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Plasmin cleavage of the amyloid beta-protein: alteration of secondary structure and stimulation of tissue plasminogen activator activity.
[hereditary cerebral hemorrhage with amyloidosis]
Cerebrovascular
amyloid
beta
-protein
(
A
beta
)
deposition
,
a
key
pathological
feature
of
Alzheimer
's
disease
and
hereditary
cerebral
hemorrhage
with
amyloidosis
Dutch
-
type
,
can
lead
to
intracerebral
hemorrhage
;
however
,
the
mechanism
for
this
remains
unclear
.
Assembled
A
beta
is
a
potent
stimulator
of
tissue-
type
plasminogen
activator
(
tPA
)
in
vitro
.
Herein
,
we
investigated
the
stimulation
of
tPA
by
freshly
solubilized
A
beta
1
-
40
.
The
rate
of
tPA
stimulation
by
A
beta
1
-
40
increased
dramatically
over
time
,
suggesting
that
A
beta
may
be
altered
during
the
course
of
the
reaction
.
SDS
-PAGE
analysis
showed
that
A
beta
1
-
40
was
cleaved
during
the
course
of
the
reaction
.
Subsequent
studies
showed
that
it
was
plasmin
,
the
product
of
tPA
activation
of
plasminogen
,
that
specifically
cleaved
A
beta
1
-
40
in
the
amino
terminal
region
between
Arg
5
and
His
6
.
Plasmin
effectively
cleaved
a
chromogenic
substrate
corresponding
to
this
cleavage
site
in
A
beta
.
Circular
dichroism
spectral
analysis
showed
that
A
beta
6
-
40
adopted
a
strong
beta
-sheet
secondary
structure
.
This
truncated
A
beta
6
-
40
peptide
was
a
potent
stimulator
of
tPA
in
vitro
.
Our
results
indicate
that
beta
-sheet
secondary
structure
of
A
beta
,
which
can
be
promoted
by
plasmin
cleavage
,
stimulates
tPA
activity
.
These
findings
suggest
that
pathologic
interactions
between
A
beta
,
tPA
,
and
plasmin
in
the
cerebral
vessel
wall
could
result
in
excessive
proteolysis
contributing
to
intracerebral
hemorrhages
.
Diseases
Validation
Diseases presenting
"key pathological feature"
symptom
hereditary cerebral hemorrhage with amyloidosis
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