPP
was
localized
to
residues
18
-
119
.
PN
-
2
/
AbetaPP
that
bound
to
fibrillar
HCHWA-D
Abeta
immobilized
either
in
plastic
wells
or
on
the
surface
of
cultured
cerebrovascular
smooth
muscle
cells
was
active
in
inhibiting
FXIa
.
Quantitative
kinetic
measurements
revealed
that
fibrillar
HCHWA-D
Abeta
caused
a
>
5
-
fold
enhancement
of
FXIa
inhibition
by
PN
-
2
/
AbetaPP
.
Similar
stimulatory
effects
on
FXIa
inhibition
by
PN
-
2
/
AbetaPP
were
also
observed
with
fibrillar
wild-
type
Abeta
.
However
,
fibrillar
Abeta
had
no
effect
on
the
inhibition
of
trypsin
by
PN
-
2
/
AbetaPP
.
These
findings
suggest
that
fibrillar
Abeta
deposits
in
cerebral
vessels
can
effectively
localize
and
enhance
the
anticoagulant
functions
of
PN
-
2
/
AbetaPP
,
thereby
contributing
to
a
microenvironment
conducive
to
hemorrhaging
.
Diseases
Validation
Diseases presenting
"severe cases"
symptom
coats disease
congenital diaphragmatic hernia
dentin dysplasia
dentinogenesis imperfecta
erythropoietic protoporphyria
hereditary cerebral hemorrhage with amyloidosis
hydrocephalus with stenosis of the aqueduct of sylvius
locked-in syndrome
megacystis-microcolon-intestinal hypoperistalsis syndrome
neuralgic amyotrophy
proteus syndrome
scrub typhus
trochlear dysplasia
typhoid
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