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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
"hereditary cerebral hemorrhage"
symptom
hereditary cerebral hemorrhage with amyloidosis
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