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Fibrillar amyloid beta-protein mediates the pathologic accumulation of its secreted precursor in human cerebrovascular smooth muscle cells.
[hereditary cerebral hemorrhage with amyloidosis]
Cerebrovascular
deposition
of
the
amyloid
beta
-protein
(
Abeta
)
is
a
key
pathologic
lesion
seen
in
patients
with
Alzheimer
's
disease
and
certain
related
disorders
,
including
hereditary
cerebral
hemorrhage
with
amyloidosis
of
the
Dutch
type
(
HCHWA-D
)
.
The
deposition
of
Abeta
has
pronounced
deleterious
effects
on
smooth
muscle
cells
within
the
cerebral
vessel
wall
.
We
have
previously
shown
that
Abeta
(
1
-
40
)
possessing
the
E
22
Q
HCHWA-D
mutation
extensively
assembles
into
fibrils
on
the
surface
of
cultured
human
cerebrovascular
smooth
muscle
(
HCSM
)
cells
.
This
cell-surface
Abeta
fibril
formation
induces
a
series
of
pathologic
responses
in
cultured
HCSM
cells
,
including
a
marked
increase
in
the
levels
of
cell-associated
amyloid
beta
-protein
precursor
(
AbetaPP
)
and
cell
death
.
In
the
present
study
,
we
investigated
the
relationship
between
HCSM
cell-surface
Abeta
fibril
formation
and
the
striking
increase
in
cell-associated
AbetaPP
.
Time
course
studies
showed
that
cell-surface
HCHWA-D
Abeta
(
1
-
40
)
fibril
formation
occurred
rapidly
,
whereas
both
the
increase
in
cell-associated
AbetaPP
and
loss
of
cell
viability
were
delayed
responses
.
Domain
analysis
using
site-
specific
antibodies
indicated
that
the
vast
majority
of
the
increase
in
cell-associated
AbetaPP
was
secreted
AbetaPP
(
sAbetaPP
)
.
Localization
studies
showed
that
the
sAbetaPP
was
present
on
the
HCSM
cell
surface
.
This
result
raised
the
possibility
that
sAbetaPP
may
bind
back
to
HCSM
cell-surface
fibrils
formed
by
HCHWA-D
Abeta
(
1
-
40
)
.
Indeed
,
binding
of
biotinylated
sAbetaPP
to
fibrillar
HCHWA-D
Abeta
(
1
-
40
)
was
demonstrated
by
transmission
electron
microscopy
.
Furthermore
,
solid-phase
binding
assays
showed
that
biotinylated
sAbetaPP
exhibited
dose-dependent
,
saturable
binding
to
fibrillar
(
but
not
soluble
)
HCHWA-D
Abeta
(
1
-
40
)
with
k
(
d
)
approximately
28
nM
.
Exon
deletion
experiments
further
defined
a
fragment
of
sAbetaPP
(
AbetaPP
(
18
-
119
)
)
,
encoded
by
AbetaPP
exons
2
and
3
,
to
contain
the
fibrillar
Abeta-binding
domain
.
In
addition
,
AbetaPP
(
18
-
119
)
effectively
blocked
the
cell-surface
accumulation
of
sAbetaPP
and
subsequent
cell
death
in
HCSM
cells
treated
with
pathogenic
Abeta
.
Together
,
these
findings
could
explain
the
accumulation
of
AbetaPP
in
cerebrovascular
Abeta
deposits
observed
both
in
vitro
and
in
vivo
and
may
contribute
to
the
pathologic
responses
evoked
by
pathogenic
forms
of
Abeta
in
HCSM
cells
.
Diseases
Validation
Diseases presenting
"marked increase in the levels of cell-associated amyloid"
symptom
hereditary cerebral hemorrhage with amyloidosis
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